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1.  Multi-Surface and Multi-Field Co-Segmentation of 3-D Retinal Optical Coherence Tomography 
IEEE transactions on medical imaging  2014;33(12):2242-2253.
When segmenting intraretinal layers from multiple optical coherence tomography (OCT) images forming a mosaic or a set of repeated scans, it is attractive to exploit the additional information from the overlapping areas rather than discarding it as redundant, especially in low contrast and noisy images. However, it is currently not clear how to effectively combine the multiple information sources available in the areas of overlap. In this paper, we propose a novel graph-theoretic method for multi-surface multi-field co-segmentation of intraretinal layers, assuring consistent segmentation of the fields across the overlapped areas. After 2-D en-face alignment, all the fields are segmented simultaneously, imposing a priori soft interfield-intrasurface constraints for each pair of overlapping fields. The constraints penalize deviations from the expected surface height differences, taken to be the depth-axis shifts that produce the maximum cross-correlation of pairwise-overlapped areas. The method’s accuracy and reproducibility are evaluated qualitatively and quantitatively on 212 OCT images (20 nine-field, 32 single-field acquisitions) from 26 patients with glaucoma. Qualitatively, the obtained thickness maps show no stitching artifacts, compared to pronounced stitches when the fields are segmented independently. Quantitatively, two ophthalmologists manually traced four intraretinal layers on 10 patients, and the average error (4.58±1.46 μm) was comparable to the average difference between the observers (5.86±1.72 μm). Furthermore, we show the benefit of the proposed approach in co-segmenting longitudinal scans. As opposed to segmenting layers in each of the fields independently, the proposed co-segmentation method obtains consistent segmentations across the overlapped areas, producing accurate, reproducible, and artifact-free results.
PMCID: PMC4326334  PMID: 25020067
Graph theory; image co-segmentation; mosaicing; ophthalmology; retinal layer segmentation
2.  Holistic assessment of covalently-labelled core-shell polymeric nanoparticles with fluorescent contrast agents towards theranostic applications 
The successful development of degradable polymeric nanostructures as optical probes for use in nanotheranostic applications requires the intelligent design of materials such that their surface response, degradation, drug delivery and imaging properties are all optimized. In the case of imaging, optimization must result in materials that allow differentiation between unbound optical contrast agents and labeled polymeric materials as they undergo degradation. In this study, we have shown that use of traditional electrophoretic gel-plate assays for determination of the purity of dye-conjugated degradable nanoparticles is limited, due to polymer degradation characteristics. To overcome these limitations, we have outlined a holistic approach to evaluating dye-and peptide-polymer nanoparticle conjugation by utilizing steady-state fluorescence, anisotropy, and emission and anisotropy life-time decay profiles, through which nanoparticle-dye binding can be assessed independent of perturbations, such as those presented during the execution of electrolyte gel-based assays. This approach has been demonstrated to provide an overall understanding of the spectral signature-structure-function relationship, ascertaining key information on interactions between the fluorophore, polymer and solvent components that have a direct and measurable impact on the emissive properties of the optical probe. The use of these powerful techniques provides feedback that can be utilized to improve nanotheranostics by evaluating dye emissivity in degradable nanotheranostic systems, which has become increasingly important as modern platforms transition to architectures intentionally reliant on degradation and built-in environmental responses.
PMCID: PMC3933954  PMID: 24392760
3.  Multilineage somatic activating mutations in HRAS and NRAS cause mosaic cutaneous and skeletal lesions, elevated FGF23 and hypophosphatemia 
Human Molecular Genetics  2013;23(2):397-407.
Pathologically elevated serum levels of fibroblast growth factor-23 (FGF23), a bone-derived hormone that regulates phosphorus homeostasis, result in renal phosphate wasting and lead to rickets or osteomalacia. Rarely, elevated serum FGF23 levels are found in association with mosaic cutaneous disorders that affect large proportions of the skin and appear in patterns corresponding to the migration of ectodermal progenitors. The cause and source of elevated serum FGF23 is unknown. In those conditions, such as epidermal and large congenital melanocytic nevi, skin lesions are variably associated with other abnormalities in the eye, brain and vasculature. The wide distribution of involved tissues and the appearance of multiple segmental skin and bone lesions suggest that these conditions result from early embryonic somatic mutations. We report five such cases with elevated serum FGF23 and bone lesions, four with large epidermal nevi and one with a giant congenital melanocytic nevus. Exome sequencing of blood and affected skin tissue identified somatic activating mutations of HRAS or NRAS in each case without recurrent secondary mutation, and we further found that the same mutation is present in dysplastic bone. Our finding of somatic activating RAS mutation in bone, the endogenous source of FGF23, provides the first evidence that elevated serum FGF23 levels, hypophosphatemia and osteomalacia are associated with pathologic Ras activation and may provide insight in the heretofore limited understanding of the regulation of FGF23.
PMCID: PMC3869357  PMID: 24006476
4.  CXCR4, but not CXCR7, discriminates metastatic behavior in non-small cell lung cancer cells 
Chemokines have been implicated as key contributors of non-small cell lung cancer (NSCLC) metastasis. However, the role of CXCR7, a recently discovered receptor for CXCL12 ligand, in the pathogenesis of NSCLC is unknown. To define the relative contribution of chemokine receptors to migration and metastasis we generated human lung A549 and H157 cell lines with stable knockdown of CXCR4, CXCR7, or both. Cancer cells exhibited chemotaxis to CXCL12 that was enhanced under hypoxic conditions, associated with a parallel induction of CXCR4, but not CXCR7. Interestingly, neither knockdown cell line differed in the rate of proliferation, apoptosis or cell adherence; however, in both cell lines, CXCL12-induced migration was abolished when CXCR4 signaling was abrogated. In contrast, inhibition of CXCR7 signaling did not alter cellular migration to CXCL12. In an in vivo heterotropic xenograft model using A549 cells, expression of CXCR4, but not CXCR7, on cancer cells was necessary for the development of metastases. In addition, cancer cells knocked-down for CXCR4 (or both CXCR4 and CXCR7) produced larger and more vascular tumors as compared to wild-type or CXCR7 knock-down tumors, an effect that was attributable to cancer cell-derived CXCR4 out competing endothelial cells for available CXCL12 in the tumor microenvironment. These results indicate that CXCR4, not CXCR7, expression engages CXCL12 to mediate NSCLC metastatic behavior.
PMCID: PMC4262747  PMID: 24025971
bronchogenic carcinoma; CXCL12; angiogenesis; chemotaxis; A549; H157
5.  Apathy and Olfactory Dysfunction in Early Parkinson’s Disease 
Journal of Movement Disorders  2015;8(1):21-25.
Olfactory and emotional dysfunctions are very common in patients with Parkinson’s disease (PD). Olfaction and emotions share common neuroanatomical substrates. Therefore, in this study, we evaluated the association between olfactory and emotional dysfunctions in patients with PD.
Parkinson’s disease patients who had been assessed for their olfactory function and neuropsychiatric symptoms including emotional dysfunction were included. A logistic regression analysis was performed to evaluate the association between low olfaction and different neuropsychiatric symptoms.
The patients with low olfaction (cross cultural smell identification test score ≤ 6) showed a higher prevalence of apathy when compared with those with high olfaction, whereas the frequencies of other neuropsychiatric symptoms were comparable between the two groups. A multivariate logistic regression analysis revealed that the presence of apathy/indifference [odds ratio (OR) = 2.859, p = 0.007], age 70 years or more (OR = 2.281, p = 0.009), and the male gender (OR = 1.916, p = 0.030) were significantly associated with low olfaction.
Our results demonstrate that apathy/indifference is a unique emotional dysfunction associated with olfactory dysfunction in PD. The findings also suggest that PD patients with low olfaction have a high prevalence of apathy.
PMCID: PMC4298715  PMID: 25614782
Apathy; Hyposmia; Parkinson’s disease; Neuropsychiatric; Emotion
6.  Characterization of HGF/Met Signaling in Cell Lines Derived From Urothelial Carcinoma of the Bladder 
Cancers  2014;6(4):2313-2329.
There is mounting evidence of oncogenic hepatocyte growth factor (HGF)/Met signaling in urothelial carcinoma (UC) of the bladder. The effects of three kinase inhibitors, cabozantinib, crizotinib and EMD1214063, on HGF-driven signaling and cell growth, invasion and tumorigenicity were analyzed in cultured UC cell lines. SW780 xenograft growth in SCID and human HGF knock-in SCID (hHGF/SCID) mice treated with cabozantinib or vehicle, as well as tumor levels of Met and pMet, were also determined. Met content was robust in most UC-derived cell lines. Basal pMet content and effector activation state in quiescent cells were low, but significantly enhanced by added HGF, as were cell invasion, proliferation and anchorage independent growth. These HGF-driven effects were reversed by Met inhibitor treatment. Tumor xenograft growth was significantly higher in hHGF/SCID mice vs. SCID mice and significantly inhibited by cabozantinib, as was tumor phospho-Met content. These studies indicate the prevalence and functionality of the HGF/Met signaling pathway in UC cells, suggest that paracrine HGF may contribute to UC tumor growth and progression, and that support further preclinical investigation of Met inhibitors for the treatment of UC is warranted.
PMCID: PMC4276968  PMID: 25534569
bladder cancer; urothelial carcinoma; hepatocyte growth factor; Met; tumor growth; tumor cell invasion
7.  Comparative Genomic Hybridization on Spotted Oligonucleotide Microarrays 
Recent advances in DNA microarray technology have enabled researchers to comprehensively characterize the complex genomes of higher eukaryotic organisms at an unprecedented level of detail. Array-based comparative genomic hybridization (Array-CGH) has been widely used for detecting DNA copy number alterations on a genomic scale, where the mapping resolution is limited only by the number of probes on the DNA microarray. In this chapter, we present a validated protocol utilizing print-tip spotted HEEBO (Human Exonic Evidence Based Oligonucleotide) microarrays for conducting array-CGH using as little as 25 ng of genomic DNA from a wide variety of sources, including cultured cell lines and clinical specimens, with high spatial resolution and array-to-array reproducibility.
PMCID: PMC4209297  PMID: 19488869
DNA microarray; array-CGH; comparative genomic hybridization; HEEBO; post-processing; epoxysilane; whole-genome amplification
8.  Reduced surround inhibition in musicians 
Experimental brain research  2012;219(3):403-408.
To investigate whether surround inhibition (SI) in the motor system is altered in professional musicians, we performed a transcranial magnetic stimulation (TMS) study in 10 professional musicians and 15 age-matched healthy non-musicians. TMS was set to be triggered by self-initiated flexion of the index finger at different intervals ranging from 3 to 1000 ms. Average motor evoked potential (MEP) amplitudes obtained from self-triggered TMS were normalized to average MEPs of the control TMS at rest and expressed as a percentage. Normalized MEP amplitudes of the abductor digiti minimi (ADM) muscles were compared between the musicians and non-musicians with the primary analysis being the intervals between 3 and 80 ms (during the movement). A mixed-design ANOVA revealed a significant difference in normalized ADM MEPs during the index finger flexion between groups, with less SI in the musicians. This study demonstrated that the functional operation of SI is less strong in musicians than non-musicians, perhaps due to practice of movement synergies involving both muscles. Reduced SI, however, could lead susceptible musicians to be prone to develop task-specific dystonia.
PMCID: PMC4161923  PMID: 22543743
Transcranial magnetic stimulation; Surround inhibition; Motor evoked potential; Musician; Dystonia
9.  Circumferential iris trans-illumination defects in exfoliation syndrome 
Journal of glaucoma  2013;22(7):555-558.
We identified a pattern of concentric circular transillumination defects in a few patients with exfoliation syndrome using an infrared detection system. This pattern of iris abnormality has also been observed in a mouse model of exfoliation syndrome. The objective of the current study is to determine if concentric iris transillumination defects are specific to exfoliation syndrome and may have some diagnostic utility for identifying early cases of disease.
Materials and Methods
A total of 68 volunteers from the University of Iowa Glaucoma Clinic with normal eyes (n=21) or diagnoses of either exfoliation syndrome (n=12), pigment dispersion syndrome (n=8), or primary open angle glaucoma (n=27) were enrolled in the study. The irides of these subjects were each examined by four ophthalmologists masked to their diagnosis, using infrared videography. The presence of concentric, circular transillumination defects on the videos was graded as none (grade 0), possible (grade 1), definite (grade 2), or prominent (grade 3) by four examiners. We searched for an association between the presence of concentric bands of trans-illumination and the diagnosis of exfoliation syndrome after removing the effect of different raters was evaluated using the Cochran-Mentel-Haenszel test. We performed the same analysis for pigment dispersion syndrome and for primary open angle glaucoma.
The presence of any concentric, circular iris trans-illumination defects (grades 1–3) was detected in a mean of 38% normal subjects, 35% POAG patients, 53% pigment dispersion syndrome patients, and 77% of exfoliation syndrome patients. When the frequency of concentric, circular iris transillumination (grades 1–3 pooled) was compared between each of the patient groups and normal controls, a significant difference was detected between exfoliation syndrome patients and controls (p-value = 0.000019). No significant difference was detected between POAG and controls (p=0.64) or between pigment dispersion syndrome and controls (p=0.20). Furthermore, prominent concentric, circular iris trans-illumination (grade 3) was only observed in exfoliation syndrome.
Detection of concentric, circular iris transillumination defects with an infrared system is easy, inexpensive, rapid, and relatively specific in exfoliation syndrome. Future larger studies will be needed to confirm the findings of this small pilot study. Furthermore, this examination technique has the potential to help physicians to make earlier diagnoses of exfoliation syndrome and to better plan for future surgeries to minimize risk of complication.
PMCID: PMC3502723  PMID: 22525123
exfoliation syndrome; iris transillumination defects; diagnostic sign
10.  Construction of a Reactive Diblock Copolymer, Polyphosphoester-block-Poly(L-lactide), as a Versatile Framework for Functional Materials that are Capable of Full Degradation and Nanoscopic Assembly Formation 
ACS macro letters  2013;2(9):10.1021/mz400229m.
The development of a diblock copolymer, polyphosphoester-block-poly(L-lactide), which has potential for being fully-degradable and biocompatible, was achieved by one-pot sequential ring-opening polymerizations (ROPs) of two cyclic monomers: alkyne-functionalized phospholane and L-lactide (LLA). A kinetic study of the polymerization in each step was investigated in a detailed manner by nuclear magnetic resonance (NMR) spectroscopy and gel permeation chromatography (GPC), revealing living/controlled characteristics with narrow molecular weight distributions and a linear increase of molecular weights vs. monomer conversion and time. Subsequently, photo-induced thiol-yne “click” reactions with small molecule thiols bearing either carboxylic acid or amino groups afforded amphiphilic diblock copolymers with carboxylate or amino side-chain functionalities along the polyphosphoester segment of the diblock copolymer backbone. Finally, direct dissolution of the two different types of amphiphilic diblock copolymers in aqueous solutions yielded well-defined spherical micelles with corresponding negative or positive surface charges, respectively, as confirmed by transmission electron microscopy (TEM), dynamic light scattering (DLS) and zeta potential analyses.
PMCID: PMC3808001  PMID: 24167757
11.  Effects of Chronic Estradiol Treatment on Delayed Spatial Alternation and Differential Reinforcement of Low Rates of Responding 
Behavioral neuroscience  2008;122(4):794-804.
Estrogens have been shown to both enhance and impair cognitive function depending on several factors including regimen of hormone treatment, age of subject, and task attributes. In rodent models, estradiol tends to enhance spatial learning and impair response or cued learning, but effects on executive functions are less well-studied. In this experiment, spatial working memory and response inhibition were tested using delayed spatial alternation (DSA) and differential reinforcement of low rates of responding (DRL) tasks in ovariectomized rats that were given chronic estradiol via Silastic implants resulting in serum estradiol concentrations of 86.2±8.2 (SEM) pg/ml. Rats were tested for 25 days DSA with variable delays of 0, 3, 6, 9, and 18 seconds between lever presentations, followed by 30 days on a DRL-15s operant schedule. Estradiol-replaced rats showed a significantly lower proportion of correct responses on the DSA task compared to vehicle-implanted ovariectomized animals. On DRL, estradiol -treated rats showed a lower ratio of reinforced to non-reinforced presses. These data suggest that chronic estrogen exposure may impair rats’ abilities on measures of executive function including working memory and response inhibition.
PMCID: PMC4026023  PMID: 18729633
estrogen; cognition; aging; DSA; DRL
12.  Reproducibility of SD-OCT–Based Ganglion Cell–Layer Thickness in Glaucoma Using Two Different Segmentation Algorithms 
To compare the reproducibility of spectral-domain optical coherence tomography (SD-OCT)–based ganglion cell–layer-plus-inner plexiform–layer (GCL+IPL) thickness measurements for glaucoma patients obtained using both a publicly available and a commercially available algorithm.
Macula SD-OCT volumes (200 × 200 × 1024 voxels, 6 × 6 × 2 mm3) were obtained prospectively from both eyes of patients with open-angle glaucoma or with suspected glaucoma on two separate visits within 4 months. The combined GCL+IPL thickness was computed for each SD-OCT volume within an elliptical annulus centered at the fovea, based on two algorithms: (1) a previously published graph-theoretical layer segmentation approach developed at the University of Iowa, and (2) a ganglion cell analysis module of version 6 of Cirrus software. The mean overall thickness of the elliptical annulus was computed as was the thickness within six sectors. For statistical analyses, eyes with an SD-OCT volume with low signal strength (<6), image acquisition errors, or errors in performing the commercial GCL+IPL analysis in at least one of the repeated acquisitions were excluded.
Using 104 eyes (from 56 patients) with repeated measurements, we found the intraclass correlation coefficient for the overall elliptical annular GCL+IPL thickness to be 0.98 (95% confidence interval [CI]: 0.97–0.99) with the Iowa algorithm and 0.95 (95% CI: 0.93–0.97) with the Cirrus algorithm; the intervisit SDs were 1.55 μm (Iowa) and 2.45 μm (Cirrus); and the coefficients of variation were 2.2% (Iowa) and 3.5% (Cirrus), P < 0.0001.
SD-OCT–based GCL+IPL thickness measurements in patients with early glaucoma are highly reproducible.
SD-OCT–based ganglion cell–layer plus inner plexiform–layer thickness measurements for glaucoma patients, obtained with both a publicly available and a commercially available algorithm, are highly reproducible.
PMCID: PMC3809946  PMID: 24045993
ganglion cell layer; glaucoma; image segmentation; reproducibility
13.  Englerin A stimulates PKCθ to inhibit insulin signaling and simultaneously activate HSF1: An example of pharmacologically induced synthetic lethality 
Cancer cell  2013;23(2):228-237.
The natural product englerin A (EA) binds to and activates protein kinase C-θ (PKCθ). EA-dependent activation of PKCθ induces an insulin resistant phenotype, limiting the access of tumor cells to glucose. At the same time, EA causes PKCθ-mediated phosphorylation and activation of the transcription factor heat shock factor 1, an inducer of glucose dependence. By promoting glucose addiction while simultaneously starving cells of glucose, EA proves to be synthetically lethal to highly glycolytic tumors.
PMCID: PMC3574184  PMID: 23352416
HSF1; englerin A; renal cell cancer; PKCθ; insulin resistance
14.  Identification of Proteins that Interact with TANK Binding Kinase 1 and Testing for Mutations Associated with Glaucoma 
Current eye research  2013;38(2):310-315.
Copy number variations (duplications) of TANK binding kinase 1 (TBK1) have been associated with normal tension glaucoma (NTG), a common cause of blindness worldwide. Mutations in other genes involved in autophagy (TLR4 and OPTN) have been associated with NTG. Here we report searching for additional proteins involved in autophagy that may also have roles in NTG.
Materials and methods
HEK-293T cells were transfected to produce synthetic TBK1 protein with FLAG and S tags. Proteins that associate with TBK1 were isolated from HEK-293T lysates using tandem affinity purification (TAP) and polyacrylamide gel electrophoresis (PAGE). Isolated proteins were identified with mass spectrometry. A cohort of 148 NTG patients and 77 controls from Iowa were tested for glaucoma-causing mutations in genes that encode identified proteins that interact with TBK1 using high resolution melt (HRM) analysis and DNA sequencing.
TAP studies show that three proteins expressed in HEK-293T cells (NAP1, TANK and TBKBP1) interact with TBK1. Testing cohorts of NTG and normal controls for disease-causing mutations in TANK, identified a total of nine unique variants including three non-synonymous changes, one synonymous changes and five intronic changes. When analyzed alone or as a group, the non-synonymous TBK1 coding sequence changes were not associated with either NTG or primary open angle glaucoma.
TAP showed that NAP1, TANK and TBKBP1 interact with TBK1 and are good candidates for contributing to NTG. A mutation screen of TANK detected three non-synonymous variants. Although, it remains possible that one or more of these TANK mutations may have a role in NTG, the data in this report do not provide statistical support for an association between TANK variants and NTG.
PMCID: PMC3700396  PMID: 23286385
Glaucoma; tandem affinity purification; TKB1
15.  Congenital Self-Healing Reticulohistiocytosis 
Congenital self-healing reticulohistiocytosis, also known as congenital self-healing Langerhans cell histiocytosis or Hashimoto-Pritzker disease, is a Langerhans cell histiocytosis. It is characterized by skin lesions in the newborn period in an otherwise healthy infant that show a Langerhans cell infiltrate in the skin on histological analysis. These findings subsequently spontaneously involute. This report describes two newborns who presented at birth with differing presentations of congenital self-healing reticulohistiocytosis. A review of the disorder, including diagnosis and evaluation, is presented.
PMCID: PMC3935651  PMID: 24578781
16.  Adjustment of the Retinal Angle in SD-OCT of Glaucomatous Eyes Provides Better Intervisit Reproducibility of Peripapillary RNFL Thickness 
To report an automated method for adjustment of the retinal angle in spectral-domain optical coherence tomography (SD-OCT) and compare its intervisit reproducibility of the peripapillary retinal nerve fiber layer (RNFL) thicknesses of glaucomatous eyes to that obtained by the Cirrus algorithm.
Fifty-six glaucoma and glaucoma suspect subjects were repeatedly imaged, and optic nerve head (ONH)–centered OCT image volumes (200 × 200 × 1024 voxels, 6 × 6 × 2 mm3, Cirrus HD-OCT machine) were acquired within a 4-month period from one eye of the 56 patients. Retinal angle correction in B-scans was accomplished by adjusting the angle using the voxel aspect ratio of the SD-OCT followed by straightening of rotated A-scans. The RNFL layer was automatically segmented using the Iowa Reference Algorithm. Reproducibility of the peripapillary RNFL thicknesses was determined by intraclass correlation coefficient (ICC), coefficient of variation (CV), repeatability coefficient (RC), and 95% tolerance limit (TL) for the Iowa Reference Algorithm without and with the retinal angle correction and for the Cirrus algorithm (Cirrus version
The angle corrected Iowa Reference Algorithm (ICC: 0.990, 95% confidence interval [CI]: 0.983–0.994) for peripapillary RNFL thicknesses showed significantly better reproducibility than the nonangle corrected algorithm (ICC: 0.964, 95% CI: 0.940–0.979) and the Cirrus algorithm (ICC: 0.960, 95% CI: 0.933–0.976) based on the 95% CIs for the ICCs.
Angle correction leads to more consistent peripapillary RNFL thicknesses. This may lead to improved management of patients with glaucoma.
We report an automated method for adjustment of the retinal angle in spectral-domain optical coherence tomography (SD-OCT) and compare its intervisit reproducibility of the peripapillary retinal nerve fiber layer (RNFL) thicknesses of glaucomatous eyes to that obtained by the Cirrus algorithm.
PMCID: PMC3720146  PMID: 23788372
spectral-domain coherence tomography (SD-OCT); retinal angle adjustment; peripapillary retinal nerve fiber layer (RNFL) thickness
17.  Mesenchymal stem cells can modulate longitudinal changes in cortical thickness and its related cognitive decline in patients with multiple system atrophy 
Multiple system atrophy (MSA) is an adult-onset, sporadic neurodegenerative disease. Because the prognosis of MSA is fatal, neuroprotective or regenerative strategies may be invaluable in MSA treatment. Previously, we obtained clinical and imaging evidence that mesenchymal stem cell (MSC) treatment could have a neuroprotective role in MSA patients. In the present study, we evaluated the effects of MSC therapy on longitudinal changes in subcortical deep gray matter volumes and cortical thickness and their association with cognitive performance. Clinical and imaging data were obtained from our previous randomized trial of autologous MSC in MSA patients. During 1-year follow-up, we assessed longitudinal differences in automatic segmentation-based subcortical deep gray matter volumes and vertex-wise cortical thickness between placebo (n = 15) and MSC groups (n = 11). Next, we performed correlation analysis between the changes in cortical thickness and changes in the Korean version of the Montreal Cognitive Assessment (MoCA) scores and cognitive performance of each cognitive subdomain using a multiple, comparison correction. There were no significant differences in age at baseline, age at disease onset, gender ratio, disease duration, clinical severity, MoCA score, or education level between the groups. The automated subcortical volumetric analysis revealed that the changes in subcortical deep gray matter volumes of the caudate, putamen, and thalamus did not differ significantly between the groups. The areas of cortical thinning over time in the placebo group were more extensive, including the frontal, temporal, and parietal areas, whereas these areas in the MSC group were less extensive. Correlation analysis indicated that declines in MoCA scores and phonemic fluency during the follow-up period were significantly correlated with cortical thinning of the frontal and posterior temporal areas and anterior temporal areas in MSA patients, respectively. In contrast, no significant correlations were observed in the MSC group. These results suggest that MSC treatment in patients with MSA may modulate cortical thinning over time and related cognitive performance, inferring a future therapeutic candidate for cognitive disorders.
PMCID: PMC4056280  PMID: 24982631
mesenchymal stem cells; multiple system atrophy; cortical thickness; cognition; clinical trial
18.  Neuroanatomical Heterogeneity of Essential Tremor According to Propranolol Response 
PLoS ONE  2013;8(12):e84054.
Recent studies have suggested that essential tremor (ET) is a more complex and heterogeneous clinical entity than initially thought. In the present study, we assessed the pattern of cortical thickness and diffusion tensor white matter (WM) changes in patients with ET according to the response to propranolol to explore the pathogenesis underlying the clinical heterogeneity of ET.
A total of 32 patients with drug naive ET were recruited prospectively from the Movement Disorders outpatient clinic. The patients were divided into a propranolol-responder group (n = 18) and a non-responder group (n = 14). We analyzed the pattern of cortical thickness and diffusion tensor WM changes between these two groups and performed correlation analysis between imaging and clinical parameters.
There were no significant differences in demographic characteristics, general cognition, or results of detailed neuropsychological tests between the groups. The non-responder group showed more severe cortical atrophy in the left orbitofrontal cortex and right temporal cortex relative to responders. However, the responders exhibited significantly lower fractional anisotropy values in the bilateral frontal, corpus callosal, and right parietotemporal WM compared with the non-responder group. There were no significant clusters where the cortical thickness or WM alterations were significantly correlated with initial tremor severity or disease duration.
The present data suggest that patients with ET have heterogeneous cortical thinning and WM alteration with respect to responsiveness to propranolol, suggesting that propranolol responsiveness may be a predictive factor to determine ET subtypes in terms of neuroanatomical heterogeneity.
PMCID: PMC3865260  PMID: 24358327
19.  Surface Charges and Shell Crosslinks Each Play Significant Roles in Mediating Degradation, Biofouling, Cytotoxicity and Immunotoxicity for Polyphosphoester-based Nanoparticles 
Scientific Reports  2013;3:3313.
The construction of nanostructures from biodegradable precursors and shell/core crosslinking have been pursued as strategies to solve the problems of toxicity and limited stability, respectively. Polyphosphoester (PPE)-based micelles and crosslinked nanoparticles with non-ionic, anionic, cationic, and zwitterionic surface characteristics for potential packaging and delivery of therapeutic and diagnostic agents, were constructed using a quick and efficient synthetic strategy, and importantly, demonstrated remarkable differences in terms of cytotoxicity, immunotoxicity, and biofouling properties, as a function of their surface characteristics and also with dependence on crosslinking throughout the shell layers. For instance, crosslinking of zwitterionic micelles significantly reduced the immunotoxicity, as evidenced from the absence of secretions of any of the 23 measured cytokines from RAW 264.7 mouse macrophages treated with the nanoparticles. The micelles and their crosslinked analogs demonstrated lower cytotoxicity than several commercially-available vehicles, and their degradation products were not cytotoxic to cells at the range of the tested concentrations. PPE-nanoparticles are expected to have broad implications in clinical nanomedicine as alternative vehicles to those involved in several of the currently available medications.
PMCID: PMC3837308  PMID: 24264796
20.  A combined machine-learning and graph-based framework for the segmentation of retinal surfaces in SD-OCT volumes 
Biomedical Optics Express  2013;4(12):2712-2728.
Optical coherence tomography is routinely used clinically for the detection and management of ocular diseases as well as in research where the studies may involve animals. This routine use requires that the developed automated segmentation methods not only be accurate and reliable, but also be adaptable to meet new requirements. We have previously proposed the use of a graph-theoretic approach for the automated 3-D segmentation of multiple retinal surfaces in volumetric human SD-OCT scans. The method ensures the global optimality of the set of surfaces with respect to a cost function. Cost functions have thus far been typically designed by hand by domain experts. This difficult and time-consuming task significantly impacts the adaptability of these methods to new models. Here, we describe a framework for the automated machine-learning based design of the cost function utilized by this graph-theoretic method. The impact of the learned components on the final segmentation accuracy are statistically assessed in order to tailor the method to specific applications. This adaptability is demonstrated by utilizing the method to segment seven, ten and five retinal surfaces from SD-OCT scans obtained from humans, mice and canines, respectively. The overall unsigned border position errors observed when using the recommended configuration of the graph-theoretic method was 6.45 ± 1.87 μm, 3.35 ± 0.62 μm and 9.75 ± 3.18 μm for the human, mouse and canine set of images, respectively.
PMCID: PMC3862166  PMID: 24409375
(100.0100) Image processing; (100.2000) Digital image processing; (100.4994) Pattern recognition, image transforms; (100.6890) Three-dimensional image processing; (110.4500) Optical coherence tomography
21.  Biotinylated Probes for Analysis of Protein Modification by Electrophiles 
Methods in molecular biology (Clifton, N.J.)  2012;803:10.1007/978-1-61779-364-6_7.
The formation of covalent protein adducts by lipid electrophiles contributes to diseases and toxicities linked to oxidative stress, but analysis of the adducts presents a challenging analytical problem. We describe selective adduct capture using biotin affinity probes to enrich protein and peptide adducts for analysis by liquid chromatography-tandem mass spectrometry (LC-MS/MS). One approach employs biotinamidohexanoic acid hydrazide to covalently label residual carbonyl groups on adducts. The other employs alkynyl analogs of lipid electrophiles, which form adducts that can be post labeled with azidobiotin tags by Cu+-catalyzed cycloaddition (Click chemistry). To enhance the selectivity of adduct capture we use an azidobiotin reagent with a photocleavable linker, which allows recovery of adducted proteins and peptides under mild conditions. This approach allows both the identification of protein targets of lipid electrophiles and sequence mapping of the adducts.
PMCID: PMC3811082  PMID: 22065220
electrophile; Click chemistry; protein adducts; lipid oxidation; photocleavable biotin; shotgun proteomics
22.  Analysis of ASB10 variants in open angle glaucoma 
Human Molecular Genetics  2012;21(20):4543-4548.
Glaucoma is a common cause of visual disability and affects ∼1.6% of individuals over 40 years of age ( 1). Non-synonymous coding sequence variations in the ankyrin repeat and SOCS box containing gene 10 (ASB10) were recently associated with 6.0% of cases of primary open angle glaucoma (POAG) in patients from Oregon and Germany. We tested a cohort of POAG patients (n= 158) and normal control subjects (n= 82), both from Iowa, for ASB10 mutations. Our study had 80% power to detect a 4.9% mutation frequency in POAG patients. A total of 11 non-synonymous coding sequence mutations were detected in the cohort, but no association with POAG was detected when analyzed individually or as a group (P > 0.05). Furthermore, a survey of the National Heart, Lung, and Blood Institute's (NHLBI's) Exome Sequencing Project revealed that non-synonymous ASB10 mutations are present in the general population at a far higher frequency than the prevalence of POAG. These data suggest that non-synonymous mutations in ASB10 do not cause Mendelian forms of POAG.
PMCID: PMC3459468  PMID: 22798626
23.  4-1BB Signaling Activates the T Cell Factor 1 Effector/β-Catenin Pathway with Delayed Kinetics via ERK Signaling and Delayed PI3K/AKT Activation to Promote the Proliferation of CD8+ T Cells 
PLoS ONE  2013;8(7):e69677.
4-1BB (CD137), an inducible costimulatory molecule, strongly enhances the proliferation and effector function of CD8+ T cells. Since the serine/threonine kinase, glycogen synthase kinase-3 (GSK-3), is involved in a variety of signaling pathways of cellular proliferation, migration, immune responses, and apoptosis, we examined whether 4-1BB signaling activates GSK-3/β-catenin signaling and downstream transcription factors to enhance the proliferation of CD8+ T cells. 4-1BB signaling induces rapid activation of ERK and IκB degradation, and shows delayed activation of AKT at 24 h post 4-1BB stimulation on anti-CD3 activated T cells. ERK and AKT signals were required for sustained β-catenin levels by inactivating GSK-3, which was also observed with delayed kinetics after 4-1BB stimulation. As a transcriptional partner of β-catenin, 4-1BB signaling decreased levels of FOXO1 and increased levels of stimulatory TCF1 in CD8+ T cells at 2–3 days but not at early time points after 4-1BB engagement. The enhanced proliferation of CD8+ T cells due to 4-1BB signaling was completely abolished by treatment with the TCF1/β-catenin inhibitor quercetin. These results show that 4-1BB signaling enhances the proliferation of activated CD8+ T cells by activating the TCF1/β-catenin axis via the PI3K/AKT/ERK pathway. As effects of 4-1BB on AKT, FOXO1, β-catenin and GSK-3β showed delayed kinetics it is likely that an intervening molecule induced by 4-1BB and ERK signaling in activated T cells is responsible for these effects. These effects were observed on CD8+ but not on CD4+ T cells. Moreover, 4-1BB appeared to be unique among several TNFRs tested in inducing increase in stimulatory over inhibitory TCF-1.
PMCID: PMC3708905  PMID: 23874982
24.  Primary Open-Angle Glaucoma 
The New England journal of medicine  2009;360(11):1113-1124.
PMCID: PMC3700399  PMID: 19279343
25.  Distribution of Damage to the Entire Retinal Ganglion Cell Pathway 
Archives of ophthalmology  2012;130(9):1118-1126.
To test the hypothesis that the amount and distribution of glaucomatous damage along the entire retinal ganglion cell–axonal complex (RGC-AC) can be quantified and to map the RGC-AC connectivity in early glaucoma using automated image analysis of standard spectral-domain optical coherence tomography.
Spectral-domain optical coherence tomography volumes were obtained from 116 eyes in 58 consecutive patients with glaucoma or suspected glaucoma. Layer and optic nerve head (ONH) analysis was performed; the mean regional retinal ganglion cell layer thickness (68 regions), nerve fiber layer (NFL) thickness (120 regions), and ONH rim area (12 wedge-shaped regions) were determined. Maps of RGC-AC connectivity were created using maximum correlation between regions’ ganglion cell layer thickness, NFL thickness, and ONH rim area; for retinal nerve fiber bundle regions, the maximum “thickness correlation paths” were determined.
The mean (SD) NFL thickness and ganglion cell layer thickness across all macular regions were 22.5 (7.5) μm and 33.9 (8.4) μm, respectively. The mean (SD) rim area across all ONH wedge regions was 0.038 (0.004) mm2. Connectivity maps were obtained successfully and showed typical nerve fiber bundle connectivity of the RGC-AC cell body segment to the initial NFL axonal segment, of the initial to the final RGC-AC NFL axonal segments, of the final RGC-AC NFL axonal to the ONH axonal segment, and of the RGC-AC cell body segment to the ONH axonal segment.
In early glaucoma, the amount and distribution of glaucomatous damage along the entire RGC-AC can be quantified and mapped using automated image analysis of standard spectral-domain optical coherence tomography. Our findings should contribute to better detection and improved management of glaucoma.
PMCID: PMC3691810  PMID: 22965586

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