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1.  Development of 107 SSR markers from whole genome shotgun sequences of Chinese bayberry (Myrica rubra) and their application in seedling identification* #  
Chinese bayberry (Myrica rubra Sieb. et Zucc.) is one of the important subtropical fruit crops native to the South of China and Asian countries. In this study, 107 novel simple sequence repeat (SSR) molecular markers, a powerful tool for genetic diversity studies, cultivar identification, and linkage map construction, were developed and characterized from whole genome shotgun sequences. M13 tailing for forward primers was applied as a simple method in different situations. In total, 828 alleles across 45 accessions were detected, with an average of 8 alleles per locus. The number of effective alleles ranged from 1.22 to 10.41 with an average of 4.08. The polymorphic information content (PIC) varied from 0.13 to 0.89, with an average of 0.63. Moreover, these markers could also be amplified in their related species Myrica cerifera (syn. Morella cerifera) and Myrica adenophora. Seventy-eight SSR markers can be used to produce a genetic map of a cross between ‘Biqi’ and ‘Dongkui’. A neighbor-joining (NJ) tree was constructed to assess the genetic relationships among accessions, and the elite accessions ‘Y2010-70’, ‘Y2012-140’, and ‘Y2012-145’, were characterized as potential new genotypes for cultivation.
PMCID: PMC4228512  PMID: 25367792
Chinese bayberry; Simple sequence repeat (SSR); Genetic diversity
2.  Effects of miR-33a-5P on ABCA1/G1-Mediated Cholesterol Efflux under Inflammatory Stress in THP-1 Macrophages 
PLoS ONE  2014;9(10):e109722.
The present study is to investigate whether inflammatory cytokines inhibit ABCA1/ABCG1-mediated cholesterol efflux by regulating miR-33a-5P in THP-1 macrophages. We used interleukin-6 and tumor necrosis factor-alpha in the presence or absence of native low density lipoprotein (LDL) to stimulate THP-1 macrophages. THP-1 macrophages were infected by either control lentivirus vectors or lentivirus encoding miR-33a-5P or antisense miR-33a-5P. The effects of inflammatory cytokines, miR-33a-5P and antisense miR-33a-5P on intracellular lipids accumulation and intracellular cholesterol contents were assessed by oil red O staining and quantitative intracellular cholesterol assay. ApoA-I-mediated cholesterol efflux was examined using the fluorescent sterol (BODIPY-cholesterol). The gene and protein expressions of the molecules involved in cholesterol trafficking were examined using quantitative real-time polymerase chain reaction and Western blotting. Inflammatory cytokines or miR-33a-5P increased intracellular lipid accumulation and decreased apoA-I-mediated cholesterol efflux via decreasing the expression of ABCA1 and ABCG1 in the absence or presence of LDL in THP-1 macrophages. However, antisense miR-33a-5P reversed the effects of inflammatory cytokines on intracellular lipid accumulation, cholesterol efflux, and the expression of miR-33a-5P, ABCA1 and ABCG1 in the absence or presence of LDL in THP-1 macrophages. This study indicated that inflammatory cytokines inhibited ABCA1/ABCG1-mediated cholesterol efflux by up-regulating miR-33a-5P in THP-1 macrophages.
PMCID: PMC4201478  PMID: 25329888
3.  Silencing of the Drosophila ortholog of SOX5 in heart leads to cardiac dysfunction as detected by optical coherence tomography 
Human Molecular Genetics  2013;22(18):3798-3806.
The SRY-related HMG-box 5 (SOX5) gene encodes a member of the SOX family of transcription factors. Recently, genome-wide association studies have implicated SOX5 as a candidate gene for susceptibility to four cardiac-related endophenotypes: higher resting heart rate (HR), the electrocardiographic PR interval, atrial fibrillation and left ventricular mass. We have determined that human SOX5 has a highly conserved Drosophila ortholog, Sox102F, and have employed transgenic Drosophila models to quantitatively measure cardiac function in adult flies. For this purpose, we have developed a high-speed and ultrahigh-resolution optical coherence tomography imaging system, which enables rapid cross-sectional imaging of the heart tube over various cardiac cycles for the measurement of cardiac structural and dynamical parameters such as HR, dimensions and areas of heart chambers, cardiac wall thickness and wall velocities. We have found that the silencing of Sox102F resulted in a significant decrease in HR, heart chamber size and cardiac wall velocities, and a significant increase in cardiac wall thickness that was accompanied by disrupted myofibril structure in adult flies. In addition, the silencing of Sox102F in the wing led to increased L2, L3 and wing marginal veins and increased and disorganized expression of wingless, the central component of the Wnt signaling pathway. Collectively, the silencing of Sox102F resulted in severe cardiac dysfunction and structural defects with disrupted Wnt signaling transduction in flies. This implicates an important functional role for SOX5 in heart and suggests that the alterations in SOX5 levels may contribute to the pathogenesis of multiple cardiac diseases or traits.
PMCID: PMC3749865  PMID: 23696452
4.  Space-division multiplexing optical coherence tomography 
Optics Express  2013;21(16):19219-19227.
High speed, high resolution and high sensitivity are desirable for optical coherence tomography (OCT). Here, we demonstrate a space-division multiplexing (SDM) technology that translates long coherence length of a commercially available wavelength tunable laser into high OCT imaging speed. We achieved an effective 800,000 A-scans/s imaging speed using a 100,000 Hz tunable vertical cavity surface-emitting laser (VCSEL). A sensitivity of 94.6 dB and a roll-off of < 2 dB over ~30 mm imaging depth were measured from a single channel in the prototype SDM-OCT system. An axial resolution of ~11 μm in air (or ~8.3 μm in tissue) was achieved throughout the entire depth range. An in vivo, 3D SDM-OCT volume of an entire Drosophila larva consisting of 400 x 605 A-scans was acquired in 0.37 seconds. Synchronized cross-sectional OCT imaging of three different segments of a beating Drosophila larva heart is demonstrated. The SDM technology provides a new orthogonal dimension for further speed improvement for OCT with favorable cost scaling. SDM-OCT also preserves image resolution and allows synchronized cross-sectional and three-dimensional (3D) imaging of biological samples, enabling new biomedical applications.
PMCID: PMC3756223  PMID: 23938839
(110.4500) Optical coherence tomography; (060.4230) Multiplexing; (110.6880) Three-dimensional image acquisition; (170.3880) Medical and biological imaging
5.  TSLP-elicited basophil responses can mediate the pathogenesis of eosinophilic esophagitis 
Nature medicine  2013;19(8):1005-1013.
Eosinophilic esophagitis (EoE) is a food allergy-associated inflammatory disease characterized by esophageal eosinophilia. EoE has become increasingly common, but current management strategies are nonspecific. Thus, there is an urgent need to identify specific immunological pathways that could be targeted to treat this disease. EoE is associated with polymorphisms in the gene that encodes thymic stromal lymphopoietin (TSLP), a cytokine that promotes allergic inflammation, but how TSLP might contribute to EoE disease pathogenesis remains unknown. Here, we describe a new mouse model of EoE-like disease that developed independently of IgE but was dependent on TSLP-elicited basophils. Therapeutic TSLP neutralization or basophil depletion also ameliorated established EoE-like disease. Critically, in human subjects with EoE, we observed elevated TSLP levels and exaggerated basophil responses in esophageal biopsies, and a gain-of-function TSLP polymorphism was associated with increased basophil responses. Together, these data suggest that the TSLP-basophil axis could be therapeutically targeted to treat EoE.
PMCID: PMC3951204  PMID: 23872715
6.  Characterization of eosinophilic esophagitis murine models using optical coherence tomography 
Biomedical Optics Express  2014;5(2):609-620.
Pre-clinical studies using murine models are critical for understanding the pathophysiological mechanisms underlying immune-mediated disorders such as Eosinophilic esophagitis (EoE). In this study, an optical coherence tomography (OCT) system capable of providing three-dimensional images with axial and transverse resolutions of 5 µm and 10 µm, respectively, was utilized to obtain esophageal images from a murine model of EoE-like disease ex vivo. Structural changes in the esophagus of wild-type (Tslpr+/+) and mutant (Tslpr−/−) mice with EoE-like disease were quantitatively evaluated and food impaction sites in the esophagus of diseased mice were monitored using OCT. Here, the capability of OCT as a label-free imaging tool devoid of tissue-processing artifacts to effectively characterize murine EoE-like disease models has been demonstrated.
PMCID: PMC3920889  PMID: 24575353
(110.4500) Optical coherence tomography; (110.6880) Three-dimensional image acquisition; (170.0110) Imaging systems; (170.2680) Gastrointestinal; (170.3880) Medical and biological imaging; (170.6935) Tissue characterization
7.  Graphene’s cousin: the present and future of graphane 
The so-called graphane is a fully hydrogenated form of graphene. Because it is fully hydrogenated, graphane is expected to have a wide bandgap and is theoretically an electrical insulator. The transition from graphene to graphane is that of an electrical conductor, to a semiconductor, and ultimately to an electrical insulator. This unique characteristic of graphane has recently gained both academic and industrial interest. Towards the end of developing novel applications of this important class of nanoscale material, computational modeling work has been carried out by a number of theoreticians to predict the structures and electronic properties of graphane. At the same time, experimental evidence has emerged to support the proposed structure of graphane. This review article covers the important aspects of graphane including its theoretically predicted structures, properties, fabrication methods, as well as its potential applications.
PMCID: PMC3896693  PMID: 24417937
Graphene; Graphane; Partially hydrogenated graphene; Nanostructure
8.  The rice enhancer of zeste [E(z)] genes SDG711 and SDG718 are respectively involved in long day and short day signaling to mediate the accurate photoperiod control of flowering time 
Recent advances in rice flowering studies have shown that the accurate control of flowering by photoperiod is regulated by key mechanisms that involve the regulation of flowering genes including Heading date1 (Hd1), Early hd1 (Ehd1), Hd3a, and RFT1. The chromatin mechanism involved in the regulation of rice flowering genes is presently not well known. Here we show that the rice enhancer of zeste [E(z)] genes SDG711 and SDG718, which encode the polycomb repressive complex2 (PRC2) key subunit that is required for trimethylation of histone H3 lysine 27 (H3K27me3), are respectively, involved in long day (LD) and short day (SD) regulation of key flowering genes. The expression of SDG711 and SDG718 is induced by LD and SD, respectively. Over-expression and down-regulation of SDG711 respectively, repressed and promoted flowering in LD, but had no effect in SD. By contrast, down-regulation of SDG718 had no effect in LD but delayed flowering in SD. SDG711 and SDG718 repressed OsLF (a repressor of Hd1) respectively in LD and SD, leading to a higher expression of Hd1 thus late flowering in LD and early flowering in SD. SDG711 was also found to be involved in the repression of Ehd1 in LD. SDG711 was shown to directly target to OsLF and Ehd1 loci to mediate H3K27me3 and gene repression. The function of the rice E(z) genes in LD repression and SD promotion of flowering suggests that PRC2-mediated epigenetic repression of gene expression is involved in the accurate photoperiod control of rice flowering.
PMCID: PMC4215622  PMID: 25400654
Oryza sativa; heading date; epigenetics; epigenomics; histone methylation; PRC2; OsCLF; OsiEZ1
9.  Enhanced SCAP Glycosylation by Inflammation Induces Macrophage Foam Cell Formation 
PLoS ONE  2013;8(10):e75650.
Inflammatory stress promotes foam cell formation by disrupting LDL receptor feedback regulation in macrophages. Sterol Regulatory Element Binding Proteins (SREBPs) Cleavage-Activating Protein (SCAP) glycosylation plays crucial roles in regulating LDL receptor and 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCoAR) feedback regulation. The present study was to investigate if inflammatory stress disrupts LDL receptor and HMGCoAR feedback regulation by affecting SCAP glycosylation in THP-1 macrophages. Intracellular cholesterol content was assessed by Oil Red O staining and quantitative assay. The expression of molecules controlling cholesterol homeostasis was examined using real-time quantitative RT-PCR and Western blotting. The translocation of SCAP from the endoplasmic reticulum (ER) to the Golgi was detected by confocal microscopy. We demonstrated that exposure to inflammatory cytokines increased lipid accumulation in THP-1 macrophages, accompanying with an increased SCAP expression even in the presence of a high concentration of LDL. These inflammatory cytokines also prolonged the half-life of SCAP by enhancing glycosylation of SCAP due to the elevated expression of the Golgi mannosidase II. This may enhance translocation and recycling of SCAP between the ER and the Golgi, escorting more SREBP2 from the ER to the Golgi for activation by proteolytic cleavages as evidenced by an increased N-terminal of SREBP2 (active form). As a consequence, the LDL receptor and HMGCoAR expression were up-regulated. Interestingly, these effects could be blocked by inhibitors of Golgi mannosidases. Our results indicated that inflammation increased native LDL uptake and endogenous cholesterol de novo synthesis, thereby causing foam cell formation via increasing transcription and protein glycosylation of SCAP in macrophages. These data imply that inhibitors of Golgi processing enzymes might have a potential vascular-protective role in prevention of atherosclerotic foam cell formation.
PMCID: PMC3797718  PMID: 24146768
10.  The Vast Majority Of Medicare Part D Beneficiaries Still Don't Choose The Cheapest Plans That Meet Their Medication Needs 
Health affairs (Project Hope)  2012;31(10):2259-2265.
The Medicare Part D program allows beneficiaries to choose among Part D plans administered by different health plans in order to encourage market competition and give beneficiaries more flexibility. Currently around 40–50 Part D plans are available per region. When faced with so many options, do beneficiaries generally choose the least expensive plan? Using 2009 Part D data, we found that only 5.2% of beneficiaries chose the cheapest plan. Nationwide, beneficiaries on average spent $368 more annually than they would have spent under the cheapest plan available in their region, given their medication needs. Beneficiaries often overprotected themselves by paying higher premiums for plan features they did not need, such as generic drug coverage in the coverage gap. Our findings suggest that beneficiaries need more targeted assistance from the government to choose plans, for example, a customized letter indicating three top plans based on beneficiaries’ medication needs.
PMCID: PMC3470484  PMID: 23048107
11.  Ultrahigh speed endoscopic optical coherence tomography using micromotor imaging catheter and VCSEL technology 
Biomedical Optics Express  2013;4(7):1119-1132.
We developed a micromotor based miniature catheter with an outer diameter of 3.2 mm for ultrahigh speed endoscopic swept source optical coherence tomography (OCT) using a vertical cavity surface-emitting laser (VCSEL) at a 1 MHz axial scan rate. The micromotor can rotate a micro-prism at several hundred frames per second with less than 5 V drive voltage to provide fast and stable scanning, which is not sensitive to the bending of the catheter. The side-viewing probe can be pulled back to acquire a three-dimensional (3D) data set covering a large area on the specimen. The VCSEL provides a high axial scan rate to support dense sampling under high frame rate operation. Using a high speed data acquisition system, in vivo 3D-OCT imaging in the rabbit GI tract and ex vivo imaging of a human colon specimen with 8 μm axial resolution, 8 μm lateral resolution and 1.2 mm depth range in tissue at a frame rate of 400 fps was demonstrated.
PMCID: PMC3704093  PMID: 23847737
(170.4500) Optical coherence tomography; (170.3880) Medical and biological imaging; (170.2150) Endoscopic imaging; (170.2680) Gastrointestinal; (140.3600) Three-dimensional image acquisition; (110.2350) Fiber optics imaging; (120.5800) Scanners; (120.3890) Medical optics instrumentation
12.  Development of CD8+ T cells expressing two distinct receptors specific for MTB and HIV-1 peptides 
The immune response in individuals co-infected with Mycobacterium tuberculosis (MTB) and the human immunodeficiency virus (MTB/HIV) gradually deteriorates, particularly in the cellular compartment. Adoptive transfer of functional effector T cells can confer protective immunity to immunodeficient MTB/HIV co-infected recipients. However, few such effector T cells exist in vivo, and their isolation and amplification to sufficient numbers is difficult. Therefore, enhancing immune responses against both pathogens is critical for treating MTB/HIV co-infected patients. One approach is adoptive transfer of T cell receptor (TCR) gene-modified T cells for the treatment of MTB/HIV co-infections because lymphocyte numbers and their functional avidity is significantly increased by TCR gene transfer. To generate bispecific CD8+ T cells, MTB Ag85B199–207 peptide-specific TCRs (MTB/TCR) and HIV-1 Env120–128 peptide-specific TCRs (HIV/TCR) were isolated and introduced into CD8+ T cells simultaneously using a retroviral vector. To avoid mispairing among exogenous and endogenous TCRs, and to improve the function and stability of the introduced TCRs, several strategies were employed, including introducing mutations in the MTB/TCR constant (C) regions, substituting part of the HIV/TCR C regions with CD3ζ, and linking gene segments with three different 2A peptides. Results presented in this report suggest that the engineered T cells possessed peptide-specific specificity resulting in cytokine production and cytotoxic activity. This is the first report describing the generation of engineered T cells specific for two different pathogens and provides new insights into TCR gene therapy for the treatment of immunocompromised MTB/HIV co-infected patients.
PMCID: PMC3823179
Mycobacterium tuberculosis; human immunodeficiency virus; co-infection; TCR gene modification; CD8+ T cell
13.  Structural Markers Observed with Endoscopic Three-dimensional Optical Coherence Tomography Correlating with Barrett's Esophagus Radiofrequency Ablation Treatment Response 
Gastrointestinal endoscopy  2012;76(6):1104-1112.
Radiofrequency ablation (RFA) is effective for treating Barrett's esophagus (BE) but often involves multiple endoscopy sessions over several months to achieve complete response.
Identify structural markers using three-dimensional optical coherence tomography (3D-OCT) that correlate with treatment response.
Single teaching hospital.
Thirty-two male and one female Caucasians with short-segment BE (<3cm) undergoing RFA treatment.
Patients were treated with focal RFA and 3D-OCT was performed at the gastroesophageal junction before and immediately after the RFA treatment. Patients were re-examined with standard endoscopy 6-8 weeks later and biopsied to rule out BE if not visibly evident.
Main outcome measurement
The thickness of BE epithelium before RFA and the presence of residual-gland-like structures immediately after RFA were determined using 3D-OCT. The presence of BE at follow-up was assessed endoscopically.
BE mucosa was significantly thinner in patients who achieved complete eradication of intestinal metaplasia (CE-IM) than in patients who did not achieve CE-IM at follow-up [257±60μm vs. 403±86μm, p<0.0001]. A threshold thickness of 333μm derived from receiver-operator characteristics corresponds to a 92.3% sensitivity, 85% specificity and 87.9% accuracy in predicting the presence of BE at follow-up. The presence of OCT-visible glands immediately after RFA also correlated with the presence residual BE at follow-up (83.3% Sensitivity, 95% specificity, and 90.6% accuracy).
Single center, cross sectional study and only patients with short-segment BE were examined.
3D-OCT assessment of BE thickness and residual glands during RFA sessions correlated with treatment response. 3D-OCT may predict response to RFA or make real-time RFA retreatment decisions in the future.
PMCID: PMC3485415  PMID: 22831857
Optical Coherence Tomography; Optical Biopsy; Barrett's Esophagus; Radiofrequency Ablation; Epithelial depth
14.  Characterization of buried glands before and after radiofrequency ablation by using 3-dimensional optical coherence tomography (with videos) 
Gastrointestinal Endoscopy  2012;76(1):32-40.
Radiofrequency ablation (RFA) is an endoscopic technique used to eradicate Barrett’s esophagus (BE). However, such ablation can commonly lead to neosquamous epithelium overlying residual BE glands not visible by conventional endoscopy and may evade detection on random biopsy samples.
To demonstrate the capability of endoscopic 3-dimensional optical coherence tomography (3D-OCT) for the identification and characterization of buried glands before and after RFA therapy.
Cross-sectional study.
Single teaching hospital.
Twenty-six male and 1 female white patients with BE undergoing RFA treatment.
3D-OCT was performed at the gastroesophageal junction in 18 patients before attaining complete eradication of intestinal metaplasia (pre–CE-IM group) and in 16 patients after CE-IM (post–CE-IM group).
Main Outcome Measurements
Prevalence, size, and location of buried glands relative to the squamocolumnar junction.
3D-OCT provided an approximately 30 to 60 times larger field of view compared with jumbo and standard biopsy and sufficient imaging depth for detecting buried glands. Based on 3D-OCT results, buried glands were found in 72% of patients (13/18) in the pre–CE-IM group and 63% of patients (10/16) in the post–CE-IM group. The number (mean [standard deviation]) of buried glands per patient in the post–CE-IM group (7.1 [9.3]) was significantly lower compared with the pre–CE-IM group (34.4 [44.6]; P = .02). The buried gland size (P = .69) and distribution (P = .54) were not significantly different before and after CE-IM.
A single-center, cross-sectional study comparing patients at different time points in treatment. Lack of 1-to-1 coregistered histology for all OCT data sets obtained in vivo.
Buried glands were frequently detected with 3D-OCT near the gastroesophageal junction before and after radiofrequency ablation.
PMCID: PMC3396122  PMID: 22482920
15.  One-step Continuous Synthesis of Biocompatible Gold Nanorods for Optical Coherence Tomography‡ 
We present a novel one-step flow process to synthesize biocompatible gold nanorods with tunable absorption and biocompatible surface ligands. Photothermal optical coherence tomography (OCT) of human breast tissue is successfully demonstrated using tailored gold nanorods designed to have strong absorption in near-infrared range.
PMCID: PMC3381516  PMID: 22634612
16.  Improved Detection Sensitivity of Line-Scanning Optical Coherence Microscopy 
Optical coherence microscopy (OCM) is a promising technology for high-resolution cellular-level imaging in human tissues. Line-scanning OCM is a new form of OCM that utilizes line-field illumination for parallel detection. In this study, we demonstrate improved detection sensitivity by using an achromatic design for line-field generation. This system operates at 830-nm wavelength with 82-nm bandwidth. The measured axial resolution is 3.9 μm in air (corresponding to ~2.9 μm in tissue), and the transverse resolutions are 2.1 μm along the line-field illumination direction and 1.7 μm perpendicular to line illumination direction. The measured sensitivity is 98 dB with 25 line averages, resulting in an imaging speed of ~2 frames/s (516 lines/s). Real-time, cellular-level imaging of scattering tissues is demonstrated using human-colon specimens.
PMCID: PMC3369695  PMID: 22685379
Confocal microscopy; medical and biological imaging; optical coherence microscopy (OCM); optical coherence tomography (OCT)
17.  Integrated Optical Coherence Tomography and Optical Coherence Microscopy Imaging of Ex Vivo Human Renal Tissues 
The Journal of Urology  2011;187(2):691-699.
We evaluated the feasibility of using optical coherence tomography and optical coherence microscopy technology to assess human kidney morphology.
Materials and Methods
A total of 35 renal specimens from 19 patients, consisting of 12 normal tissues and 23 tumors (16 clear cell renal cell carcinomas, 5 papillary renal cell carcinomas and 2 oncocytomas) were imaged ex vivo after surgical resection. Optical coherence tomography and optical coherence microscopy images were compared to corresponding hematoxylin and eosin histology to identify characteristic features of normal and pathological renal tissues. Three pathologists blinded to histology evaluated the sensitivity and specificity of optical coherence microscopy images to differentiate normal from neoplastic renal tissues.
Optical coherence tomography and optical coherence microscopy images of normal kidney revealed architectural features, including glomeruli, convoluted tubules, collecting tubules and loops of Henle. Each method of imaging renal tumors clearly demonstrated morphological changes and decreased imaging depth. Optical coherence tomography and microscopy features matched well with the corresponding histology. Three observers achieved 88%, 100% and 100% sensitivity, and 100%, 88% and 100% specificity, respectively, when evaluating normal vs neoplastic specimens using optical coherence microscopy images with substantial interobserver agreement (κ = 0.82, p <0.01).
Integrated optical coherence tomography and optical coherence microscopy imaging provides coregistered, multiscale images of renal pathology in real time without exogenous contrast medium or histological processing. High sensitivity and specificity were achieved using optical coherence microscopy to differentiate normal from neoplastic renal tissues, suggesting possible applications for guiding renal mass biopsy or evaluating surgical margins.
PMCID: PMC3366589  PMID: 22177199
kidney; tomography; optical coherence; microscopy; imaging; three-dimensional; kidney neoplasms
19.  Cervical inlet patch-optical coherence tomography imaging and clinical significance 
AIM: To demonstrate the feasibility of optical coherence tomography (OCT) imaging in differentiating cervical inlet patch (CIP) from normal esophagus, Barrett’s esophagus (BE), normal stomach and duodenum.
METHODS: This study was conducted at the Veterans Affairs Boston Healthcare System (VABHS). Patients undergoing standard esophagogastroduodenoscopy at VABHS, including one patient with CIP, one representative patient with BE and three representative normal subjects were included. White light video endoscopy was performed and endoscopic 3D-OCT images were obtained in each patient using a prototype OCT system. The OCT imaging probe passes through the working channel of the endoscope to enable simultaneous video endoscopy and 3D-OCT examination of the human gastrointestinal (GI) tract. Standard hematoxylin and eosin (H and E) histology was performed on biopsy or endoscopic mucosal resection specimens in order to compare and validate the 3D-OCT data.
RESULTS: CIP was observed from a 68-year old male with gastroesophageal reflux disease. The CIP region appeared as a pink circular lesion in the upper esophagus under white light endoscopy. OCT imaging over the CIP region showed columnar epithelium structure, which clearly contrasted the squamous epithelium structure from adjacent normal esophagus. 3D-OCT images obtained from other representative patients demonstrated distinctive patterns of the normal esophagus, BE, normal stomach, and normal duodenum bulb. Microstructures, such as squamous epithelium, lamina propria, muscularis mucosa, muscularis propria, esophageal glands, Barrett’s glands, gastric mucosa, gastric glands, and intestinal mucosal villi were clearly observed with OCT and matched with H and E histology. These results demonstrated the feasibility of using OCT to evaluate GI tissue morphology in situ and in real-time.
CONCLUSION: We demonstrate in situ evaluation of CIP microstructures using 3D-OCT, which may be a useful tool for future diagnosis and follow-up of patients with CIP.
PMCID: PMC3360448  PMID: 22654447
Cervical inlet patch; Heterotopic gastric mucosa; Optical coherence tomography; Optical biopsy; Barrett’s esophagus
20.  HGF-Transgenic MSCs Can Improve the Effects of Tissue Self-Repair in a Rabbit Model of Traumatic Osteonecrosis of the Femoral Head 
PLoS ONE  2012;7(5):e37503.
Osteonecrosis of the femoral head (ONFH) is generally characterized as an irreversible disease and tends to cause permanent disability. Therefore, understanding the pathogenesis and molecular mechanisms of ONFH and developing effective therapeutic methods is critical for slowing the progress of the disease.
Methodology/Principal Findings
In this study, an experimental rabbit model of early stage traumatic ONFH was established, validated, and used for an evaluation of therapy. Computed tomography (CT) and magnetic resonance (MR) imaging confirmed that this model represents clinical Association Research Circulation Osseous (ARCO) phase I or II ONFH, which was also confirmed by the presence of significant tissue damage in osseous tissue and vasculature. Pathological examination detected obvious self-repair of bone tissue up to 2 weeks after trauma, as indicated by revascularization (marked by CD105) and expression of collagen type I (Col I), osteocalcin, and proliferating cell nuclear antigen. Transplantation of hepatocyte growth factor (HGF)-transgenic mesenchymal stem cells (MSCs) 1 week after trauma promoted recovery from ONFH, as evidenced by a reversed pattern of Col I expression compared with animals receiving no therapeutic treatment, as well as increased expression of vascular endothelial growth factor.
These results indicate that the transplantation of HGF-transgenic MSCs is a promising method for the treatment for ONFH and suggest that appropriate interference therapy during the tissue self-repair stage contributes to the positive outcomes. This study also provides a model for the further study of the ONFH etiology and therapeutic interventions.
PMCID: PMC3357393  PMID: 22629409
21.  Integrated Optical Coherence Tomography and Microscopy for Ex Vivo Multiscale Evaluation of Human Breast Tissues 
Cancer research  2010;70(24):10071-10079.
3D tissue imaging methods are expected to improve surgical management of cancer. In this study, we examined the feasibility of two 3D imaging technologies, optical coherence tomography (OCT) and optical coherence microscopy (OCM), to view human breast specimens based on intrinsic optical contrast. Specifically, we imaged 44 ex vivo breast specimens including 34 benign and 10 malignant lesions with an integrated OCT and OCM system developed in our laboratory. The system enabled 4 μm axial resolution (OCT and OCM) with 14 μm (OCT) and 2 μm (OCM) transverse resolution, respectively. OCT and OCM images were compared with corresponding histologic sections to identify characteristic features from benign and malignant breast lesions at multiple resolution scales. OCT and OCM provide complimentary information about tissue microstructure, demonstrating distinctive patterns for adipose tissue, fibrous stroma, breast lobules and ducts, cysts and microcysts, as well as in situ and invasive carcinomas. The 3D imaging capability of OCT and OCM provided complementary information to individual 2D images, allowing tracking features from different levels to identify low contrast structures that were difficult to appreciate from single images alone. Our results lay the foundation for future in vivo optical evaluation of breast tissues using OCT and OCM, which has the potential to guide core needle biopsies, assess surgical margins and evaluate nodal involvement in breast cancer.
PMCID: PMC3028517  PMID: 21056988
Optical coherence tomography (OCT); Optical coherence microscopy (OCM); Breast; Pathology; Cancer
22.  Direct measurement of tissue blood flow and metabolism with diffuse optics 
Diffuse optics has proven useful for quantitative assessment of tissue oxy- and deoxyhaemoglobin concentrations and, more recently, for measurement of microvascular blood flow. In this paper, we focus on the flow monitoring technique: diffuse correlation spectroscopy (DCS). Representative clinical and pre-clinical studies from our laboratory illustrate the potential of DCS. Validation of DCS blood flow indices in human brain and muscle is presented. Comparison of DCS with arterial spin-labelled MRI, xenon-CT and Doppler ultrasound shows good agreement (0.50
PMCID: PMC3263785  PMID: 22006897
diffuse correlation spectroscopy; blood flow; cerebral blood flow; oxygen metabolism; brain; cancer
Journal of biomedical optics  2009;14(3):034015.
We used a nonimpact inertial rotational model of a closed head injury in neonatal piglets to simulate the conditions following traumatic brain injury in infants. Diffuse optical techniques, including diffuse reflectance spectroscopy and diffuse correlation spectroscopy (DCS), were used to measure cerebral blood oxygenation and blood flow continuously and noninvasively before injury and up to 6 h after the injury. The DCS measurements of relative cerebral blood flow were validated against the fluorescent microsphere method. A strong linear correlation was observed between the two techniques (R = 0.89, p < 0.00001). Injury-induced cerebral hemodynamic changes were quantified, and significant changes were found in oxy- and deoxy-hemoglobin concentrations, total hemoglobin concentration, blood oxygen saturation, and cerebral blood flow after the injury. The diffuse optical measurements were robust and also correlated well with recordings of vital physiological parameters over the 6-h monitoring period, such as mean arterial blood pressure, arterial oxygen saturation, and heart rate. Finally, the diffuse optical techniques demonstrated sensitivity to dynamic physiological events, such as apnea, cardiac arrest, and hypertonic saline infusion. In total, the investigation corraborates potential of the optical methods for bedside monitoring of pediatric and adult human patients in the neurointensive care unit.
PMCID: PMC3169814  PMID: 19566308
diffuse correlation spectroscopy (DCS); diffuse reflectance spectroscopy (DRS); cerebral hemodynamics; cerebral blood flow; traumatic brain injury; near—infrared spectroscopy (NIRS)
Biomedical Optics Express  2011;2(8):2438-2448.
We developed a piezoelectric-transducer- (PZT) based miniature catheter with an outer diameter of 3.5 mm for ultrahigh-speed endoscopic optical coherence tomography (OCT). A miniaturized PZT bender actuates a fiber and the beam is scanned through a GRIN lens and micro-prism to provide high-speed, side-viewing capability. The probe optics can be pulled back over a long distance to acquire three-dimensional (3D) data sets covering a large area. Imaging is performed with 11 μm axial resolution in air (8 μm in tissue) and 20 μm transverse resolution, at 960 frames per second with a Fourier domain mode-locked laser operating at 480 kHz axial scan rate. Using a high-speed data acquisition system, endoscopic OCT imaging of the rabbit esophagus and colon in vivo and human colon specimens ex vivo is demonstrated.
PMCID: PMC3149540  PMID: 21833379
(170.4500) Optical coherence tomography; (170.3880) Medical and biological imaging; (170.2150) Endoscopic imaging; (170.2680) Gastrointestinal; (140.3600) Three-dimensional image acquisition; (110.2350) Fiber optics imaging; (120.5800) Scanner; (120.3890) Medical optics instrumentation
Neurocritical care  2010;12(2):173-180.
This study assesses the utility of a hybrid optical instrument for noninvasive transcranial monitoring in the neurointensive care unit. The instrument is based on diffuse correlation spectroscopy (DCS) for measurement of cerebral blood flow (CBF), and near-infrared spectroscopy (NIRS) for measurement of oxy- and deoxy-hemoglobin concentration. DCS/NIRS measurements of CBF and oxygenation from frontal lobes are compared with concurrent xenon-enhanced computed tomography (XeCT) in patients during induced blood pressure changes and carbon dioxide arterial partial pressure variation.
Seven neurocritical care patients were included in the study. Relative CBF measured by DCS (rCBFDCS), and changes in oxy-hemoglobin (ΔHbO2), deoxy-hemoglobin (ΔHb), and total hemoglobin concentration (ΔTHC), measured by NIRS, were continuously monitored throughout XeCT during a baseline scan and a scan after intervention. CBF from XeCT regions-of-interest (ROIs) under the optical probes were used to calculate relative XeCT CBF (rCBFXeCT) and were then compared to rCBFDCS. Spearman’s rank coefficients were employed to test for associations between rCBFDCS and rCBFXeCT, as well as between rCBF from both modalities and NIRS parameters.
rCBFDCS and rCBFXeCT showed good correlation (rs = 0.73, P = 0.010) across the patient cohort. Moderate correlations between rCBFDCS and ΔHbO2/ΔTHC were also observed. Both NIRS and DCS distinguished the effects of xenon inhalation on CBF, which varied among the patients.
DCS measurements of CBF and NIRS measurements of tissue blood oxygenation were successfully obtained in neurocritical care patients. The potential for DCS to provide continuous, noninvasive bedside monitoring for the purpose of CBF management and individualized care is demonstrated.
PMCID: PMC2844468  PMID: 19908166
Near-infrared spectroscopy; Diffuse correlation spectroscopy; Cerebral blood flow; Xenon CT; Neurocritical care

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