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1.  Wnt-Responsive Cancer Stem Cells Are Located Close to Distorted Blood Vessels and Not in Hypoxic Regions in a p53-Null Mouse Model of Human Breast Cancer 
High-resolution imaging techniques were used to analyze the relationship between a Wnt-responsive cancer stem cell (CSC)-enriched population and the tumor vasculature using p53-null mouse mammary tumors transduced with a Wnt signaling pathway reporter. The results demonstrate that the combined strategy of monitoring the fluorescently labeled CSCs and vasculature using high-resolution imaging techniques provides a unique opportunity to study the CSC microenvironment.
Cancer stem cells (CSCs, or tumor-initiating cells) may be responsible for tumor formation in many types of cancer, including breast cancer. Using high-resolution imaging techniques, we analyzed the relationship between a Wnt-responsive, CSC-enriched population and the tumor vasculature using p53-null mouse mammary tumors transduced with a lentiviral Wnt signaling reporter. Consistent with their localization in the normal mammary gland, Wnt-responsive cells in tumors were enriched in the basal/myoepithelial population and generally located in close proximity to blood vessels. The Wnt-responsive CSCs did not colocalize with the hypoxia-inducible factor 1α-positive cells in these p53-null basal-like tumors. Average vessel diameter and vessel tortuosity were increased in p53-null mouse tumors, as well as in a human tumor xenograft as compared with the normal mammary gland. The combined strategy of monitoring the fluorescently labeled CSCs and vasculature using high-resolution imaging techniques provides a unique opportunity to study the CSC and its surrounding vasculature.
doi:10.5966/sctm.2013-0088
PMCID: PMC4073819  PMID: 24797826
Cancer stem cells; Stem cell microenvironment; In vivo optical imaging; Microvasculature; Signal transduction; p53
2.  Robust 3D Reconstruction and Identification of Dendritic Spines from Optical Microscopy Imaging 
Medical image analysis  2008;13(1):167-179.
In neuro-biology, the 3D reconstruction of neurons followed by the identification of dendritic spines is essential for studying neuronal morphology, function and biophysical properties. Most existing methods suffer from problems of low reliability, poor accuracy and require much user interaction. In this paper, we present a method to reconstruct dendrites using a surface representation of the neuron. The skeleton of the dendrite is extracted by a procedure based on the medial geodesic function that is robust and topologically correct, and it is used to accurately identify spines. The sensitivity of the algorithm on the various parameters is explored in detail and the method is shown to be robust.
doi:10.1016/j.media.2008.06.019
PMCID: PMC2663851  PMID: 18819835
Neuron; dendrite; spine; 3D reconstruction; curve-skeleton; medial geodesic function
3.  DrugComboRanker: drug combination discovery based on target network analysis 
Bioinformatics  2014;30(12):i228-i236.
Motivation: Currently there are no curative anticancer drugs, and drug resistance is often acquired after drug treatment. One of the reasons is that cancers are complex diseases, regulated by multiple signaling pathways and cross talks among the pathways. It is expected that drug combinations can reduce drug resistance and improve patients’ outcomes. In clinical practice, the ideal and feasible drug combinations are combinations of existing Food and Drug Administration-approved drugs or bioactive compounds that are already used on patients or have entered clinical trials and passed safety tests. These drug combinations could directly be used on patients with less concern of toxic effects. However, there is so far no effective computational approach to search effective drug combinations from the enormous number of possibilities.
Results: In this study, we propose a novel systematic computational tool DrugComboRanker to prioritize synergistic drug combinations and uncover their mechanisms of action. We first build a drug functional network based on their genomic profiles, and partition the network into numerous drug network communities by using a Bayesian non-negative matrix factorization approach. As drugs within overlapping community share common mechanisms of action, we next uncover potential targets of drugs by applying a recommendation system on drug communities. We meanwhile build disease-specific signaling networks based on patients’ genomic profiles and interactome data. We then identify drug combinations by searching drugs whose targets are enriched in the complementary signaling modules of the disease signaling network. The novel method was evaluated on lung adenocarcinoma and endocrine receptor positive breast cancer, and compared with other drug combination approaches. These case studies discovered a set of effective drug combinations top ranked in our prediction list, and mapped the drug targets on the disease signaling network to highlight the mechanisms of action of the drug combinations.
Availability and implementation: The program is available on request.
Contact: stwong@tmhs.org
doi:10.1093/bioinformatics/btu278
PMCID: PMC4058933  PMID: 24931988
4.  A Screen for Morphological Complexity Identifies Regulators of Switch-like Transitions between Discrete Cell Shapes 
Nature cell biology  2013;15(7):860-871.
The way in which cells adopt different morphologies is not fully understood. Cell shape could be a continuous variable or restricted to a set of discrete forms. We developed quantitative methods to describe cell shape and show that Drosophila hemocytes in culture are a heterogeneous mixture of five discrete morphologies. In an RNAi screen of genes affecting the morphological complexity of heterogeneous populations, we found that most genes regulate the transition between discrete shapes rather than generating new morphologies. In particular, we identified a subset of genes, including the tumour suppressor PTEN, that decrease the heterogeneity of the population leading to populations enriched in rounded or elongated forms. We show that these genes have a highly conserved function as regulators of cell shape in both mouse and human metastatic melanoma cells.
doi:10.1038/ncb2764
PMCID: PMC3712499  PMID: 23748611
5.  Activation of the Inflammasome and Enhanced Migration of Microparticle-Stimulated Dendritic Cells to the Draining Lymph Node 
Molecular pharmaceutics  2012;9(7):2049-2062.
Porous silicon microparticles presenting pathogen-associated molecular patterns mimic pathogens, enhancing internalization of the microparticles and activation of antigen presenting dendritic cells. We demonstrate abundant uptake of microparticles bound by the TLR-4 ligands LPS and MPL by murine bone marrow-derived dendritic cells (BMDC). Labeled microparticles induce concentration-dependent production of IL-1β, with inhibition by the caspase inhibitor Z-VAD-FMK supporting activation of the NLRP3-dependent inflammasome. Inoculation of BALB/c mice with ligand-bound microparticles induces a significant increase in circulating levels of IL-1β, TNF-α, and IL-6. Stimulation of BMDC with ligand-bound microparticles increases surface expression of co-stimulatory and MHC molecules, and enhances migration of BMDC to the draining lymph node. LPS-microparticles stimulate in vivo C57BL/6 BMDC and OT-1 transgenic T cell interactions in the presence of OVA SIINFEKL peptide in lymph nodes, with intact nodes imaged using two-photon microscopy. Formation of in vivo and in vitro immunological synapses between BMDC, loaded with OVA peptide and LPS-microparticles, and OT-1 T cells are presented, as well as elevated intracellular interferon gamma levels in CD8+ T cells stimulated by BMDC carrying peptide-loaded microparticles. In short, ligand-bound microparticles enhance 1) phagocytosis of microparticles; 2) BMDC inflammasome activation and up-regulation of co-stimulatory and MHC molecules; 3) cellular migration of BMDC to lymphatic tissue; and 4) cellular interactions leading to T cell activation in the presence of antigen.
doi:10.1021/mp3001292
PMCID: PMC3524399  PMID: 22680980
microparticle; vaccine; dendritic cell; migration; phagocytosis; atomic force microscopy; LPS; monophosphoryl lipid A
6.  Multimodal non-linear optical imaging for label-free differentiation of lung cancerous lesions from normal and desmoplastic tissues 
Biomedical Optics Express  2013;4(12):2855-2868.
Lung carcinoma is the leading cause of cancer-related death in the United States, and non-small cell carcinoma accounts for 85% of all lung cancer cases. One major characteristic of non-small cell carcinoma is the appearance of desmoplasia and deposition of dense extracellular collagen around the tumor. The desmoplastic response provides a radiologic target but may impair sampling during traditional image-guided needle biopsy and is difficult to differentiate from normal tissues using single label free imaging modality; for translational purposes, label-free techniques provide a more promising route to clinics. We thus investigated the potential of using multimodal, label free optical microscopy that incorporates Coherent Anti-Stokes Raman Scattering (CARS), Two-Photon Excited AutoFluorescence (TPEAF), and Second Harmonic Generation (SHG) techniques for differentiating lung cancer from normal and desmoplastic tissues. Lung tissue samples from patients were imaged using CARS, TPEAF, and SHG for comparison and showed that the combination of the three non-linear optics techniques is essential for attaining reliable differentiation. These images also illustrated good pathological correlation with hematoxylin and eosin (H&E) stained sections from the same tissue samples. Automated image analysis algorithms were developed for quantitative segmentation and feature extraction to enable lung tissue differentiation. Our results indicate that coupled with automated morphology analysis, the proposed tri-modal nonlinear optical imaging technique potentially offers a powerful translational strategy to differentiate cancer lesions reliably from surrounding non-tumor and desmoplastic tissues.
doi:10.1364/BOE.4.002855
PMCID: PMC3862152  PMID: 24409386
(170.3880) Medical and biological imaging; (300.6230) Spectroscopy, coherent anti-Stokes Raman scattering; (170.2520) Fluorescence microscopy; (270.4180) Multiphoton processes; (170.4580) Optical diagnostics for medicine; (190.1900) Diagnostic applications of nonlinear optics
7.  Activation of the ATM-Snail pathway promotes breast cancer metastasis 
The DNA damage response (DDR) is critical for the maintenance of genetic stability and serves as an anti-cancer barrier during early tumorigenesis. However, the role of the DDR in tumor progression and metastasis is less known. Here, we demonstrate that the ATM kinase, one of the critical DDR elements, is hyperactive in late stage breast tumor tissues with lymph-node metastasis and this hyperactivity correlates with elevated expression of the epithelial–mesenchymal transition marker, Snail. At the molecular level, we demonstrate that ATM regulates Snail stabilization by phosphorylation on Serine-100. Using mass spectrometry, we identified HSP90 as a critical binding protein of Snail in response to DNA damage. HSP90 binds to and stabilizes phosphorylated Snail. We further provide in vitro and in vivo evidence that activation of ATM-mediated Snail phosphorylation promotes tumor invasion and metastasis. Finally, we demonstrate that Snail Serine-100 phosphorylation is elevated in breast cancer tissues with lymph-node metastasis, indicating clinical significance of the ATM-Snail pathway. Together, our findings provide strong evidence that the ATM-Snail pathway promotes tumor metastasis, highlighting a previously undescribed role of the DDR in tumor invasion and metastasis.
doi:10.1093/jmcb/mjs048
PMCID: PMC3464396  PMID: 22923499
ATM; snail; metastasis
8.  A quantitative analytic pipeline for evaluating neuronal activities by high throughput synaptic vesicle imaging 
NeuroImage  2012;62(3):2040-2054.
Synaptic vesicle dynamics play an important role in the study of neuronal and synaptic activities of neurodegradation diseases ranging from the epidemic Alzheimer’s disease to the rare Rett syndrome. A high-throughput assay with a large population of neurons would be useful and efficient to characterize neuronal activity based on the dynamics of synaptic vesicles for the study of mechanisms or to discover drug candidates for neurodegenerative and neurodevelopmental disorders. However, the massive amounts of image data generated via high throughput screening require enormous manual processing time and effort, restricting the practical use of such an assay. This paper presents an automated analytic system to process and interpret the huge data set generated by such assays. Our system enables the automated detection, segmentation, quantification, and measurement of neuron activities based on the synaptic vesicle assay. To overcome challenges such as noisy background, inhomogeneity, and tiny object size, we first employ MSVST (Multi-Scale Variance Stabilizing Transform) to obtain a denoised and enhanced map of the original image data. Then, we propose an adaptive thresholding strategy to solve the inhomogeneity issue, based on the local information, and to accurately segment synaptic vesicles. We design algorithms to address the issue of tiny objects-of-interest overlapping. Several post-processing criteria are defined to filter false positives. A total of 152 features are extracted for each detected vesicle. A score is defined for each synaptic vesicle image to quantify the neuron activity. We also compare the unsupervised strategy with the supervised method. Our experiments on hippocampal neuron assays showed that the proposed system can automatically detect vesicles and quantify their dynamics for evaluating neuron activities. The availability of such an automated system will open opportunities for investigation of synaptic neuropathology and identification of candidate therapeutics for neurodegeneration.
doi:10.1016/j.neuroimage.2012.06.020
PMCID: PMC3437259  PMID: 22732566
synaptic vesicle; neuron activity; detection and quantification; neurodegenerative disease; high throughput image screening
9.  The kinetochore protein Bub1 participates in the DNA damage response 
DNA repair  2011;11(2):185-191.
The DNA damage response (DDR) and the spindle assembly checkpoint (SAC) are two critical mechanisms by which mammalian cells maintain genome stability. There is a growing body of evidence that DDR elements and SAC components crosstalk. Here we report that Bub1 (Budding Uninhibited by Benzimidazoles 1), one of the critical kinetochore proteins essential for SAC, is required for optimal DDRs. We found that knocking-down Bub1 resulted in prolonged H2AX foci and comet tail formation as well as hypersensitivity in response to ionizing radiation (IR). Further, we found that Bub1-mediated Histone H2A Threonine 121 phosphorylation was induced after IR in an ATM-dependent manner. We demonstrated that ATM phosphorylated Bub1 on serine 314 in response to DNA damage in vivo. Finally, we showed that ATM-mediated Bub1 serine 314 phosphorylation was required for IR-induced Bub1 activation and for the optimal DDR. Together, we elucidate the molecular mechanism of DNA damage-induced Bub1 activation and highlight a critical role of Bub1 in DDR.
doi:10.1016/j.dnarep.2011.10.018
PMCID: PMC3758123  PMID: 22071147
ATM; Bub1; DNA damage response
10.  Brain tissue segmentation based on DTI data 
NeuroImage  2007;38(1):114-123.
We present a method for automated brain tissue segmentation based on the multi-channel fusion of diffusion tensor imaging (DTI) data. The method is motivated by the evidence that independent tissue segmentation based on DTI parametric images provides complementary information of tissue contrast to the tissue segmentation based on structural MRI data. This has important applications in defining accurate tissue maps when fusing structural data with diffusion data. In the absence of structural data, tissue segmentation based on DTI data provides an alternative means to obtain brain tissue segmentation. Our approach to the tissue segmentation based on DTI data is to classify the brain into two compartments by utilizing the tissue contrast existing in a single channel. Specifically, because the apparent diffusion coefficient (ADC) values in the cerebrospinal fluid (CSF) are more than twice that of gray matter (GM) and white matter (WM), we use ADC images to distinguish CSF and non-CSF tissues. Additionally, fractional anisotropy (FA) images are used to separate WM from non-WM tissues, as highly directional white matter structures have much larger fractional anisotropy values. Moreover, other channels to separate tissue are explored, such as eigenvalues of the tensor, relative anisotropy (RA), and volume ratio (VR). We developed an approach based on the Simultaneous Truth and Performance Level Estimation (STAPLE) algorithm that combines these two-class maps to obtain a complete tissue segmentation map of CSF, GM, and WM. Evaluations are provided to demonstrate the performance of our approach. Experimental results of applying this approach to brain tissue segmentation and deformable registration of DTI data and spoiled gradient-echo (SPGR) data are also provided.
doi:10.1016/j.neuroimage.2007.07.002
PMCID: PMC2430665  PMID: 17804258
11.  A novel method of transcriptional response analysis to facilitate drug repositioning for cancer therapy 
Cancer research  2011;72(1):33-44.
Little research has been done to address the huge opportunities that may exist to reposition existing approved or generic drugs for alternate uses in cancer therapy. Additionally, there has been little work on strategies to reposition experimental cancer agents for testing in alternate settings that could shorten their clinical development time. Progress in each area has lagged in part due to the lack of systematic methods to define drug off-target effects (OTEs) that might affect important cancer cell signaling pathways. In this study, we addressed this critical gap by developing an OTE-based method to repurpose drugs for cancer therapeutics, based on transcriptional responses made in cells before and after drug treatment. Specifically, we defined a new network component called cancer-signaling bridges (CSBs) and integrated it with Bayesian Factor Regression Model (BFRM) to form a new hybrid method termed CSB-BFRM. Proof of concept studies were performed in breast and prostate cancer cells and in promyelocytic leukemia cells. In each system, CSB-BFRM analysis could accurately predict clinical responses to >90% of FDA-approved drugs and >75% of experimental clinical drugs that were tested. Mechanistic investigation of OTEs for several high-ranking drug-dose pairs suggested repositioning opportunities for cancer therapy, based on the ability to enforce Rb-dependent repression of important E2F-dependent cell cycle genes. Together, our findings establish new methods to identify opportunities for drug repositioning or to elucidate the mechanisms of action of repositioned drugs.
doi:10.1158/0008-5472.CAN-11-2333
PMCID: PMC3251651  PMID: 22108825
Off-target drug repositioning; cancer systems biology; cancer transcriptional response
12.  Aurora-B Mediated ATM Serine 1403 Phosphorylation Is Required For Mitotic ATM Activation and the Spindle Checkpoint 
Molecular cell  2011;44(4):597-608.
Summary
The ATM kinase plays a critical role in the maintenance of genetic stability. ATM is activated in response to DNA damage and is essential for cell cycle checkpoints. Here, we report that ATM is activated in mitosis in the absence of DNA damage. We demonstrate that mitotic ATM activation is dependent on the Aurora-B kinase and that Aurora-B phosphorylates ATM on serine 1403. This phosphorylation event is required for mitotic ATM activation. Further, we show that loss of ATM function results in shortened mitotic timing and a defective spindle checkpoint, and that abrogation of ATM Ser1403 phosphorylation leads to this spindle checkpoint defect. We also demonstrate that mitotically-activated ATM phosphorylates Bub1, a critical kinetochore protein, on Ser314. ATM-mediated Bub1 Ser314 phosphorylation is required for Bub1 activity and is essential for the activation of the spindle checkpoint. Collectively, our data highlight mechanisms of a critical function of ATM in mitosis.
doi:10.1016/j.molcel.2011.09.016
PMCID: PMC3228519  PMID: 22099307
13.  Diffusion Tensor-Based Fast Marching for Modeling Human Brain Connectivity Network 
Diffusion tensor imaging (DTI) is an effective modality in studying the connectivity of the brain. To eliminate possible biases caused by fiber extraction approaches due to low spatial resolution of DTI and the number of fibers obtained, the fast marching (FM) algorithm based on the whole diffusion tensor information is proposed to model and study the brain connectivity network. Our observation is that the connectivity extracted from the whole tensor field would be more robust and reliable for constructing brain connectivity network using DTI data. To construct the connectivity network, in this paper, the arrival time map and the velocity map generated by the FM algorithm are combined to define the connectivity strength among different brain regions. The conventional fiber tracking-based and the proposed tensor-based FM connectivity methods are compared, and the results indicate that the connectivity features obtained using the FM-based method agree better with the neuromorphical studies of the human brain.
doi:10.1016/j.compmedimag.2010.07.008
PMCID: PMC3058145  PMID: 21035304
diffusion tensor imaging; fast marching; brain connectivity analysis; fiber tracking; tractography
14.  A computational framework for studying neuron morphology from in vitro high content neuron-based screening 
Journal of neuroscience methods  2010;190(2):299-309.
High content neuron image processing is considered as an important method for quantitative neurobiological studies. The main goal of analysis in this paper is to provide automatic image processing approaches to process neuron images for studying neuron mechanism in high content screening. In the nuclei channel, all nuclei are segmented and detected by applying the gradient vector field based watershed. Then the neuronal nuclei are selected based on the soma region detected in neurite channel. In neurite images, we propose a novel neurite centerline extraction approach using the improved line-pixel detection technique. The proposed neurite tracing method can detect the curvilinear structure more accurately compared with the current existing methods. An interface called NeuriteIQ based on the proposed algorithms is developed finally for better application in high content screening.
doi:10.1016/j.jneumeth.2010.05.012
PMCID: PMC3184395  PMID: 20580743
High content screening; Microscopy image; Nuclei segmentation; Neurite outgrowth; Line-pixel detection; Branch area
15.  ONLINE THREE-DIMENSIONAL DENDRITIC SPINES MOPHOLOGICAL CLASSIFICATION BASED ON SEMI-SUPERVISED LEARNING 
Recent studies on neuron imaging show that there is a strong relationship between the functional properties of a neuron and its morphology, especially its dendritic spine structures. However, most of the current methods for morphological spine classification only concern features in two-dimensional (2D) space, which consequently decreases the accuracy of dendritic spine analysis. In this paper, we propose a semi-supervised learning (SSL) framework, in which spine phenotypes in three-dimensional (3D) space are considered. With training only on a few pre-classified inputs, the rest of the spines can be identified effectively. We also derived a new scheme using an affinity matrix between features to further improve the accuracy. Our experimental results indicate that a small training dataset is sufficient to classify detected dendritic spines.
doi:10.1109/ISBI.2009.5193228
PMCID: PMC3171508  PMID: 21922077
dendritic spine; semi-supervised learning; morphological spine classification
16.  An Image Driven Systems Biology Approach for Neurodegenerative Disease Studies in the TSC-mTOR Pathway 
In this brief paper we present an overview of the TSC-mTOR pathway and its importance in neurodegenerative disease (ND). We illustrate the influence of ND on dendritic spine morphology. Then we discuss some details of functional gene networks (FGN) and use this information to propose an image driven systems biology approach for the construction of a FGN for ND. We conclude on its importance and the prospective outcome of our study.
doi:10.1109/LISSA.2009.4906703
PMCID: PMC3171509  PMID: 21922078
17.  Bioluminescence Imaging of Heme Oxygenase-1 Upregulation in the Gua Sha Procedure 
Gua Sha is a traditional Chinese folk therapy that employs skin scraping to cause subcutaneous microvascular blood extravasation and bruises. The protocol for bioluminescent optical imaging of HO-1-luciferase transgenic mice reported in this manuscript provides a rapid in vivo assay of the upregulation of the heme oxygenase-1 (HO-1) gene expression in response to the Gua Sha procedure. HO-1 has long been known to provide cytoprotection against oxidative stress. The upregulation of HO-1, assessed by the bioluminescence output, is thought to represent an antioxidative response to circulating hemoglobin products released by Gua Sha. Gua Sha was administered by repeated strokes of a smooth spoon edge over lubricated skin on the back or other targeted body part of the transgenic mouse until petechiae (splinter hemorrhages) or ecchymosis (bruises) indicative of extravasation of blood from subcutaneous capillaries was observed. After Gua Sha, bioluminescence imaging sessions were carried out daily for several days to follow the dynamics of HO-1 expression in multiple internal organs.
doi:10.3791/1385
PMCID: PMC3149908  PMID: 19718012
18.  A Local Fast Marching-Based Diffusion Tensor Image Registration Algorithm by Simultaneously Considering Spatial Deformation and Tensor Orientation 
NeuroImage  2010;52(1):119-130.
It is a key step to spatially align diffusion tensor images (DTI) to quantitatively compare neural images obtained from different subjects or the same subject at different timepoints. Different from traditional scalar or multi-channel image registration methods, tensor orientation should be considered in DTI registration. Recently, several DTI registration methods have been proposed in the literature, but deformation fields are purely dependent on the tensor features not the whole tensor information. Other methods, such as the piece-wise affine transformation and the diffeomorphic non-linear registration algorithms, use analytical gradients of the registration objective functions by simultaneously considering the reorientation and deformation of tensors during the registration. However, only relatively local tensor information such as voxel-wise tensor-similarity, is utilized. This paper proposes a new DTI image registration algorithm, called local fast marching (FM)-based simultaneous registration. The algorithm not only considers the orientation of tensors during registration but also utilizes the neighborhood tensor information of each voxel to drive the deformation, and such neighborhood tensor information is extracted from a local fast marching algorithm around the voxels of interest. These local fast marching-based tensor features efficiently reflect the diffusion patterns around each voxel within a spherical neighborhood and can capture relatively distinctive features of the anatomical structures. Using simulated and real DTI human brain data the experimental results show that the proposed algorithm is more accurate compared with the FA-based registration and is more efficient than its counterpart, the neighborhood tensor similarity-based registration.
doi:10.1016/j.neuroimage.2010.04.004
PMCID: PMC2883676  PMID: 20382233
Diffusion tensor imaging; image registration; tensor reorientation; fast marching
19.  A Neurocomputational Method for Fully Automated 3D Dendritic Spine Detection and Segmentation of Medium-sized Spiny Neurons 
NeuroImage  2010;50(4):1472-1484.
Acquisition and quantitative analysis of high resolution images of dendritic spines are challenging tasks but are necessary for the study of animal models of neurological and psychiatric diseases. Currently available methods for automated dendritic spine detection are for the most part customized for 2D image slices, not volumetric 3D images. In this work, a fully automated method is proposed to detect and segment dendritic spines from 3D confocal microscopy images of medium-sized spiny neurons (MSNs). MSNs constitute a major neuronal population in striatum, and abnormalities in their function are associated with several neurological and psychiatric diseases. Such automated detection is critical for the development of new 3D neuronal assays which can be used for the screening of drugs and the studies of their therapeutic effects. The proposed method utilizes a generalized gradient vector flow (GGVF) with a new smoothing constraint and then detects feature points near the central regions of dendrites and spines. Then, the central regions are refined and separated based on eigen-analysis and multiple shape measurements. Finally, the spines are segmented in 3D space using the fast marching algorithm, taking the detected central regions of spines as initial points. The proposed method is compared with three popular existing methods for centerline extraction and also with manual results for dendritic spine detection in 3D space. The experimental results and comparisons show that the proposed method is able to automatically and accurately detect, segment, and quantitate dendritic spines in 3D images of MSNs.
doi:10.1016/j.neuroimage.2010.01.048
PMCID: PMC2839064  PMID: 20100579
dendritic spine; confocal microscopy image; central region extraction; gradient vector flow; fast marching; neurological disease; psychiatric disease
20.  Computer-Assisted Quantitative Evaluation of Therapeutic Responses for Lymphoma Using Serial PET/CT Imaging 
Academic radiology  2010;17(4):479-488.
Rationale and Objectives
Molecular imaging modalities such as PET/CT have emerged as an essential diagnostic tool for monitoring treatment response in lymphoma patients. However, quantitative assessment of treatment outcomes from serial scans is often difficult, laborious, and time consuming. Automatic quantization of longitudinal PET/CT scans provides more efficient and comprehensive quantitative evaluation of cancer therapeutic responses. This study develops and validates a Longitudinal Image Navigation and Analysis (LINA) system for this quantitative imaging application.
Materials and Methods
LINA is designed to automatically construct longitudinal correspondence along serial images of individual patients for changes in tumor volume and metabolic activity via regions of interest (ROI) segmented from a given time-point image and propagated into the space of all follow-up PET/CT images. We applied LINA retrospectively to nine lymphoma patients enrolled in an immunotherapy clinical trial conducted at the Center for Cell and Gene Therapy, Baylor College of Medicine. This methodology was compared to the readout by a diagnostic radiologist, who manually measured the ROI metabolic activity as defined by the maximal Standardized Uptake Value (SUVmax).
Results
Quantitative results showed that the measured SUVs obtained from automatic mapping are as accurate as semi-automatic segmentation and consistent with clinical examination finding. The average of relative squared differences of SUVmax between automatic and semi-automatic segmentation was found to be 0.02.
Conclusion
These data support a role for LINA in facilitating quantitative analysis of serial PET/CT images to efficiently assess cancer treatment responses in a comprehensive and intuitive software platform.
doi:10.1016/j.acra.2009.10.026
PMCID: PMC2846835  PMID: 20060747
Lymphoma; quantitative evaluation of treatment outcomes; PET/CT; longitudinal registration of serial images
21.  Joint Registration and Segmentation of Serial Lung CT Images for Image-Guided Lung Cancer Diagnosis and Therapy 
In image-guided diagnosis and treatment of small peripheral lung lesions the alignment of the pre-procedural lung CT images and the intra-procedural images is an important step to accurately guide and monitor the interventional procedure. Registering the serial images often relies on correct segmentation of the images and, on the other hand, the segmentation results can be further improved by temporal alignment of the serial images. This paper presents a joint serial image registration and segmentation algorithm. In this algorithm, serial images are segmented based on the current deformations, and the deformations among the serial images are iteratively refined based on the updated segmentation results. No temporal smoothness about the deformation fields is enforced so that the algorithm can tolerate larger or discontinuous temporal changes that often appear during image-guided therapy. Physical procedure models could also be incorporated to our framework to better handle the temporal changes of the serial images during intervention. In experiments, we apply the proposed algorithm to align serial lung CT images. Results using both simulated and clinical images show that the new algorithm is more robust compared to the method that only uses deformable registration.
doi:10.1016/j.compmedimag.2009.05.007
PMCID: PMC2818020  PMID: 19709855
22.  A Novel Peak Detection Approach with Chemical Noise Removal Using Short-Time FFT for prOTOF MS Data 
Proteomics  2009;9(15):3833-3842.
Peak detection is a pivotal first step in biomarker discovery from mass spectrometry (MS) data and can significantly influence the results of downstream data analysis steps. We developed a novel automatic peak detection method for prOTOF MS data which does not require a priori knowledge of protein masses. Random noise is removed by an undecimated wavelet transform and chemical noise is attenuated by an adaptive short-time discrete Fourier transform. Isotopic peaks corresponding to a single protein are combined by extracting an envelope over them. Depending on the signal-to-noise ratio (SNR), the desired peaks in each individual spectrum are detected and those with the highest intensity among their peak clusters are recorded. The common peaks among all the spectra are identified by choosing an appropriate cut-off threshold in the complete linkage hierarchical clustering. To remove the 1Da shifting of the peaks, the peak corresponding to the same protein is determined as the detected peak with the largest number among its neighborhood. We validated this method using a dataset of serial peptide and protein calibration standards. Compared with MoverZ program, our new method detects more peaks and significantly enhances SNR of the peak after the chemical noise removal. We then successfully applied this method to a dataset from prOTOF MS spectra of albumin and albumin-bound proteins from serum samples of 59 patients with carotid artery disease to detect peaks with SNR ≥2. Our method is easily implemented and is highly effective to define peaks that will be used for disease classification or to highlight potential biomarkers.
doi:10.1002/pmic.200800030
PMCID: PMC2782493  PMID: 19681055
adaptive short-time discrete Fourier transform; complete linkage hierarchical clustering; peak detection; peak alignment; nudecimated wavelet transform
23.  Cell Segmentation Using Front Vector Flow Guided Active Contours 
Phase-contrast microscopy is a common approach for studying the dynamics of cell behaviors, such as cell migration. Cell segmentation is the basis of quantitative analysis of the immense cellular images. However, the complicated cell morphological appearance in phase-contrast microscopy images challenges the existing segmentation methods. This paper proposes a new cell segmentation method for cancer cell migration studies using phase-contrast images. Instead of segmenting cells directly based on commonly used low-level features, e.g. intensity and gradient, we first identify the leading protrusions, a high level feature, of cancer cells. Based on the identified cell leading protrusions, we introduce a front vector flow guided active contour, which guides the initial cell boundaries to the real boundaries. The experimental validation on a set of breast cancer cell images shows that the proposed method demonstrates fast, stable, and accurate segmentation for breast cancer cells with wide range of sizes and shapes.
PMCID: PMC2896022  PMID: 20426162
24.  A Confident Scale-Space Shape Representation Framework for Cell Migration Detection 
Journal of microscopy  2008;231(3):395-407.
SUMMARY
Automated segmentation of time-lapse images is a method to facilitate the understanding of the intricate biological progression, e.g., cancer cell migration. To address this problem, we introduce a shape representation enhancement over popular snake models in the context of confident scale-space such that a higher level of interpretation can hopefully be achieved. Our proposed system consists of a hierarchical analytic framework including feedback loops, self-adaptive and demand-adaptive adjustment, incorporating a steerable boundary detail term constraint based on multiscale B-spline interpolation. To minimize the noise interference inherited from microscopy acquisition, the coarse boundary derived from the initial segmentation with refined watershed line is coupled with microscopy compensation using the mean shift filtering. A progressive approximation is applied to achieve represented as a balance between a relief function of watershed algorithm and local minima concerning multi-scale optimality, convergence, and robust constraints. Experimental results show that the proposed method overcomes problems with spurious branches, arbitrary gaps, low contrast boundaries and low signal-to-noise ratio. The proposed system has the potential to serve as an automated data processing tool for cell migration applications.
doi:10.1111/j.1365-2818.2008.02050.x
PMCID: PMC2896032  PMID: 18754994
cellular image segmentation; 3T3 cell; time-lapse microscopy; snake model; multiscale detail detection; mean shift filtering
25.  INTEGRATING MULTI-SCALE BLOB/CURVILINEAR DETECTOR TECHNIQUES AND MULTI-LEVEL SETS FOR AUTOMATED SEGMENTATION OF STEM CELL IMAGES 
Studies of differentiation abilities of stem cells have been attracting a lot of attention over the last years. Microscopy can be used to record details of the differentiation process of stem cells under different perturbations and is an important tool for studying stem cell differentiation. Since it is infeasible to quantitatively analyze a huge amount of image data manually, automated image analysis systems are urgently needed. However, the complicated morphological appearances of stem cells are challenging to the existing segmentation methods. Herein, we propose a new, automated scheme for stem cell segmentation. This scheme first uses the multi-scale blob and curvilinear structure detectors to delineate the skeletons of stem cells quickly and then segment out stem cells by refining the skeletons to the cell boundaries using multi-level sets. The initial experimental results indicate the effectiveness of the proposed scheme.
doi:10.1109/ISBI.2009.5193318
PMCID: PMC2888517  PMID: 20585412
stem cell differentiation; blob detection; curvilinear structure detection; cell segmentation; level set

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