Digital Commons Network^™

Image Guided Near-Infrared Spectroscopy Of Breast Tissue In Vivo Using Boundary Element Method, Subhadra Srinivasan, Colin M. Carpenter, Hamid R. Ghadyani, Senate J. Taka, Peter A. Kaufman, Roberta M. Diflorio-Alexander, Wendy A. Wells, Brian W. Pogue, Keith D. Paulsen

Dartmouth Scholarship

We demonstrate quantitative functional imaging using image-guided near-infrared spectroscopy (IG-NIRS) implemented with the boundary element method (BEM) for reconstructing 3-D optical property estimates in breast tissue in vivo. A multimodality MRI-NIR system was used to collect measurements of light reflectance from breast tissue. The BEM was used to model light propagation in 3-D based only on surface discretization in order to reconstruct quantitative values of total hemoglobin (HbT), oxygen saturation, water, and scatter. The technique was validated in experimental measurements from heterogeneous breast-shaped phantoms with known values and applied to a total of seven subjects comprising six healthy individuals …

Alterations In Multiple Measures Of White Matter Integrity In Normal Women At High Risk For Alzheimer's Disease, Brian T. Gold, David K. Powell, Anders H. Andersen, Charles D. Smith

Neuroscience Faculty Publications

There is evidence that disruption of white matter (WM) microstructure is an early event in the course of Alzheimer's disease (AD). However, the neurobiological bases of WM microstructural declines in presymptomatic AD are unknown. In the present study we address this issue using a multimodal imaging approach to the study of presymptomatic AD. Participants were 37 high-risk (both family history of dementia and one or more APOE4 alleles) women and 20 low-risk (neither family history nor APOE4) women. Groups were matched for age, education, neuropsychological performance, and vascular factors that could affect white matter. Whole-brain analyses of diffusion tensor imaging …

S100a1: A Multifaceted Therapeutic Target In Cardiovascular Disease., David Rohde, Julia Ritterhoff, Mirko Voelkers, Hugo A Katus, Thomas G Parker, Patrick Most

Department of Medicine Faculty Papers

Cardiovascular disease is the leading cause of death worldwide, showing a dramatically growing prevalence. It is still associated with a poor clinical prognosis, indicating insufficient long-term treatment success of currently available therapeutic strategies. Investigations of the pathomechanisms underlying cardiovascular disorders uncovered the Ca(2+) binding protein S100A1 as a critical regulator of both cardiac performance and vascular biology. In cardiomyocytes, S100A1 was found to interact with both the sarcoplasmic reticulum ATPase (SERCA2a) and the ryanodine receptor 2 (RyR2), resulting in substantially improved Ca(2+) handling and contractile performance. Additionally, S100A1 has been described to target the cardiac sarcomere and mitochondria, leading to …

Microrna-21 Dysregulates The Expression Of Mef2c In Neurons In Monkey And Human Siv/Hiv Neurological Disease., Sowmya V. Yelamanchili, A Datta Chaudhuri, L N. Chen, Huangui Xiong, Howard S. Fox

Journal Articles: Pharmacology & Experimental Neuroscience

MicroRNAs (miRNAs) play important roles in regulating a plethora of physiological and pathophysiogical processes including neurodegeneration. In both HIV associated dementia in humans and its monkey model SIV encephalitis we find miR-21, a miRNA largely known for its link to oncogenesis, to be significantly upregulated in the brain. In situ hybridization of the diseased brain sections revealed induction of miR-21 in neurons. MiR-21 can be induced in neurons by prolonged N-methyl-D-aspartic acid receptor stimulation, an excitotoxic process active in HIV and other neurodegenerative diseases. Introduction of miR-21 into human neurons leads to pathological functional defects. Furthermore, we show that miR-21 …

Identification Of Thioaptamer Ligand Against E-Selectin: Potential Application For Inflamed Vasculature Targeting., Aman P Mann, Anoma Somasunderam, René Nieves-Alicea, Xin Li, Austin Hu, Anil K Sood, Mauro Ferrari, David G Gorenstein, Takemi Tanaka

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Active targeting of a drug carrier to a specific target site is crucial to provide a safe and efficient delivery of therapeutics and imaging contrast agents. E-selectin expression is induced on the endothelial cell surface of vessels in response to inflammatory stimuli but is absent in the normal vessels. Thus, E-selectin is an attractive molecular target, and high affinity ligands for E-selectin could be powerful tools for the delivery of therapeutics and/or imaging agents to inflamed vessels. In this study, we identified a thiophosphate modified aptamer (thioaptamer, TA) against E-selectin (ESTA-1) by employing a two-step selection strategy: a recombinant protein-based …

Quantitative Imaging Reveals Heterogeneous Growth Dynamics And Treatment-Dependent Residual Tumor Distributions In A Three-Dimensional Ovarian Cancer Model, Jonathan P. Celli, Imran Rizvi, Conor L. Evans, Adnan O. Abu-Yousif, Tayyaba Hasan

Dartmouth Scholarship

Three-dimensional tumor models have emerged as valuable in vitro research tools, though the power of such systems as quantitative reporters of tumor growth and treatment response has not been adequately explored. We introduce an approach combining a 3-D model of disseminated ovarian cancer with high-throughput processing of image data for quantification of growth characteristics and cytotoxic response. We developed custom MATLAB routines to analyze longitudinally acquired dark-field microscopy images containing thousands of 3-D nodules. These data reveal a reproducible bimodal log-normal size distribution. Growth behavior is driven by migration and assembly, causing an exponential decay in spatial density concomitant with …

Comparing Implementations Of Magnetic-Resonance-Guided Fluorescence Molecular Tomography For Diagnostic Classification Of Brain Tumors, Scott C. Davis, Kimberley S. Samkoe, Julia A. O’Hara, Summer L. Gibbs-Strauss, Keith D. Paulsen, Brian W. Pogue

Dartmouth Scholarship

Fluorescence molecular tomography (FMT) systems coupled to conventional imaging modalities such as magnetic resonance imaging (MRI) and computed tomography provide unique opportunities to combine data sets and improve image quality and content. Yet, the ideal approach to combine these complementary data is still not obvious. This preclinical study compares several methods for incorporating MRI spatial prior information into FMT imaging algorithms in the context of in vivo tissue diagnosis. Populations of mice inoculated with brain tumors that expressed either high or low levels of epidermal growth factor receptor (EGFR) were imaged using an EGF-bound near-infrared dye and a spectrometer-based MRI-FMT …

Noninvasive Fluorescence Monitoring Of Protoporphyrin Ix Production And Clinical Outcomes In Actinic Keratoses Following Short-Contact Application Of 5-Aminolevulinate, Christine B. Warren, Sara Lohser, Lauren C. Wene, Brian W. Pogue, Philip Bailin, Edward Maytin

Dartmouth Scholarship

Topical 5-aminolevulinic acid (ALA) is widely used in photodynamic therapy (PDT) of actinic keratoses (AK), a type of premalignant skin lesion. However, the optimal time between ALA application and exposure to light has not been carefully investigated. Our objective is to study the kinetics of protoporphyrin IX (P_pIX) accumulation in AK after short contact ALA and relate this to erythemal responses. Using a noninvasive dosimeter, P_pIX fluorescence measurements (5 replicates) were taken at 20-min intervals for 2 h following ALA application, in 63 AK in 20 patients. Data were analyzed for maximal fluorescent signal obtained, kinetic …

Event Study Method For Validating Agent-Based Trading Simulations, Shih-Fen Cheng

Research Collection School Of Computing and Information Systems

In this paper, we introduce how one can validate an event-centric trading simulation platform that is built with multi-agent technology. The issue of validation is extremely important for agent-based simulations, but unfortunately, so far there is no one universal method that would work in all domains. The primary contribution of this paper is a novel combination of event-centric simulation design and event study approach for market dynamics generation and validation. In our event-centric design, the simulation is progressed by announcing news events that affect market prices. Upon receiving these events, event-aware software agents would adjust their views on the market …

Harnessing The Effect Of Adoptively Transferred Tumor-Reactive T Cells On Endogenous (Host-Derived) Antitumor Immunity, Yolanda Nesbeth, Jose R. Conejo-Garcia

Dartmouth Scholarship

Adoptive T cell transfer therapy, the ex vivo activation, expansion, and subsequent administration of tumor-reactive T cells, is already the most effective therapy against certain types of cancer. However, recent evidence in animal models and clinical trials suggests that host conditioning interventions tailored for some of the most aggressive and frequent epithelial cancers will be needed to maximize the benefit of this approach. Similarly, the subsets, stage of differentiation, and ex vivo expansion procedure of tumor-reactive T cells to be adoptively transferred influence their in vivo effectiveness and may need to be adapted for different types of cancer and host …

Cross-Reactivity Of Antibodies Against Leptospiral Recurrent Uveitis-Associated Proteins A And B (Lrua And Lrub) With Eye Proteins, Ashutosh Verma, Pawan Kumar, Kelly Babb, John F. Timoney, Brian Stevenson

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Infection by Leptospira interrogans has been causally associated with human and equine uveitis. Studies in our laboratories have demonstrated that leptospiral lipoprotein LruA and LruB are expressed in the eyes of uveitic horses, and that antibodies directed against LruA and LruB react with equine lenticular and retinal extracts, respectively. These reactivities were investigated further by performing immunofluorescent assays on lenticular and retinal tissue sections. Incubation of lens tissue sections with LruA-antiserum and retinal sections with LruB-antiserum resulted in positive fluorescence. By employing two-dimensional gel analyses followed by immunoblotting and mass spectrometry, lens proteins cross-reacting with LruA antiserum were identified to …

Reverse Engineering Of Oxygen Transport In The Lung: Adaptation To Changing Demands And Resources Through Space-Filling Networks, Chen Hou, Stefan Gheorghiu, Virginia H. Huxley, Peter Pfeifer

Biological Sciences Faculty Research & Creative Works

The space-filling fractal network in the human lung creates a remarkable distribution system for gas exchange. Landmark studies have illuminated how the fractal network guarantees minimum energy dissipation, slows air down with minimum hardware, maximizes the gas- exchange surface area, and creates respiratory flexibility between rest and exercise. In this paper, we investigate how the fractal architecture affects oxygen transport and exchange under varying physiological conditions, with respect to performance metrics not previously studied. We present a renormalization treatment of the diffusion-reaction equation which describes how oxygen concentrations drop in the airways as oxygen crosses the alveolar membrane system. The …

Density Estimation And Adaptive Bandwidths: A Primer For Public Health Practitioners, Heather A. Carlos, Xun Shi, James Sargent, Susanne Tanski, Ethan M. Berke

Dartmouth Scholarship

Background: Geographic information systems have advanced the ability to both visualize and analyze point data. While point-based maps can be aggregated to differing areal units and examined at varying resolutions, two problems arise 1) the modifiable areal unit problem and 2) any corresponding data must be available both at the scale of analysis and in the same geographic units. Kernel density estimation (KDE) produces a smooth, continuous surface where each location in the study area is assigned a density value irrespective of arbitrary administrative boundaries. We review KDE, and introduce the technique of utilizing an adaptive bandwidth to address the …

A Biological Global Positioning System: Considerations For Tracking Stem Cell Behaviors In The Whole Body., Shengwen Calvin Li, Lisa May Ling Tachiki, Jane Luo, Brent A Dethlefs, Zhongping Chen, William G Loudon

Department of Stem Cell Biology and Regenerative Medicine Faculty Papers & Presentations

Many recent research studies have proposed stem cell therapy as a treatment for cancer, spinal cord injuries, brain damage, cardiovascular disease, and other conditions. Some of these experimental therapies have been tested in small animals and, in rare cases, in humans. Medical researchers anticipate extensive clinical applications of stem cell therapy in the future. The lack of basic knowledge concerning basic stem cell biology-survival, migration, differentiation, integration in a real time manner when transplanted into damaged CNS remains an absolute bottleneck for attempt to design stem cell therapies for CNS diseases. A major challenge to the development of clinical applied …

Gc-Biased Evolution Near Human Accelerated Regions, Sol Katzman, Andrew D. Kern, Katherine S. Pollard, Sofie R. Salama, David Haussler

Dartmouth Scholarship

Regions of the genome that have been the target of positive selection specifically along the human lineage are of special importance in human biology. We used high throughput sequencing combined with methods to enrich human genomic samples for particular targets to obtain the sequence of 22 chromosomal samples at high depth in 40 kb neighborhoods of 49 previously identified 100–400 bp elements that show evidence for human accelerated evolution. In addition to selection, the pattern of nucleotide substitutions in several of these elements suggested an historical bias favoring the conversion of weak (A or T) alleles into strong (G or …

Mimosa: A System For Minimotif Annotation, Jay Vyas, Ronald J. Nowling, Thomas Meusburger, David P. Sargeant, Krishna Kadaveru, Michael R. Gryk, Vamsi Kundeti, Sanguthevar Rajasekaran, Martin Schiller

Life Sciences Faculty Research

BACKGROUND:

Minimotifs are short peptide sequences within one protein, which are recognized by other proteins or molecules. While there are now several minimotif databases, they are incomplete. There are reports of many minimotifs in the primary literature, which have yet to be annotated, while entirely novel minimotifs continue to be published on a weekly basis. Our recently proposed function and sequence syntax for minimotifs enables us to build a general tool that will facilitate structured annotation and management of minimotif data from the biomedical literature.

RESULTS:

We have built the MimoSA application for minimotif annotation. The application supports management of …

Imaging Targeted-Agent Binding In Vivo With Two Probes, Brian W. Pogue, Kimberley S. Samkoe, Shannon Hextrum, Julia A. O'Hara, Michael Jermyn, Subhadra Srinivasan, Tayyaba Hasan

Dartmouth Scholarship

An approach to quantitatively image targeted-agent binding rate in vivo is demonstrated with dual-probe injection of both targeted and nontargeted fluorescent dyes. Images of a binding rate constant are created that reveal lower than expected uptake of epidermal growth factor in an orthotopic xenograft pancreas tumor (2.3×10−5 s−1), as compared to the normal pancreas (3.4×10−5 s−1). This approach allows noninvasive assessment of tumor receptor targeting in vivo to determine the expected contrast, spatial localization, and efficacy in therapeutic agent delivery.

Targeting therapeutic drugs to tumors based on their overexpression of cellular receptors is widely researched and has important clinical success. …

Inspired Gas-Induced Vascular Change In Tumors With Magnetic-Resonance-Guided Near-Infrared Imaging: Human Breast Pilot Study, Colin M. Carpenter, Rebecca Rakow-Penner, Shudong Jiang, Bruce L. Daniel, Brian W. Pogue, Gary H. Glover, Keith D. Paulsen

Dartmouth Scholarship

This study investigates differences in the response of breast tumor tissue versus healthy fibroglandular tissue to inspired gases. Cycles of carbogen and oxygen gas are administered while measuring the changes with magnetic-resonance-guided near-infrared imaging in a pilot study of breast cancers. For two patients, analyses are performed with cross-correlation techniques, which measure the strength of hemodynamic modulation. The results show that the overall vasoresponse, indicated by total hemoglobin, of healthy tissue has approximately a 72% and 41% greater correlation to the gas stimulus than the tumor region, in two patients respectively, when background physiological changes are controlled. These data support …

Acetylation Of Wrn Protein Regulates Its Stability By Inhibiting Ubiquitination, Kai Li, Rui Wang, Enerlyn Lozada, Wei Fan, David K. Orren, Jianyuan Luo

Toxicology and Cancer Biology Faculty Publications

BACKGROUND: WRN is a multi-functional protein involving DNA replication, recombination and repair. WRN acetylation has been demonstrated playing an important role in response to DNA damage. We previously found that WRN acetylation can regulate its enzymatic activities and nuclear distribution.

METHODOLOGY/PRINCIPAL FINDING: Here, we investigated the factors involved in WRN acetylation and found that CBP and p300 are the only major acetyltransferases for WRN acetylation. We further identified 6 lysine residues in WRN that are subject to acetylation. Interestingly, WRN acetylation can increase its protein stability. SIRT1-mediated deacetylation of WRN reverses this effect. CBP dramatically increases the half-life of wild …

Partitioning Of Minimotifs Based On Function With Improved Prediction Accuracy, Sanguthevar Rajasekaran, Tian Mi, Jerlin Camilus Merlin, Aaron Oommen, Patrick R. Gradie, Martin R. Schiller

Life Sciences Faculty Research

Background

Minimotifs are short contiguous peptide sequences in proteins that are known to have a function in at least one other protein. One of the principal limitations in minimotif prediction is that false positives limit the usefulness of this approach. As a step toward resolving this problem we have built, implemented, and tested a new data-driven algorithm that reduces false-positive predictions.

Methodology/Principal Findings

Certain domains and minimotifs are known to be strongly associated with a known cellular process or molecular function. Therefore, we hypothesized that by restricting minimotif predictions to those where the minimotif containing protein and target protein have …

Microrna-31 Functions As An Oncogenic Microrna In Mouse And Human Lung Cancer Cells By Repressing Specific Tumor Suppressors, Xi Liu, Lorenzo F. Sempere, Haoxu Ouyang, Vincent A. Memoli, Angeline S. Andrew, Yue Luo, Eugene Demidenko, Murray Korc, Wei Shi, Meir Preis, Konstantin H. Dragnev, Hua Li, James Direnzo, Mads Bak, Sarah J. Freemantle, Sakari Kauppinen, Ethan Dmitrovsky

Dartmouth Scholarship

MicroRNAs (miRNAs) regulate gene expression. It has been suggested that obtaining miRNA expression profiles can improve classification, diagnostic, and prognostic information in oncology. Here, we sought to comprehensively identify the miRNAs that are overexpressed in lung cancer by conducting miRNA microarray expression profiling on normal lung versus adjacent lung cancers from transgenic mice. We found that miR-136, miR-376a, and miR-31 were each prominently overexpressed in murine lung cancers. Real-time RT-PCR and in situ hybridization (ISH) assays confirmed these miRNA expression profiles in paired normal-malignant lung tissues from mice and humans. Engineered knockdown of miR-31, but not other highlighted miRNAs, substantially …

Electrically Mediated Delivery Of Plasmid Dna To The Skin, Using A Multielectrode Array, Richard Heller, Yolmari Criz, Loree C. Heller, Richard A. Gilbert, Mark J. Jaroszeski

Bioelectrics Publications

The easy accessibility of skin makes it an excellent target for gene transfer protocols. To take full advantage of skin as a target for gene transfer, it is important to establish an efficient and reproducible delivery system. Electroporation is a strong candidate to meet this delivery criterion. Electroporation of the skin is a simple, direct, in vivo method to deliver genes for therapy. Previously, delivery to the skin was performed by means of applicators with relatively large distances between electrodes, resulting in significant muscle stimulation and pain. These applicators also had limitations in controlling the directionality of the applied field. …

What Is Biomedical Informatics?, Elmer V Bernstam, Jack W Smith, Todd R Johnson

Faculty, Staff and Student Publications

Biomedical informatics lacks a clear and theoretically-grounded definition. Many proposed definitions focus on data, information, and knowledge, but do not provide an adequate definition of these terms. Leveraging insights from the philosophy of information, we define informatics as the science of information, where information is data plus meaning. Biomedical informatics is the science of information as applied to or studied in the context of biomedicine. Defining the object of study of informatics as data plus meaning clearly distinguishes the field from related fields, such as computer science, statistics and biomedicine, which have different objects of study. The emphasis on data …

Myosin Light Chain Kinase Mediates Transcellular Intravasation Of Breast Cancer Cells Through The Underlying Endothelial Cells: A Three-Dimensional Fret Study, S. Khuon, L. Liang, R. W. Dettman, P. H. S. Sporn, R. B. Wysolmerski, T.-L. Chew

Faculty & Staff Scholarship

No abstract provided.

Biological Impact Of Geometric Uncertainties: What Margin Is Needed For Intra-Hepatic Tumors?, Hsiang-Chi Kuo, Wen-Shan Liu, Andrew Wu, Dennis Mah, Keh-Shih Chuang, Linda Hong, Ravi Yaparpalvi, Chandan Guha, Shalom Kalnicki

Department of Radiologic Sciences Faculty Papers

BACKGROUND: To evaluate and compare the biological impact on different proposed margin recipes for the same geometric uncertainties for intra-hepatic tumors with different tumor cell types or clinical stages. METHOD: Three different margin recipes based on tumor motion were applied to sixteen IMRT plans with a total of twenty two intra-hepatic tumors. One recipe used the full amplitude of motion measured from patients to generate margins. A second used 70% of the full amplitude of motion, while the third had no margin for motion. The biological effects of geometric uncertainty in these three situations were evaluated with Equivalent Uniform Doses …

Imaging Spontaneous Mmtvneu Transgenic Murine Mammary Tumors: Targeting Metabolic Activity Versus Genetic Products., Mathew L Thakur, Devakumar Devadhas, Kaijun Zhang, Richard G Pestell, Chenguang Wang, Peter Mccue, Eric Wickstrom

Department of Radiology Faculty Papers

INTRODUCTION: Despite the great strides made in imaging breast cancer (BC) in humans, the current imaging modalities miss up to 30% of BC, do not distinguish malignant lesions from benign ones, and require histologic examinations for which invasive biopsy must be performed. Annually in the United States, approximately 5.6 million biopsies find benign lesions. More than 50% of human BCs overexpress cyclin D1, and all BCs exhibit VPAC1 oncogene products. Together, these gene products may provide an excellent biomarker for the early and accurate detection of BC. We have evaluated 4 biologically active peptide analogs that have high affinity for …

System Development For High Frequency Ultrasound-Guided Fluorescence Quantification Of Skin Layers, Josiah D. Gruber, Akshat Paliwal, Venkataramanan Krishnaswamy, Hamid Ghadyani

Dartmouth Scholarship

No abstract provided.

Recent Advances On Skin-Resident Stem/Progenitor Cell Functions In Skin Regeneration, Aging And Cancers And Novel Anti-Aging And Cancer Therapies., Murielle Mimeault, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

Recent advances in skin-resident adult stem/progenitor cell research have revealed that these immature and regenerative cells with a high longevity provide critical functions in maintaining skin homeostasis and repair after severe injuries along the lifespan of individuals. The establishment of the functional properties of distinct adult stem/progenitor cells found in skin epidermis and hair follicles and extrinsic signals from their niches, which are deregulated during their aging and malignant transformation, has significantly improved our understanding on the etiopathogenesis of diverse human skin disorders and cancers. Particularly, enhanced ultraviolet radiation exposure, inflammation and oxidative stress and telomere attrition during chronological aging …

A Review Of Human Factors Principles For The Design And Implementation Of Medication Safety Alerts In Clinical Information Systems., Shobha Phansalkar, Judy Edworthy, Elizabeth Hellier, Diane L. Seger, Angela Schedlbauer, Anthony J. Avery, David W. Bates

School of Psychology

The objective of this review is to describe the implementation of human factors principles for the design of alerts in clinical information systems. First, we conduct a review of alarm systems to identify human factors principles that are employed in the design and implementation of alerts. Second, we review the medical informatics literature to provide examples of the implementation of human factors principles in current clinical information systems using alerts to provide medication decision support. Last, we suggest actionable recommendations for delivering effective clinical decision support using alerts. A review of studies from the medical informatics literature suggests that many …

Recent Diarrhea Is Associated With Elevated Salivary Igg Responses To Cryptosporidium In Residents Of An Eastern Massachusetts Community, A. I. Egorov, L. M. Montuori Trimble, L. Ascolillo, H. D. Ward, Deborah A. Levy, R. D. Morris, E. N. Naumova, J. K. Griffiths

Journal Articles: Epidemiology

BACKGROUND: Serological data suggest that Cryptosporidium infections are common but underreported. The invasiveness of blood sampling limits the application of serology in epidemiological surveillance. We pilot-tested a non-invasive salivary anti-Cryptosporidium antibody assay in a community survey involving children and adults.

MATERIALS AND METHODS: Families with children were recruited in a Massachusetts community in July; symptoms data were collected at 3 monthly follow-up mail surveys. One saliva sample per person (n = 349) was collected via mail, with the last survey in October. Samples were analyzed for IgG and IgA responses to a recombinant C. hominis gp15 sporozoite protein using a …