Richard M Caprioli

Vanderbilt University, Нашвилл, Michigan, United States

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Publications (410)1862.55 Total impact

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    ABSTRACT: Lung cancer is the leading cause of cancer death. Beyond first line treatment, few therapeutic options are available, particularly for squamous cell carcinoma (SCC). Here, we have explored the phospholipidomes of 30 human SCCs and found that they almost invariably (in 96.7% of cases) contain phospholipids with longer acyl chains compared to matched normal tissues. This trait was confirmed using in situ 2D-imaging MS on tissue sections and by phospholipidomics of tumor and normal lung tissue of the L-IkkαKA/KA mouse model of lung SCC. In both human and mouse, the increase in acyl chain length in cancer tissue was accompanied by significant changes in the expression of acyl chain elongases (ELOVLs). Functional screening of differentially expressed ELOVLs by selective gene knockdown in SCC cell lines followed by phospholipidomics revealed ELOVL6 as the main elongation enzyme responsible for acyl chain elongation in cancer cells. Interestingly, inhibition of ELOVL6 drastically reduced colony formation of multiple SCC cell lines in vitro and significantly attenuated their growth as xenografts in vivo in mouse models. These findings identify acyl chain elongation as one of the most common traits of lung SCC discovered so far and pinpoint ELOVL6 as a novel potential target for cancer intervention.
    No preview · Article · Feb 2016 · Oncotarget
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    ABSTRACT: Matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) elucidates molecular distributions in thin tissue sections. Absolute pixel-to-pixel quantitation has remained a challenge, primarily lacking validation of the appropriate analytical methods. In the present work, isotopically labeled internal standards are applied to tissue sections to maximize quantitative reproducibility and yield accurate quantitative results. We have developed a tissue model for rifampicin (RIF), an antibiotic used to treat tuberculosis, and have tested different methods of applying an isotopically labeled internal standard for MALDI IMS analysis. The application of the standard and subsequently the matrix onto tissue sections resulted in quantitation that was not statistically significantly different from results obtained using HPLC-MS/MS of tissue extracts. Quantitative IMS experiments were performed on liver tissue from an animal dosed in vivo. Each microspot in the quantitative images measures the local concentration of RIF in the thin tissue section. Lower concentrations were detected from the blood vessels and around the portal tracts. The quantitative values obtained from these measurements were comparable (>90% similarity) to HPLC-MS/MS results obtained from extracts of the same tissue.
    No preview · Article · Jan 2016 · Analytical Chemistry
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    ABSTRACT: Matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) is a powerful molecular mapping technology that offers unbiased visualization of the spatial arrangement of biomolecules in tissue. Although there has been a significant increase in the number of applications employing this technology, the extracellular matrix (ECM) has received little attention, likely because ECM proteins are mostly large, insoluble and heavily cross-linked. We have developed a new sample preparation approach to enable MALDI IMS analysis of ECM proteins in tissue. Prior to freezing and sectioning, intact tissues are decellularized by incubation in sodium dodecyl sulfate. Decellularization removes the highly abundant, soluble species that dominate a MALDI IMS spectrum while preserving the structural integrity of the ECM. In situ tryptic hydrolysis and imaging of tryptic peptides are then carried out to accommodate the large sizes of ECM proteins. This new approach allows the use of MALDI IMS for identification of spatially specific changes in ECM protein expression and modification in tissue. Copyright © 2015 John Wiley & Sons, Ltd.
    No preview · Article · Nov 2015 · Journal of Mass Spectrometry
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    ABSTRACT: Herein we present a simple, reproducible, and versatile approach for in situ protein digestion and identification on formalin-fixed paraffin-embedded tissues (FFPE). This adaptation is based on the use of an enzyme delivery platform (hydrogel discs) that can be positioned on the surface of a tissue section. By simultaneous deposition of multiple hydrogels over select regions of interest within the same tissue section, multiple peptide extracts can be obtained from discrete histologic areas. After enzymatic digestion, the hydrogel extracts are submitted for LC-MS/MS analysis followed by database inquiry for protein identification. Further, imaging mass spectrometry (IMS) is used to reveal the spatial distribution of the identified peptides within a serial tissue section. Optimization was achieved using cutaneous tissue from surgically excised pressure ulcers that were subdivided into two prime regions of interest: the wound bed and the adjacent dermal area. The robust display of tryptic peptides within these spectral analyses of histologically defined tissue regions suggests that LC-MS/MS in combination with IMS can serve as useful exploratory tools.This article is protected by copyright. All rights reserved.
    No preview · Article · Oct 2015 · Experimental Dermatology
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    ABSTRACT: A hallmark of pancreatic ductal adenocarcinoma (PDAC) is the presence of a dense desmoplastic reaction (stroma) that impedes drug delivery to the tumor. Attempts to deplete the tumor stroma have resulted in formation of more aggressive tumors. We have identified STAT3 as a biomarker of resistance to cytotoxic and molecularly targeted therapy in PDAC. The purpose of this study is to investigate the effects of targeting STAT3 on the PDAC stroma and on therapeutic resistance. Activated STAT3 protein expression was determined in human pancreatic tissues and tumor cell lines. In vivo effects of AZD1480, a JAK/STAT3 inhibitor, gemcitabine or the combination were determined in Ptf1a(cre/+);LSL-Kras(G12D/+);Tgfbr2(flox/flox) (PKT) mice and in orthotopic tumor xenografts. Drug delivery was analyzed by MALDI-imaging mass spectrometry. Collagen second harmonic generation (SHG) imaging quantified tumor collagen alignment and density. STAT3 activation correlates with decreased survival and advanced tumor stage in patients with PDAC. STAT3 inhibition combined with gemcitabine significantly inhibits tumor growth in both an orthotopic and the PKT mouse model of PDAC. This combined therapy attenuates in vivo expression of SPARC, increases microvessel density and enhances drug delivery to the tumor without depletion of stromal collagen or hyaluronan. Instead, the PDAC tumors demonstrate vascular normalization, remodeling of the tumor stroma and downregulation of cytidine deaminase (Cda). Targeted inhibition of STAT3 combined with gemcitabine enhances in vivo drug delivery and therapeutic response in PDAC. These effects occur through tumor stromal remodeling and downregulation of Cda without depletion of tumor stromal content. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.
    No preview · Article · Aug 2015 · Gastroenterology
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    ABSTRACT: Phenotypic differences between otherwise similar tumors arising from different gynecologic locations may be highly significant in understanding the underlying driver molecular events at each site and may potentially offer insights into differential responses to treatment. In this study, the authors sought to identify and quantify phenotypic differences between ovarian clear cell carcinoma (OCCC) and endometrial clear cell carcinoma (ECCC) using a proteomic approach. Tissue microarrays were constructed from tumor samples of 108 patients (54 ECCCs and 54 OCCCs). Formalin-fixed samples on microarray slides were analyzed by matrix-assisted laser desorption/ionization mass spectrometry, and 730 spectral peaks were generated from the combined data set. A linear mixed-effect model with random intercept was used to generate 93 (12.7%) peaks that were significantly different between OCCCs and ECCCs at the fold cutoffs of 1.5 and 0.667 and an adjusted P value cutoff of 1.0 × 10(-10). Liquid chromatography-tandem mass spectrometry was performed on selected cores from each group, and peptides identified therefrom were compared with lists of statistically significant peaks from the aforementioned linear mixed-effects model to find matches within 0.2 Da. A total of 53 candidate proteins were thus identified as being differentially expressed in OCCCs and ECCCs, 45 (85%) of which were expressed at higher levels in ECCCs than OCCCs. These proteins were functionally diverse and did not highlight a clearly dominant cellular theme or molecular pathway. Although ECCCs and OCCCs are very similar, some phenotypic differences are demonstrable. Additional studies of these differentially expressed proteins may ultimately clarify the significance of these differences. Copyright © 2015. Published by Elsevier Inc.
    No preview · Article · Jun 2015 · Human pathology
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    ABSTRACT: Motivation: Matrix Assisted Laser Desorption Ionization-Imaging Mass Spectrometry (MALDI-IMS) in “omics” data acquisition generates detailed information about the spatial distribution of molecules in a given biological sample. Various data processing methods have been developed for exploring the resultant high volume data. However, most of these methods process data in the spectral domain and do not make the most of the important spatial information available through this technology. Therefore, we propose a novel streamlined data analysis pipeline specifically developed for MALDI-IMS data utilizing significant spatial information for identifying hidden significant molecular distribution patterns in these complex datasets. Methods: The proposed unsupervised algorithm uses Sliding Window Normalization (SWN) and a new spatial distribution based peak picking method developed based on Gray level Co-Occurrence (GCO) matrices followed by clustering of biomolecules. We also use gist descriptors and an improved version of GCO matrices to extract features from molecular images and minimum medoid distance to automatically estimate the number of possible groups. Results: We evaluated our algorithm using a new MALDI-IMS metabolomics dataset of a plant (Eucalypt) leaf. The algorithm revealed hidden significant molecular distribution patterns in the dataset, which the current Component Analysis and Segmentation Map based approaches failed to extract. We further demonstrate the performance of our peak picking method over other traditional approaches by using a publicly available MALDI-IMS proteomics dataset of a rat brain. Although SWN did not show any significant improvement as compared with using no normalization, the visual assessment showed an improvement as compared to using the median normalization. Availability and implementation: The source code and sample data are freely available at
    No preview · Article · Jun 2015 · Bioinformatics
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    ABSTRACT: A 37-year-old pregnant woman presented with a 2-cm irregular reddish nodule on her left upper arm during pregnancy. A biopsy from the lesion showed a 2.2-mm thick malignant melanoma with intravascular invasion, 25 mitosis/mm2 and no ulceration. Following induction of labor, the patient underwent re-excision with sentinel lymph node biopsy. This showed no residual melanoma and no lymph node metastasis. The newborn boy had multiple pigmented lesions on the trunk, some of which were large and irregular. Two were biopsied and histologic examination showed dense dermal proliferation of medium sized melanocytes with multiple mitotic figures and no maturation with their descent into the dermis, raising suspicion of transplacental metastases. Examination of the placenta failed to show metastatic lesions. Multiplex polymerase chain reaction (PCR)-based genotyping, including testing for amelogenin locus for sex chromosome determination, demonstrated the presence of Y chromosome material in the melanocytes of the newborn's lesions excluding maternal origin. A diagnosis of congenital nevi was rendered. Subsequently, Imaging Mass Spectrometric analysis of the mother's lesion showed proteomic signature expression indicative of malignant melanoma, whereas the two lesions in the newborn showed changes indicative of nevi. This case demonstrates the utility of genotyping and Mass Spectrometry analysis in this challenging clinical scenario
    Full-text · Article · May 2015 · Journal of Cutaneous Pathology
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    ABSTRACT: MALDI imaging mass spectrometry is a highly sensitive and selective tool used to visualize biomolecules in tissue. However, identification of detected proteins remains a difficult task. Indirect identification strategies have been limited by insufficient mass accuracy to confidently link ion images to proteomics data. Here, we demonstrate the capabilities of MALDI FTICR MS for imaging intact proteins. MALDI FTICR IMS provides an unprecedented combination of mass resolving power (~75,000 at m/z 5000) and accuracy (<5ppm) for proteins up to ~12kDa, enabling identification based on correlation with LC-MS/MS proteomics data. Analysis of rat brain tissue was performed as a proof-of-concept highlighting the capabilities of this approach by imaging and identifying a number of proteins including N-terminally acetylated thymosin β4 (m/z 4,963.502, 0.6ppm) and ATP synthase subunit ε (m/z 5,636.074, -2.3ppm). MALDI FTICR IMS was also used to differentiate a series of oxidation products of S100A8 (m/z 10,164.03, -2.1ppm), a subunit of the heterodimer calprotectin, in kidney tissue from mice infected with Staphylococcus aureus. S100A8 - M37O/C42O3 (m/z 10228.00, -2.6ppm) was found to co-localize with bacterial microcolonies at the center of infectious foci. The ability of MALDI FTICR IMS to distinguish S100A8 modifications is critical to understanding calprotectin's roll in nutritional immunity.
    No preview · Article · Apr 2015 · Journal of the American Society for Mass Spectrometry
  • Boone M. Prentice · Chad W. Chumbley · Richard M. Caprioli
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    ABSTRACT: A matrix-assisted laser desorption/ionization time of flight/time of flight tandem mass spectrometer (MALDI TOF/TOF) has been used for high-speed precursor/fragment ion transition image acquisition. High-throughput analysis is facilitated by an Nd:YLF solid state laser capable of pulse repetition rates up to 5 kHz, a high digitizer acquisition rate (up to 50 pixels/s), and continuous laser raster sampling. MS/MS experiments are enabled through the use of a precision timed ion selector, second source acceleration, and a dedicated collision cell. Continuous raster sampling is shown here to facilitate rapid MS/MS ion image acquisition from thin tissue sections for the drug rifampicin and for a common kidney lipid, SM4s(d18:1/24:1). The ability to confirm the structural identity of an analyte as part of the MS/MS imaging experiment is an essential part of the analysis. Additionally, the increase in sensitivity and specificity afforded by an MS/MS approach is highly advantageous, especially when interrogating complex chemical environments such as those in biological tissues. Herein, we report continuous laser raster sampling TOF/TOF imaging methodologies which demonstrate 8 to 14-fold increases in throughput compared with existing MS/MS instrumentation, an important advantage when imaging large areas on tissues. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.
    No preview · Article · Apr 2015 · Journal of Mass Spectrometry
  • Richard M Caprioli
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    ABSTRACT: Imaging mass spectrometry (IMS) has become a valuable tool for the production of molecular maps in samples ranging from solid inorganic materials to biologicals such as cells and tissues. The unique features of IMS are its ability to map a wide variety of different types of molecules, its superb molecular specificity, and its potential for discovery since no target-specific reagents are needed. IMS has made significant contributions in biology and medicine and promises to be a next generation tool in anatomic pathology.
    No preview · Article · Mar 2015 · Journal of the American Society for Mass Spectrometry
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    ABSTRACT: The 2013 Children's Oncology Group (COG) blueprint for renal tumor research challenges investigators to develop new, risk-specific biological therapies for unfavorable histology and higher-risk Wilms tumor (WT) in an effort to close a persistent survival gap and to reduce treatment toxicities. As an initial response to this call from the COG, we used imaging mass spectrometry to determine peptide profiles of WT associated with adverse outcomes. We created a WT tissue microarray containing 2-mm punches of formalin-fixed, paraffin-embedded specimens archived from 48 sequentially treated WT patients at our institutions. Imaging mass spectrometry was performed to compare peptide spectra between three patient groups as follows: unfavorable versus favorable histology, treatment success versus failure, and COG higher- versus lower-risk disease. Statistically significant peptide peaks differentiating groups were identified and incorporated into a predictive model using a genetic algorithm. One hundred thirty-one peptide peaks were differentially expressed in unfavorable versus favorable histology WT (P < 0.05). Two hundred three peaks differentiated treatment failure from success (P < 0.05). Seventy-one peaks differentiated COG higher-risk disease from the very-low, low, and standard-risk groups (P < 0.05). These peaks were used to develop predictive models that could differentiate among patient groups 98.49%, 94.46%, and 98.55% of the time, respectively. Spectral patterns were internally cross-validated using a leave-20% out model. Peptide spectra can discriminate adverse behavior of WT. After future external validation and refinement, these models could be used to predict WT behavior and to stratify intensity of chemotherapy regimens. Furthermore, peptides discovered in the model could be sequenced to identify potential risk-specific drug targets. Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · Mar 2015 · Journal of Surgical Research
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    ABSTRACT: Non-small cell lung cancer (NSCLC) is the leading cause of cancer death globally. In order to develop better diagnostics and more effective treatments, research in the past decades has focused on identification of molecular changes in the genome, transcriptome, proteome, and more recently also the metabolome. Phospholipids, which nevertheless play a central role in cell functioning, remain poorly explored. Here, using a mass spectrometry (MS)-based phospholipidomics approach, we profiled 179 phospholipid species in malignant and matched non-malignant lung tissue of 162 NSCLC patients (73 in a discovery cohort and 89 in a validation cohort). We identified 91 phospholipid species that were differentially expressed in cancer versus non-malignant tissues. Most prominent changes included a decrease in sphingomyelins (SMs) and an increase in specific phosphatidylinositols (PIs). Also a decrease in multiple phosphatidylserines (PSs) was observed, along with an increase in several phosphatidylethanolamine (PE) and phosphatidylcholine (PC) species, particularly those with 40 or 42 carbon atoms in both fatty acyl chains together. 2D-imaging MS of the most differentially expressed phospholipids confirmed their differential abundance in cancer cells. We identified lipid markers that can discriminate tumor versus normal tissue and different NSCLC subtypes with an AUC (area under the ROC curve) of 0.999 and 0.885, respectively. In conclusion, using both shotgun and 2D-imaging lipidomics analysis, we uncovered a hitherto unrecognized alteration in phospholipid profiles in NSCLC. These changes may have important biological implications and may have significant potential for biomarker development. This article is protected by copyright. All rights reserved. © 2015 UICC.
    No preview · Article · Mar 2015 · International Journal of Cancer
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    ABSTRACT: We performed high-throughput mass spectrometry at high spatial resolution from individual regions (anterior cingulate and primary motor, somatosensory, and visual cortices) and layers of the neocortex (layers III, IV, and V) and cerebellum (granule cell layer), as well as the caudate nucleus in humans and chimpanzees. A total of 39 mass spectrometry peaks were matched with probable protein identifications in both species, allowing for direct comparison in expression. We explored how the pattern of protein expression varies across regions and cortical layers to provide insights into the differences in molecular phenotype of these neural structures between species. The expression of proteins differed principally in a region- and layer-specific pattern, with more subtle differences between species. Specifically, human and chimpanzee brains were similar in their distribution of proteins related to the regulation of transcription and enzyme activity but differed in their expression of proteins supporting aerobic metabolism. While most work assessing molecular expression differences in the brains of primates has been performed on gene transcripts, this dataset extends current understanding of differential molecular expression that may underlie human cognitive specializations.This article is protected by copyright. All rights reserved. © 2015 Wiley Periodicals, Inc.
    Full-text · Article · Mar 2015 · The Journal of Comparative Neurology

  • No preview · Conference Paper · Mar 2015
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    ABSTRACT: Bacterial biofilms account for a significant number of hospital-acquired infections and complicate treatment options, because bacteria within biofilms are generally more tolerant to antibiotic treatment. This resilience is attributed to transient bacterial subpopulations that arise in response to variations in the microenvironment surrounding the biofilm. Here, we probed the spatial proteome of surface-associated single-species biofilms formed by uropathogenic Escherichia coli (UPEC), the major causative agent of community-acquired and catheter-associated urinary tract infections. We used matrix-assisted laser desorption/ionization (MALDI) time-of-flight (TOF) imaging mass spectrometry (IMS) to analyze the spatial proteome of intact biofilms in situ. MALDI-TOF IMS revealed protein species exhibiting distinct localizations within surface-associated UPEC biofilms, including two adhesive fibers critical for UPEC biofilm formation and virulence: type 1 pili (Fim) localized exclusively to the air-exposed region, while curli amyloid fibers localized to the air-liquid interface. Comparison of cells grown aerobically, fermentatively, or utilizing an alternative terminal electron acceptor showed that the phase-variable fim promoter switched to the "OFF" orientation under oxygen-deplete conditions, leading to marked reduction of type 1 pili on the bacterial cell surface. Conversely, S pili whose expression is inversely related to fim expression were up-regulated under anoxic conditions. Tethering the fim promoter in the "ON" orientation in anaerobically grown cells only restored type 1 pili production in the presence of an alternative terminal electron acceptor beyond oxygen. Together these data support the presence of at least two regulatory mechanisms controlling fim expression in response to oxygen availability and may contribute to the stratification of extracellular matrix components within the biofilm. MALDI IMS facilitated the discovery of these mechanisms, and we have demonstrated that this technology can be used to interrogate subpopulations within bacterial biofilms.
    Full-text · Article · Mar 2015 · PLoS Pathogens
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    Raf Van de Plas · Junhai Yang · Jeffrey Spraggins · Richard M Caprioli
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    ABSTRACT: We describe a predictive imaging modality created by 'fusing' two distinct technologies: imaging mass spectrometry (IMS) and microscopy. IMS-generated molecular maps, rich in chemical information but having coarse spatial resolution, are combined with optical microscopy maps, which have relatively low chemical specificity but high spatial information. The resulting images combine the advantages of both technologies, enabling prediction of a molecular distribution both at high spatial resolution and with high chemical specificity. Multivariate regression is used to model variables in one technology, using variables from the other technology. We demonstrate the potential of image fusion through several applications: (i) 'sharpening' of IMS images, which uses microscopy measurements to predict ion distributions at a spatial resolution that exceeds that of measured ion images by ten times or more; (ii) prediction of ion distributions in tissue areas that were not measured by IMS; and (iii) enrichment of bi
    Full-text · Article · Feb 2015 · Nature Methods
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    Andre Zavalin · Junhai Yang · Kevin Hayden · Marvin Vestal · Richard M Caprioli
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    ABSTRACT: We have achieved protein imaging mass spectrometry capabilities at sub-cellular spatial resolution and at high acquisition speed by integrating a transmission geometry ion source with time of flight mass spectrometry. The transmission geometry principle allowed us to achieve a 1-μm laser spot diameter on target. A minimal raster step size of the instrument was 2.5 μm. Use of 2,5-dihydroxyacetophenone robotically sprayed on top of a tissue sample as a matrix together with additional sample preparation steps resulted in single pixel mass spectra from mouse cerebellum tissue sections having more than 20 peaks in a range 3-22 kDa. Mass spectrometry images were acquired in a standard step raster microprobe mode at 5 pixels/s and in a continuous raster mode at 40 pixels/s.
    Full-text · Article · Feb 2015 · Analytical and Bioanalytical Chemistry
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    ABSTRACT: The present study was designed to demonstrate the potential of an optimized histology directed protein identification combined with imaging mass spectrometry technology to reveal and identify molecules associated to ectopic calcification in human tissue. As a proof of concept, mineralized and non-mineralized areas were compared within the same dermal tissue obtained from a patient affected by Pseudoxanthoma elasticum, a genetic disorder characterized by calcification only at specific sites of soft connective tissues. Data have been technically validated on a contralateral dermal tissue from the same subject and compared with those from control healthy skin. Results demonstrate that this approach 1) significantly reduces the effects generated by techniques that, disrupting tissue organization, blend data from affected and unaffected areas; 2) demonstrates that, abolishing differences due to inter-individual variability, mineralized and non-mineralized areas within the same sample have a specific protein profile and have a different distribution of molecules; 3) avoiding the bias of focusing on already known molecules, reveals a number of proteins that have been never related to the disease nor to the calcification process, thus paving the way for the selection of new molecules to be validated as pathogenic or as potential pharmacological targets.
    Full-text · Article · Jan 2015 · Bone
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    ABSTRACT: Imaging mass spectrometry (IMS) was employed for the analysis of frozen skin biopsies to investigate the differences between stage IV pressure ulcers that remain stalled, stagnant and unhealed versus those exhibiting clinical and histological signs of improvement. Our data reveal a rich diversity of proteins that are dynamically modulated and we selectively highlight a family of calcium binding proteins (S-100 molecules) including calcyclin (S100-A6), calgranulins A (S100-A8) and B (S100-A9), and calgizzarin (S100-A11). IMS allowed us to target 3 discrete regions of interest: the wound bed, adjacent dermis, and hypertrophic epidermis. Plots derived using unsupervised principal component analysis of the global protein signatures within these 3 spatial niches indicate that these data from wound signatures have potential as a prognostic tool since they appear to delineate wounds that are favorably responding to therapeutic interventions versus those that remain stagnant or intractable in their healing status. Our discovery based approach with IMS augments current knowledge of the molecular signatures within pressure ulcers while providing a rationale for a focused examination of the role of calcium modulators within the context of impaired wound healing.
    Preview · Article · Dec 2014 · Journal of Proteome Research

Publication Stats

19k Citations
1,862.55 Total Impact Points


  • 1998-2015
    • Vanderbilt University
      • • Department of Chemistry
      • • Department of Biochemistry
      • • Mass Spectrometry Research Center
      Нашвилл, Michigan, United States
  • 2012
    • Nashville Online
      Нашвилл, Michigan, United States
  • 2007
    • University of Pittsburgh
      Pittsburgh, Pennsylvania, United States
  • 2004-2007
    • Uppsala University
      • Department of Pharmaceutical Biosciences
      Uppsala, Uppsala, Sweden
  • 2003-2007
    • Gateway-Vanderbilt Cancer Treatment Center
      Clarksville, Tennessee, United States
  • 2006
    • University of Rochester
      Rochester, New York, United States
    • University of Alabama at Birmingham
      Birmingham, Alabama, United States
  • 2005
    • University of Greifswald
      • Institute of Pharmacy
      Griefswald, Mecklenburg-Vorpommern, Germany
  • 2001
    • Indian Institute of Technology Ropar
      Rūpar, Punjab, India
  • 1978-1998
    • University of Texas Medical School
      • • Department of Biochemistry and Molecular Biology
      • • Department of Neurobiology and Anatomy
      • • Department of Anesthesiology
      • • Department of Internal Medicine
      Houston, Texas, United States
  • 1990
    • Columbia University
      New York, New York, United States
  • 1978-1990
    • University of Houston
      Houston, Texas, United States
  • 1987
    • The University of Manchester
      Manchester, England, United Kingdom
  • 1983
    • University of Texas MD Anderson Cancer Center
      Houston, Texas, United States
  • 1982
    • University of Texas Health Science Center at Houston
      Houston, Texas, United States
  • 1979
    • Johns Hopkins University
      Baltimore, Maryland, United States
    • Purdue University
      ウェストラファイエット, Indiana, United States