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  1. AU="Alexander Marx"
  2. AU="Robinson, Jill"
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  1. Buch ; Online ; Dissertation / Habilitation: The role of WNT4 in the non-canonical WNT/PCP pathway in thymic epithelial tumors

    Zhang, Xiaonan [Verfasser] / Alexander, Marx [Akademischer Betreuer]

    2022  

    Verfasserangabe Xiaonan Zhang ; Betreuer: Marx Alexander
    Schlagwörter Biowissenschaften, Biologie ; Life Science, Biology
    Thema/Rubrik (Code) sg570
    Sprache Englisch
    Verlag Universitätsbibliothek Heidelberg
    Erscheinungsort Heidelberg
    Dokumenttyp Buch ; Online ; Dissertation / Habilitation
    Datenquelle Digitale Dissertationen im Internet

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  2. Artikel ; Online: Molecular and Pathological Profiling of Corresponding Treatment-Naïve and Neoadjuvant Pazopanib-Treated High-Risk Soft Tissue Sarcoma Samples of the GISG-04/NOPASS Study

    Timo Gaiser / Christian Sauer / Alexander Marx / Jens Jakob / Bernd Kasper / Peter Hohenberger / Daniela Hirsch / Ulrich Ronellenfitsch

    Biology, Vol 10, Iss 639, p

    2021  Band 639

    Abstract: In the framework of the German Interdisciplinary Sarcoma Group GISG-04/NOPASS trial, we evaluated soft tissue sarcoma samples taken before and after neoadjuvant pazopanib therapy using histopathology and next generation sequencing (NGS) to find potential ...

    Abstract In the framework of the German Interdisciplinary Sarcoma Group GISG-04/NOPASS trial, we evaluated soft tissue sarcoma samples taken before and after neoadjuvant pazopanib therapy using histopathology and next generation sequencing (NGS) to find potential predictive biomarkers. We also aimed to improve the genetically based sarcoma classification and to elucidate additional potentially druggable mutations. In total, 30 tumor samples from 18 patients consisting of 12 pre-therapeutic biopsies and 18 resection specimens following neoadjuvant pazopanib therapy were available for analyses. NGS was performed with the Oncomine Focus Assay (Ion Torrent) covering 0.03 Mb of DNA and enabled the detection of genetic variants in 52 cancer-relevant genes. Pathological analysis showed significant regression (≥50%) after pazopanib treatment in only one undifferentiated (pleomorphic) sarcoma. NGS analyses revealed a very high frequency of CDK4 amplification (88%; 7/8) in the group of dedifferentiated liposarcoma. In addition, two potentially druggable mutations, a MAP2K1 missense mutation (E203K) and a BRAF missense mutation (V600E), were traceable in two undifferentiated (pleomorphic) sarcoma patients (11%; 2/18). Our findings demonstrate that NGS testing is a powerful technology helping to improve diagnostic accuracy and offering some patients the chance for personalized medicine even in a “mutation unlikely” cohort like STS.
    Schlagwörter soft tissue sarcoma ; STS ; pazopanib ; next generation sequencing ; NGS ; CDK4 ; Biology (General) ; QH301-705.5
    Thema/Rubrik (Code) 610 ; 616
    Sprache Englisch
    Erscheinungsdatum 2021-07-01T00:00:00Z
    Verlag MDPI AG
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  3. Artikel: Scores for standardization of on-tissue digestion of formalin-fixed paraffin-embedded tissue in MALDI-MS imaging

    Erich, Katrin / Alexander Marx / Carsten Hopf / Denis A. Sammour

    Biochimica et biophysica acta. 2017 July, v. 1865, no. 7

    2017  

    Abstract: On-slide digestion of formalin-fixed and paraffin-embedded human biopsy tissue followed by mass spectrometry imaging of resulting peptides may have the potential to become an additional analytical modality in future ePathology. Multiple workflows have ... ...

    Abstract On-slide digestion of formalin-fixed and paraffin-embedded human biopsy tissue followed by mass spectrometry imaging of resulting peptides may have the potential to become an additional analytical modality in future ePathology. Multiple workflows have been described for dewaxing, antigen retrieval, digestion and imaging in the past decade. However, little is known about suitable statistical scores for method comparison and systematic workflow standardization required for development of processes that would be robust enough to be compatible with clinical routine. To define scores for homogeneity of tissue processing and imaging as well as inter-day repeatability for five different processing methods, we used human liver and gastrointestinal stromal tumor tissue, both judged by an expert pathologist to be >98% histologically homogeneous. For mean spectra-based as well as pixel-wise data analysis, we propose the coefficient of determination R2, the natural fold-change (natFC) value and the digest efficiency DE% as readily accessible scores. Moreover, we introduce two scores derived from principal component analysis, the variance of the mean absolute deviation, MAD, and the interclass overlap, Joverlap, as computational scores that may help to avoid user bias during future workflow development. This article is part of a Special Issue entitled: MALDI Imaging, edited by Dr. Corinna Henkel and Prof. Peter Hoffmann.
    Schlagwörter antigens ; biopsy ; gastrointestinal neoplasms ; humans ; image analysis ; liver ; mass spectrometry ; peptides ; principal component analysis ; processing technology ; proteins ; proteomics ; variance
    Sprache Englisch
    Erscheinungsverlauf 2017-07
    Umfang p. 907-915.
    Erscheinungsort Elsevier B.V.
    Dokumenttyp Artikel
    ZDB-ID 2918798-9
    ISSN 1878-1454 ; 1570-9639
    ISSN (online) 1878-1454
    ISSN 1570-9639
    DOI 10.1016/j.bbapap.2016.08.020
    Datenquelle NAL Katalog (AGRICOLA)

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  4. Artikel ; Online: EDISON-WMW

    Alexander Marx / Christina Backes / Eckart Meese / Hans-Peter Lenhof / Andreas Keller

    Genomics, Proteomics & Bioinformatics, Vol 14, Iss 1, Pp 55-

    Exact Dynamic Programing Solution of the Wilcoxon–Mann–Whitney Test

    2016  Band 61

    Abstract: In many research disciplines, hypothesis tests are applied to evaluate whether findings are statistically significant or could be explained by chance. The Wilcoxon–Mann–Whitney (WMW) test is among the most popular hypothesis tests in medicine and life ... ...

    Abstract In many research disciplines, hypothesis tests are applied to evaluate whether findings are statistically significant or could be explained by chance. The Wilcoxon–Mann–Whitney (WMW) test is among the most popular hypothesis tests in medicine and life science to analyze if two groups of samples are equally distributed. This nonparametric statistical homogeneity test is commonly applied in molecular diagnosis. Generally, the solution of the WMW test takes a high combinatorial effort for large sample cohorts containing a significant number of ties. Hence, P value is frequently approximated by a normal distribution. We developed EDISON-WMW, a new approach to calculate the exact permutation of the two-tailed unpaired WMW test without any corrections required and allowing for ties. The method relies on dynamic programing to solve the combinatorial problem of the WMW test efficiently. Beyond a straightforward implementation of the algorithm, we presented different optimization strategies and developed a parallel solution. Using our program, the exact P value for large cohorts containing more than 1000 samples with ties can be calculated within minutes. We demonstrate the performance of this novel approach on randomly-generated data, benchmark it against 13 other commonly-applied approaches and moreover evaluate molecular biomarkers for lung carcinoma and chronic obstructive pulmonary disease (COPD). We found that approximated P values were generally higher than the exact solution provided by EDISON-WMW. Importantly, the algorithm can also be applied to high-throughput omics datasets, where hundreds or thousands of features are included. To provide easy access to the multi-threaded version of EDISON-WMW, a web-based solution of our algorithm is freely available at http://www.ccb.uni-saarland.de/software/wtest/.
    Schlagwörter Wilcoxon–Mann–Whitney test ; Wilcoxon rank-sum test ; Dynamic programing ; Exact permutation ; Parallel optimization ; Biology (General) ; QH301-705.5
    Thema/Rubrik (Code) 000
    Sprache Englisch
    Erscheinungsdatum 2016-02-01T00:00:00Z
    Verlag Elsevier
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  5. Artikel ; Online: MicroRNA and mRNA expression associated with ectopic germinal centers in thymus of myasthenia gravis.

    Manjistha Sengupta / Bi-Dar Wang / Norman H Lee / Alexander Marx / Linda L Kusner / Henry J Kaminski

    PLoS ONE, Vol 13, Iss 10, p e

    2018  Band 0205464

    Abstract: BACKGROUND:A characteristic pathology of early onset myasthenia gravis is thymic hyperplasia with ectopic germinal centers (GC). However, the mechanisms that trigger and maintain thymic hyperplasia are poorly characterized. Dysregulation of small, non- ... ...

    Abstract BACKGROUND:A characteristic pathology of early onset myasthenia gravis is thymic hyperplasia with ectopic germinal centers (GC). However, the mechanisms that trigger and maintain thymic hyperplasia are poorly characterized. Dysregulation of small, non-coding microRNAs (miRNAs) and their target genes has been identified in the pathology of several autoimmune diseases. We assessed the miRNA and mRNA profiles of the MG thymus and have investigated their role in GC formation and maintenance. METHODS:MG thymus samples were assessed by histology and grouped based upon the appearance of GC; GC positive and GC negative. A systems biology approach was used to study the differences between the groups. Our study included miRNA and mRNA profiling, quantitative real-time PCR validation, miRNA target identification, pathway analysis, miRNA-mRNA reciprocal expression pairing and interaction. RESULTS:Thirty-eight mature miRNAs and forty-six annotated mRNA transcripts were differentially expressed between the two groups (>1.5 fold change, ANOVA p<0.05). The miRNAs were found to be involved in immune response pathways and identified in other autoimmune diseases. The cellular and molecular functions of the mRNAs showed involvement in cell death and cell survival, cellular proliferation, cytokine signaling and extra-cellular matrix reorganization. Eleven miRNA and mRNA pairs were reciprocally regulated. The Regulator of G protein Signalling 13 (RGS13), known to be involved in GC regulation, was identified in specimens with GC and was paired with downregulation of miR-452-5p and miR-139-5p. MiRNA target sites were validated by dual luciferase assay. Transfection of miRNA mimics led to down regulation of RGS13 expression in Raji cells. CONCLUSION:Our study indicates a distinct miRNA and mRNA expression pattern in ectopic GC in MG thymus. These miRNAs and mRNAs are involved in regulatory pathways common to inflammation and immune response, cell cycle regulation and anti-apoptotic pathways suggesting their involvement in support ...
    Schlagwörter Medicine ; R ; Science ; Q
    Thema/Rubrik (Code) 570
    Sprache Englisch
    Erscheinungsdatum 2018-01-01T00:00:00Z
    Verlag Public Library of Science (PLoS)
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  6. Artikel ; Online: Quantitative Mass Spectrometry Imaging Reveals Mutation Status-independent Lack of Imatinib in Liver Metastases of Gastrointestinal Stromal Tumors

    Denis Abu Sammour / Christian Marsching / Alexander Geisel / Katrin Erich / Sandra Schulz / Carina Ramallo Guevara / Jan-Hinrich Rabe / Alexander Marx / Peter Findeisen / Peter Hohenberger / Carsten Hopf

    Scientific Reports, Vol 9, Iss 1, Pp 1-

    2019  Band 9

    Abstract: Abstract Mass spectrometry imaging (MSI) is an enabling technology for label-free drug disposition studies at high spatial resolution in life science- and pharmaceutical research. We present the first extensive clinical matrix-assisted laser desorption/ ... ...

    Abstract Abstract Mass spectrometry imaging (MSI) is an enabling technology for label-free drug disposition studies at high spatial resolution in life science- and pharmaceutical research. We present the first extensive clinical matrix-assisted laser desorption/ionization (MALDI) quantitative mass spectrometry imaging (qMSI) study of drug uptake and distribution in clinical specimen, analyzing 56 specimens of tumor and corresponding non-tumor tissues from 27 imatinib-treated patients with the biopsy-proven rare disease gastrointestinal stromal tumors (GIST). For validation, we compared MALDI-TOF-qMSI with conventional UPLC-ESI-QTOF-MS-based quantification from tissue extracts and with ultra-high resolution MALDI-FTICR-qMSI. We introduced a novel generalized nonlinear calibration model of drug quantities based on computational evaluation of drug-containing areas that enabled better data fitting and assessment of the inherent method nonlinearities. Imatinib tissue spatial maps revealed striking inefficiency in drug penetration into GIST liver metastases even though the corresponding healthy liver tissues in the vicinity showed abundant imatinib levels beyond the limit of quantification (LOQ), thus providing evidence for secondary drug resistance independent of mutation status. Taken together, these findings underscore the important application of MALDI-qMSI in studying the spatial distribution of molecularly targeted therapeutics in oncology, namely to serve as orthogonal post-surgical approach to evaluate the contribution of anticancer drug disposition to resistance against treatment.
    Schlagwörter Medicine ; R ; Science ; Q
    Thema/Rubrik (Code) 610
    Sprache Englisch
    Erscheinungsdatum 2019-07-01T00:00:00Z
    Verlag Nature Publishing Group
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  7. Artikel ; Online: CD163+ immune cell infiltrates and presence of CD54+ microvessels are prognostic markers for patients with embryonal rhabdomyosarcoma

    Jakob Nikolas Kather / Christian Hörner / Cleo-Aron Weis / Thiha Aung / Christian Vokuhl / Christel Weiss / Monika Scheer / Alexander Marx / Katja Simon-Keller

    Scientific Reports, Vol 9, Iss 1, Pp 1-

    2019  Band 12

    Abstract: Abstract Rhabdomyosarcomas (RMS) are rare and often lethal diseases. It is assumed that the tumor microenvironment (TME) of RMS exerts an immunosuppressive function, but there is currently no systematic analysis of the immune cells infiltrating sarcoma ... ...

    Abstract Abstract Rhabdomyosarcomas (RMS) are rare and often lethal diseases. It is assumed that the tumor microenvironment (TME) of RMS exerts an immunosuppressive function, but there is currently no systematic analysis of the immune cells infiltrating sarcoma tissue. Focusing on two common types of RMS (alveolar [RMA] and embryonal [RME]), we performed a comprehensive immunohistochemical analysis of tumor-infiltrating immune cells in the TME. We performed a qualitative estimation of infiltrating immune cells in the tumor microenvironment by an experienced pathologist as well as a quantitative digital pathology analysis. We found that (1) manual and automatic quantification of tumor-infiltrating immune cells were consistent; (2) RME tumors showed a higher degree of immune cell infiltration than RMA tumors but (3) the number of tumor infiltrating lymphocytes was low compared to other solid tumor types; (4) microvascular density correlated with immune cell infiltration and (5) CD163 positive macrophages as well as CD54 positive microvessels were more often detected in RME than in RMA and correlated with patient overall and event free survival. Our systematic analysis provides a comprehensive view of the immune landscape of RMS which needs to be taken into account for developing immunotherapies for this rare type of cancer.
    Schlagwörter Medicine ; R ; Science ; Q
    Thema/Rubrik (Code) 616
    Sprache Englisch
    Erscheinungsdatum 2019-06-01T00:00:00Z
    Verlag Nature Publishing Group
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  8. Artikel ; Online: Survivin as a potential mediator to support autoreactive cell survival in myasthenia gravis

    Linda L Kusner / Michael J Ciesielski / Alexander Marx / Henry J Kaminski / Robert A Fenstermaker

    PLoS ONE, Vol 9, Iss 7, p e

    a human and animal model study.

    2014  Band 102231

    Abstract: The mechanisms that underlie the development and maintenance of autoimmunity in myasthenia gravis are poorly understood. In this investigation, we evaluate the role of survivin, a member of the inhibitor of apoptosis protein family, in humans and in two ... ...

    Abstract The mechanisms that underlie the development and maintenance of autoimmunity in myasthenia gravis are poorly understood. In this investigation, we evaluate the role of survivin, a member of the inhibitor of apoptosis protein family, in humans and in two animal models. We identified survivin expression in cells with B lymphocyte and plasma cells markers, and in the thymuses of patients with myasthenia gravis. A portion of survivin-expressing cells specifically bound a peptide derived from the alpha subunit of acetylcholine receptor indicating that they recognize the peptide. Thymuses of patients with myasthenia gravis had large numbers of survivin-positive cells with fewer cells in the thymuses of corticosteroid-treated patients. Application of a survivin vaccination strategy in mouse and rat models of myasthenia gravis demonstrated improved motor assessment, a reduction in acetylcholine receptor specific autoantibodies, and a retention of acetylcholine receptor at the neuromuscular junction, associated with marked reduction of survivin-expressing circulating CD20+ cells. These data strongly suggest that survivin expression in cells with lymphocyte and plasma cell markers occurs in patients with myasthenia gravis and in two animal models of myasthenia gravis. Survivin expression may be part of a mechanism that inhibits the apoptosis of autoreactive B cells in myasthenia gravis and other autoimmune disorders.
    Schlagwörter Medicine ; R ; Science ; Q
    Thema/Rubrik (Code) 610
    Sprache Englisch
    Erscheinungsdatum 2014-01-01T00:00:00Z
    Verlag Public Library of Science (PLoS)
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  9. Artikel: GPR182 is a novel marker for sinusoidal endothelial differentiation with distinct GPCR signaling activity in vitro

    Schmid, Christian David / Kai Schledzewski / Carolin Mogler / Nina Waldburger / Viktoria Kalna / Alexander Marx / Anna Maria Randi / Cyrill Géraud / Sergij Goerdt / Philipp-Sebastian Koch

    Biochemical and biophysical research communications. 2018 Feb. 26, v. 497, no. 1

    2018  

    Abstract: Endothelial cells (EC) along the vascular tree exhibit organ-specific angiodiversity. Compared to most other ECs, liver sinusoidal endothelial cells (LSEC) that constitute the organ-specific microvasculature of the liver are morphologically and ... ...

    Abstract Endothelial cells (EC) along the vascular tree exhibit organ-specific angiodiversity. Compared to most other ECs, liver sinusoidal endothelial cells (LSEC) that constitute the organ-specific microvasculature of the liver are morphologically and functionally unique. Previously, we showed that transcription factor Gata4 acts as a master regulator controlling LSEC differentiation. Upon analysis of the molecular signature of LSEC, we identified GPR182 as a potential LSEC-specific orphan G-protein coupled receptor (GPCR). Here, we demonstrate that GPR182 is expressed by LSEC and by EC with sinusoidal differentiation in spleen, lymph node and bone marrow in healthy human tissues. In a tissue microarray analysis of human hepatocellular carcinoma (HCC) samples, endothelial GPR182 expression was significantly reduced in tumor samples compared to peritumoral liver tissue samples (p = 0.0105). Loss of endothelial GPR182 expression was also seen in fibrotic and cirrhotic liver tissues. In vitro, GPR182 differentially regulated canonical GPCR signaling pathways as shown using reporter luciferase assays in HEK293T cells. Whereas ERK and RhoA signaling were inhibited, CREB and Calcium signaling were activated by ectopic GPR182 overexpression. Our data demonstrate that GPR182 is an endothelial subtype-specific marker for human sinusoidal EC of the liver, spleen, lymph node and bone marrow. In addition, we provide evidence for GPR182-dependent downstream signaling via ERK and SRF pathways that may be involved in regulating endothelial subtype-specific sinusoidal differentiation and sinusoidal functions such as permeability.
    Schlagwörter G-protein coupled receptors ; GATA transcription factors ; bone marrow ; calcium signaling ; endothelial cells ; hepatoma ; humans ; liver ; luciferase ; lymph nodes ; microarray technology ; mitogen-activated protein kinase ; permeability ; spleen ; transcription (genetics)
    Sprache Englisch
    Erscheinungsverlauf 2018-0226
    Umfang p. 32-38.
    Erscheinungsort Elsevier Inc.
    Dokumenttyp Artikel
    ZDB-ID 205723-2
    ISSN 0006-291X ; 0006-291X
    ISSN (online) 0006-291X
    ISSN 0006-291X
    DOI 10.1016/j.bbrc.2018.01.185
    Datenquelle NAL Katalog (AGRICOLA)

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    Verfügbar in ZB MED Bonn

    Z 71/706: Hefte anzeigen
    Z 3.8: Hefte anzeigen

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  10. Artikel ; Online: Fourier Transform Infrared Microscopy Enables Guidance of Automated Mass Spectrometry Imaging to Predefined Tissue Morphologies

    Jan-Hinrich Rabe / Denis A. Sammour / Sandra Schulz / Bogdan Munteanu / Martina Ott / Katharina Ochs / Peter Hohenberger / Alexander Marx / Michael Platten / Christiane A. Opitz / Daniel S. Ory / Carsten Hopf

    Scientific Reports, Vol 8, Iss 1, Pp 1-

    2018  Band 11

    Abstract: Abstract Multimodal imaging combines complementary platforms for spatially resolved tissue analysis that are poised for application in life science and personalized medicine. Unlike established clinical in vivo multimodality imaging, automated workflows ... ...

    Abstract Abstract Multimodal imaging combines complementary platforms for spatially resolved tissue analysis that are poised for application in life science and personalized medicine. Unlike established clinical in vivo multimodality imaging, automated workflows for in-depth multimodal molecular ex vivo tissue analysis that combine the speed and ease of spectroscopic imaging with molecular details provided by mass spectrometry imaging (MSI) are lagging behind. Here, we present an integrated approach that utilizes non-destructive Fourier transform infrared (FTIR) microscopy and matrix assisted laser desorption/ionization (MALDI) MSI for analysing single-slide tissue specimen. We show that FTIR microscopy can automatically guide high-resolution MSI data acquisition and interpretation without requiring prior histopathological tissue annotation, thus circumventing potential human-annotation-bias while achieving >90% reductions of data load and acquisition time. We apply FTIR imaging as an upstream modality to improve accuracy of tissue-morphology detection and to retrieve diagnostic molecular signatures in an automated, unbiased and spatially aware manner. We show the general applicability of multimodal FTIR-guided MALDI-MSI by demonstrating precise tumor localization in mouse brain bearing glioma xenografts and in human primary gastrointestinal stromal tumors. Finally, the presented multimodal tissue analysis method allows for morphology-sensitive lipid signature retrieval from brains of mice suffering from lipidosis caused by Niemann-Pick type C disease.
    Schlagwörter Medicine ; R ; Science ; Q
    Thema/Rubrik (Code) 610
    Sprache Englisch
    Erscheinungsdatum 2018-01-01T00:00:00Z
    Verlag Nature Publishing Group
    Dokumenttyp Artikel ; Online
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