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  1. Article ; Online: The Angiomotins--from discovery to function.

    Moleirinho, Susana / Guerrant, William / Kissil, Joseph L

    FEBS letters

    2014  Volume 588, Issue 16, Page(s) 2693–2703

    Abstract: Angiomotins were originally identified as angiostatin binding proteins and implicated in the regulation of endothelial cell migration. Recent studies have shed light on the role of Angiomotins and other members of the Motin protein family in epithelial ... ...

    Abstract Angiomotins were originally identified as angiostatin binding proteins and implicated in the regulation of endothelial cell migration. Recent studies have shed light on the role of Angiomotins and other members of the Motin protein family in epithelial cells and in pathways directly linked to the pathogenesis of cancer. In particular, Motins have been shown to play a role in signaling pathways regulated by small G-proteins and the Hippo-YAP pathway. In this review the role of the Motin protein family in these signaling pathways will be described and open questions will be discussed.
    MeSH term(s) Animals ; Disease ; Endothelial Cells/metabolism ; Gene Expression Regulation ; Humans ; Intercellular Signaling Peptides and Proteins/metabolism ; Membrane Proteins/metabolism ; Microfilament Proteins ; Neovascularization, Physiologic ; Signal Transduction
    Chemical Substances AMOT protein, human ; Intercellular Signaling Peptides and Proteins ; Membrane Proteins ; Microfilament Proteins
    Language English
    Publishing date 2014-02-15
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 212746-5
    ISSN 1873-3468 ; 0014-5793
    ISSN (online) 1873-3468
    ISSN 0014-5793
    DOI 10.1016/j.febslet.2014.02.006
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.B 282: Show issues Location:
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  2. Article ; Online: Detecting Glucose Fluctuations in the

    Nothaft, Harald / Bian, Xiaoming / Shajahan, Asif / Miller, William G / Bolick, David T / Guerrant, Richard L / Azadi, Parastoo / Ng, Kenneth K S / Szymanski, Christine M

    ACS chemical biology

    2021  Volume 16, Issue 11, Page(s) 2690–2701

    Abstract: Campylobacter ... ...

    Abstract Campylobacter jejuni
    MeSH term(s) Amino Acid Sequence ; Animals ; Aspartic Acid/chemistry ; Campylobacter jejuni/metabolism ; Carbohydrate Conformation ; Carbohydrate Sequence ; Enzyme-Linked Immunosorbent Assay ; Escherichia coli/metabolism ; Glucose/metabolism ; Glycosylation ; Immune Sera ; Mice ; Phagocytosis ; Polysaccharides/chemistry ; Polysaccharides/metabolism ; Sequence Alignment
    Chemical Substances Immune Sera ; Polysaccharides ; Aspartic Acid (30KYC7MIAI) ; Glucose (IY9XDZ35W2)
    Language English
    Publishing date 2021-11-02
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 1554-8937
    ISSN (online) 1554-8937
    DOI 10.1021/acschembio.1c00498
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Pharmacological Disruption of the Notch1 Transcriptional Complex Inhibits Tumor Growth by Selectively Targeting Cancer Stem Cells.

    Alvarez-Trotta, Annamil / Guerrant, William / Astudillo, Luisana / Lahiry, Mohini / Diluvio, Giulia / Shersher, Elena / Kaneku, Hugo / Robbins, David J / Orton, Darren / Capobianco, Anthony J

    Cancer research

    2021  Volume 81, Issue 12, Page(s) 3347–3357

    Abstract: In many human cancers, deregulation of the Notch pathway has been shown to play a role in the initiation and maintenance of the neoplastic phenotype. Aberrant Notch activity also plays a central role in the maintenance and survival of cancer stem cells ( ... ...

    Abstract In many human cancers, deregulation of the Notch pathway has been shown to play a role in the initiation and maintenance of the neoplastic phenotype. Aberrant Notch activity also plays a central role in the maintenance and survival of cancer stem cells (CSC), which underlie metastasis and resistance to therapy. For these reasons, inhibition of Notch signaling has become an exceedingly attractive target for cancer therapeutic development. However, attempts to develop Notch pathway-specific drugs have largely failed in the clinic, in part due to intestinal toxicity. Here, we report the discovery of NADI-351, the first specific small-molecule inhibitor of Notch1 transcriptional complexes. NADI-351 selectively disrupted Notch1 transcription complexes and reduced Notch1 recruitment to target genes. NADI-351 demonstrated robust antitumor activity without inducing intestinal toxicity in mouse models, and CSCs were ablated by NADI-351 treatment. Our study demonstrates that NADI-351 is an orally available and potent inhibitor of Notch1-mediated transcription that inhibits tumor growth with low toxicity, providing a potential therapeutic approach for improved cancer treatment. SIGNIFICANCE: This study showcases the first Notch1-selective inhibitor that suppresses tumor growth with limited toxicity by selectively ablating cancer stem cells.
    MeSH term(s) Adenocarcinoma/drug therapy ; Adenocarcinoma/metabolism ; Adenocarcinoma/pathology ; Animals ; Antineoplastic Agents/pharmacology ; Apoptosis ; Cell Proliferation ; Esophageal Neoplasms/drug therapy ; Esophageal Neoplasms/metabolism ; Esophageal Neoplasms/pathology ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Mice ; Mice, Nude ; Neoplastic Stem Cells/drug effects ; Neoplastic Stem Cells/metabolism ; Neoplastic Stem Cells/pathology ; Receptor, Notch1/antagonists & inhibitors ; Small Molecule Libraries/pharmacology ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays
    Chemical Substances Antineoplastic Agents ; NOTCH1 protein, human ; Receptor, Notch1 ; Small Molecule Libraries
    Language English
    Publishing date 2021-04-05
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-20-3611
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: The Angiomotins – From discovery to function

    Moleirinho, Susana / William Guerrant / Joseph L. Kissil

    Federation of European Biochemical Societies FEBS letters. 2014 Aug. 19, v. 588, no. 16

    2014  

    Abstract: Angiomotins were originally identified as angiostatin binding proteins and implicated in the regulation of endothelial cell migration. Recent studies have shed light on the role of Angiomotins and other members of the Motin protein family in epithelial ... ...

    Abstract Angiomotins were originally identified as angiostatin binding proteins and implicated in the regulation of endothelial cell migration. Recent studies have shed light on the role of Angiomotins and other members of the Motin protein family in epithelial cells and in pathways directly linked to the pathogenesis of cancer. In particular, Motins have been shown to play a role in signaling pathways regulated by small G-proteins and the Hippo–YAP pathway. In this review the role of the Motin protein family in these signaling pathways will be described and open questions will be discussed.
    Keywords G-proteins ; cell movement ; endothelial cells ; epithelial cells ; neoplasms ; pathogenesis ; signal transduction
    Language English
    Dates of publication 2014-0819
    Size p. 2693-2703.
    Publishing place Elsevier B.V.
    Document type Article
    ZDB-ID 212746-5
    ISSN 1873-3468 ; 0014-5793
    ISSN (online) 1873-3468
    ISSN 0014-5793
    DOI 10.1016/j.febslet.2014.02.006
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  5. Article ; Online: Dual targeting of histone deacetylase and topoisomerase II with novel bifunctional inhibitors.

    Guerrant, William / Patil, Vishal / Canzoneri, Joshua C / Oyelere, Adegboyega K

    Journal of medicinal chemistry

    2012  Volume 55, Issue 4, Page(s) 1465–1477

    Abstract: Strategies to ameliorate the flaws of current chemotherapeutic agents, while maintaining potent anticancer activity, are of particular interest. Agents which can modulate multiple targets may have superior utility and fewer side effects than current ... ...

    Abstract Strategies to ameliorate the flaws of current chemotherapeutic agents, while maintaining potent anticancer activity, are of particular interest. Agents which can modulate multiple targets may have superior utility and fewer side effects than current single-target drugs. To explore the prospect in cancer therapy of a bivalent agent that combines two complementary chemo-active groups within a single molecular architecture, we have synthesized dual-acting histone deacetylase and topoisomerase II inhibitors. These dual-acting agents are derived from suberoylanilide hydroxamic acid (SAHA) and anthracycline daunorubicin, prototypical histone deacetylase (HDAC) and topoisomerase II (Topo II) inhibitors, respectively. We report herein that these agents present the signatures of inhibition of HDAC and Topo II in both cell-free and whole-cell assays. Moreover, these agents potently inhibit the proliferation of representative cancer cell lines.
    MeSH term(s) Acetylation ; Antineoplastic Agents/chemical synthesis ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Cell-Free System ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; DNA Topoisomerases, Type II/metabolism ; Daunorubicin/analogs & derivatives ; Daunorubicin/chemical synthesis ; Daunorubicin/chemistry ; Daunorubicin/pharmacology ; Drug Screening Assays, Antitumor ; Histone Deacetylase Inhibitors/chemical synthesis ; Histone Deacetylase Inhibitors/chemistry ; Histone Deacetylase Inhibitors/pharmacology ; Histone Deacetylases/metabolism ; Humans ; Hydroxamic Acids/chemical synthesis ; Hydroxamic Acids/chemistry ; Hydroxamic Acids/pharmacology ; Models, Molecular ; Structure-Activity Relationship ; Topoisomerase Inhibitors/chemical synthesis ; Topoisomerase Inhibitors/chemistry ; Topoisomerase Inhibitors/pharmacology ; Tubulin/metabolism ; Vorinostat
    Chemical Substances Antineoplastic Agents ; CDKN1A protein, human ; Cyclin-Dependent Kinase Inhibitor p21 ; Histone Deacetylase Inhibitors ; Hydroxamic Acids ; Topoisomerase Inhibitors ; Tubulin ; Vorinostat (58IFB293JI) ; Histone Deacetylases (EC 3.5.1.98) ; DNA Topoisomerases, Type II (EC 5.99.1.3) ; Daunorubicin (ZS7284E0ZP)
    Language English
    Publishing date 2012-02-13
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/jm200799p
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.B 151: Show issues Location:
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  6. Article ; Online: Disease surveillance methods used in the 8-site MAL-ED cohort study.

    Richard, Stephanie A / Barrett, Leah J / Guerrant, Richard L / Checkley, William / Miller, Mark A

    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

    2014  Volume 59 Suppl 4, Page(s) S220–4

    Abstract: Describing the early life associations between infectious disease episodes and growth, cognitive development, and vaccine response in the first 2 years of life is one of the primary goals of the Etiology, Risk Factors and Interactions of Enteric ... ...

    Abstract Describing the early life associations between infectious disease episodes and growth, cognitive development, and vaccine response in the first 2 years of life is one of the primary goals of the Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) cohort study. To collect high-resolution data during a critical early period of development, field staff visit each study participant at their house twice weekly from birth to 2 years of age to collect daily reported illness and treatment data from caregivers. Detailed infectious disease histories will not only allow us to relate the overall burden of infectious disease with the primary outcomes of the study, but will also allow us to describe the ages at which infectious diseases have the greatest effect on child health. In addition, twice-weekly visits allow for sample collection when diarrhea episodes are identified. This article describes the methods used to collect illness and treatment history data and discusses the a priori definitions of diarrhea and acute lower respiratory illness episodes.
    MeSH term(s) Child Development ; Child, Preschool ; Communicable Diseases/epidemiology ; Diarrhea/epidemiology ; Epidemiologic Research Design ; Epidemiological Monitoring ; Humans ; Infant ; Infant, Newborn ; Longitudinal Studies ; Risk Factors ; Vaccination
    Language English
    Publishing date 2014-10-09
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1099781-7
    ISSN 1537-6591 ; 1058-4838
    ISSN (online) 1537-6591
    ISSN 1058-4838
    DOI 10.1093/cid/ciu435
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  7. Article ; Online: YAP Mediates Tumorigenesis in Neurofibromatosis Type 2 by Promoting Cell Survival and Proliferation through a COX-2-EGFR Signaling Axis.

    Guerrant, William / Kota, Smitha / Troutman, Scott / Mandati, Vinay / Fallahi, Mohammad / Stemmer-Rachamimov, Anat / Kissil, Joseph L

    Cancer research

    2016  Volume 76, Issue 12, Page(s) 3507–3519

    Abstract: The Hippo-YAP pathway has emerged as a major driver of tumorigenesis in many human cancers. YAP is a transcriptional coactivator and while details of YAP regulation are quickly emerging, it remains unknown what downstream targets are critical for the ... ...

    Abstract The Hippo-YAP pathway has emerged as a major driver of tumorigenesis in many human cancers. YAP is a transcriptional coactivator and while details of YAP regulation are quickly emerging, it remains unknown what downstream targets are critical for the oncogenic functions of YAP. To determine the mechanisms involved and to identify disease-relevant targets, we examined the role of YAP in neurofibromatosis type 2 (NF2) using cell and animal models. We found that YAP function is required for NF2-null Schwann cell survival, proliferation, and tumor growth in vivo Moreover, YAP promotes transcription of several targets including PTGS2, which codes for COX-2, a key enzyme in prostaglandin biosynthesis, and AREG, which codes for the EGFR ligand, amphiregulin. Both AREG and prostaglandin E2 converge to activate signaling through EGFR. Importantly, treatment with the COX-2 inhibitor celecoxib significantly inhibited the growth of NF2-null Schwann cells and tumor growth in a mouse model of NF2. Cancer Res; 76(12); 3507-19. ©2016 AACR.
    MeSH term(s) Adaptor Proteins, Signal Transducing/physiology ; Amphiregulin/physiology ; Carcinogenesis ; Cell Proliferation ; Cell Survival ; Cells, Cultured ; Cyclooxygenase 2/physiology ; ErbB Receptors/physiology ; Humans ; Neurofibromatosis 2/etiology ; Phosphoproteins/physiology ; Schwann Cells/physiology ; Signal Transduction/physiology ; Transcription Factors
    Chemical Substances AREG protein, human ; Adaptor Proteins, Signal Transducing ; Amphiregulin ; Phosphoproteins ; Transcription Factors ; YAP1 protein, human ; Cyclooxygenase 2 (EC 1.14.99.1) ; ErbB Receptors (EC 2.7.10.1)
    Language English
    Publishing date 2016-05-23
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-15-1144
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Dual-acting histone deacetylase-topoisomerase I inhibitors.

    Guerrant, William / Patil, Vishal / Canzoneri, Joshua C / Yao, Li-Pan / Hood, Rebecca / Oyelere, Adegboyega K

    Bioorganic & medicinal chemistry letters

    2013  Volume 23, Issue 11, Page(s) 3283–3287

    Abstract: Current chemotherapy regimens are comprised mostly of single-target drugs which are often plagued by toxic side effects and resistance development. A pharmacological strategy for circumventing these drawbacks could involve designing multivalent ligands ... ...

    Abstract Current chemotherapy regimens are comprised mostly of single-target drugs which are often plagued by toxic side effects and resistance development. A pharmacological strategy for circumventing these drawbacks could involve designing multivalent ligands that can modulate multiple targets while avoiding the toxicity of a single-targeted agent. Two attractive targets, histone deacetylase (HDAC) and topoisomerase I (Topo I), are cellular modulators that can broadly arrest cancer proliferation through a range of downstream effects. Both are clinically validated targets with multiple inhibitors in therapeutic use. We describe herein the design and synthesis of dual-acting histone deacetylase-topoisomerase I inhibitors. We also show that these dual-acting agents retain activity against HDAC and Topo I, and potently arrest cancer proliferation.
    MeSH term(s) Camptothecin/chemistry ; Cell Line, Tumor ; Cell Survival/drug effects ; DNA Topoisomerases, Type I/chemistry ; DNA Topoisomerases, Type I/metabolism ; Drug Design ; HeLa Cells ; Histone Deacetylase Inhibitors/chemical synthesis ; Histone Deacetylase Inhibitors/chemistry ; Histone Deacetylase Inhibitors/toxicity ; Histone Deacetylases/chemistry ; Histone Deacetylases/metabolism ; Humans ; Protein Isoforms/antagonists & inhibitors ; Protein Isoforms/metabolism ; Structure-Activity Relationship ; Topoisomerase I Inhibitors/chemical synthesis ; Topoisomerase I Inhibitors/chemistry ; Topoisomerase I Inhibitors/toxicity
    Chemical Substances Histone Deacetylase Inhibitors ; Protein Isoforms ; Topoisomerase I Inhibitors ; Histone Deacetylases (EC 3.5.1.98) ; DNA Topoisomerases, Type I (EC 5.99.1.2) ; Camptothecin (XT3Z54Z28A)
    Language English
    Publishing date 2013-04-04
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1063195-1
    ISSN 1464-3405 ; 0960-894X
    ISSN (online) 1464-3405
    ISSN 0960-894X
    DOI 10.1016/j.bmcl.2013.03.108
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 3203: Show issues Location:
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  9. Article ; Online: A novel three-dimensional high-throughput screening approach identifies inducers of a mutant KRAS selective lethal phenotype.

    Kota, Smitha / Hou, Shurong / Guerrant, William / Madoux, Franck / Troutman, Scott / Fernandez-Vega, Virneliz / Alekseeva, Nina / Madala, Neeharika / Scampavia, Louis / Kissil, Joseph / Spicer, Timothy P

    Oncogene

    2018  Volume 37, Issue 32, Page(s) 4372–4384

    Abstract: The RAS proteins are the most frequently mutated oncogenes in cancer, with highest frequency found in pancreatic, lung, and colon tumors. Moreover, the activity of RAS is required for the proliferation and/or survival of these tumor cells and thus ... ...

    Abstract The RAS proteins are the most frequently mutated oncogenes in cancer, with highest frequency found in pancreatic, lung, and colon tumors. Moreover, the activity of RAS is required for the proliferation and/or survival of these tumor cells and thus represents a high-value target for therapeutic development. Direct targeting of RAS has proven challenging for multiple reasons stemming from the biology of the protein, the complexity of downstream effector pathways and upstream regulatory networks. Thus, significant efforts have been directed at identifying downstream targets on which RAS is dependent. These efforts have proven challenging, in part due to confounding factors such as reliance on two-dimensional adherent monolayer cell cultures that inadequately recapitulate the physiologic context to which cells are exposed in vivo. To overcome these issues, we implemented a high-throughput screening (HTS) approach using a spheroid-based 3-dimensional culture format, thought to more closely reflect conditions experienced by cells in vivo. Using isogenic cell pairs, differing in the status of KRAS, we identified Proscillaridin A as a selective inhibitor of cells harboring the oncogenic KRas
    MeSH term(s) Antineoplastic Agents/pharmacology ; Cell Culture Techniques ; Cell Line, Tumor ; Drug Screening Assays, Antitumor/methods ; Humans ; Mutation/genetics ; Phenotype ; Proscillaridin/pharmacology ; Proto-Oncogene Proteins p21(ras)/genetics ; Signal Transduction/genetics
    Chemical Substances Antineoplastic Agents ; KRAS protein, human ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; Proscillaridin (KC6BL281EN)
    Language English
    Publishing date 2018-05-10
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 639046-8
    ISSN 1476-5594 ; 0950-9232
    ISSN (online) 1476-5594
    ISSN 0950-9232
    DOI 10.1038/s41388-018-0257-5
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 2218: Show issues Location:
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  10. Article ; Online: Macrocyclic histone deacetylase inhibitors.

    Mwakwari, Sandra C / Patil, Vishal / Guerrant, William / Oyelere, Adegboyega K

    Current topics in medicinal chemistry

    2010  Volume 10, Issue 14, Page(s) 1423–1440

    Abstract: Histone deacetylase inhibitors (HDACi) are an emerging class of novel anti-cancer drugs that cause growth arrest, differentiation, and apoptosis of tumor cells. In addition, they have shown promise as anti-parasitic, anti-neurodegenerative, anti- ... ...

    Abstract Histone deacetylase inhibitors (HDACi) are an emerging class of novel anti-cancer drugs that cause growth arrest, differentiation, and apoptosis of tumor cells. In addition, they have shown promise as anti-parasitic, anti-neurodegenerative, anti-rheumatologic and immunosuppressant agents. To date, several structurally distinct small molecule HDACi have been reported including aryl hydroxamates, benzamides, short-chain fatty acids, electrophilic ketones, and macrocyclic peptides. Macrocyclic HDACi possess the most complex cap-groups which interact with HDAC enzyme's outer rim and have demonstrated excellent HDAC inhibition potency and isoform selectivity. This review focuses on the recent progress and current state of macrocyclic HDACi.
    MeSH term(s) Animals ; Cell Differentiation ; Cell Proliferation ; Histone Deacetylase Inhibitors/chemistry ; Histone Deacetylases/metabolism ; Humans ; Hydroxamic Acids/chemistry ; Macrocyclic Compounds/chemistry
    Chemical Substances Histone Deacetylase Inhibitors ; Hydroxamic Acids ; Macrocyclic Compounds ; Histone Deacetylases (EC 3.5.1.98)
    Language English
    Publishing date 2010-06-03
    Publishing country United Arab Emirates
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2064823-6
    ISSN 1873-4294 ; 1568-0266
    ISSN (online) 1873-4294
    ISSN 1568-0266
    DOI 10.2174/156802610792232079
    Database MEDical Literature Analysis and Retrieval System OnLINE

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