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  1. Article ; Online: A review of COVID-19 biomarkers and drug targets: resources and tools.

    Caruso, Francesca P / Scala, Giovanni / Cerulo, Luigi / Ceccarelli, Michele

    Briefings in bioinformatics

    2021  Volume 22, Issue 2, Page(s) 701–713

    Abstract: The stratification of patients at risk of progression of COVID-19 and their molecular characterization is of extreme importance to optimize treatment and to identify therapeutic options. The bioinformatics community has responded to the outbreak ... ...

    Abstract The stratification of patients at risk of progression of COVID-19 and their molecular characterization is of extreme importance to optimize treatment and to identify therapeutic options. The bioinformatics community has responded to the outbreak emergency with a set of tools and resource to identify biomarkers and drug targets that we review here. Starting from a consolidated corpus of 27 570 papers, we adopt latent Dirichlet analysis to extract relevant topics and select those associated with computational methods for biomarker identification and drug repurposing. The selected topics span from machine learning and artificial intelligence for disease characterization to vaccine development and to therapeutic target identification. Although the way to go for the ultimate defeat of the pandemic is still long, the amount of knowledge, data and tools generated so far constitutes an unprecedented example of global cooperation to this threat.
    MeSH term(s) Antiviral Agents/therapeutic use ; Biomarkers/blood ; COVID-19/blood ; COVID-19/virology ; Drug Delivery Systems ; Drug Repositioning/methods ; Humans ; Machine Learning ; SARS-CoV-2/isolation & purification ; COVID-19 Drug Treatment
    Chemical Substances Antiviral Agents ; Biomarkers
    Language English
    Publishing date 2021-01-04
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2068142-2
    ISSN 1477-4054 ; 1467-5463
    ISSN (online) 1477-4054
    ISSN 1467-5463
    DOI 10.1093/bib/bbaa328
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: The combination of neoantigen quality and T lymphocyte infiltrates identifies glioblastomas with the longest survival.

    Zhang, Jing / Caruso, Francesca P / Sa, Jason K / Justesen, Sune / Nam, Do-Hyun / Sims, Peter / Ceccarelli, Michele / Lasorella, Anna / Iavarone, Antonio

    Communications biology

    2019  Volume 2, Page(s) 135

    Abstract: Glioblastoma (GBM) is resistant to multimodality therapeutic approaches. A high burden of tumor-specific mutant peptides (neoantigens) correlates with better survival and response to immunotherapies in selected solid tumors but how neoantigens impact ... ...

    Abstract Glioblastoma (GBM) is resistant to multimodality therapeutic approaches. A high burden of tumor-specific mutant peptides (neoantigens) correlates with better survival and response to immunotherapies in selected solid tumors but how neoantigens impact clinical outcome in GBM remains unclear. Here, we exploit the similarity between tumor neoantigens and infectious disease-derived immune epitopes and apply a neoantigen fitness model for identifying high-quality neoantigens in a human pan-glioma dataset. We find that the neoantigen quality fitness model stratifies GBM patients with more favorable clinical outcome and, together with CD8
    MeSH term(s) Amino Acid Sequence ; Antigens, Neoplasm/genetics ; Antigens, Neoplasm/immunology ; Brain Neoplasms/immunology ; Brain Neoplasms/mortality ; Cohort Studies ; Epitopes/genetics ; Epitopes/immunology ; Gene Ontology ; Glioblastoma/immunology ; Glioblastoma/mortality ; HLA Antigens/immunology ; Humans ; Inhibitory Concentration 50 ; Kaplan-Meier Estimate ; Lymphocytes, Tumor-Infiltrating/immunology ; Models, Immunological ; Oligopeptides/immunology ; Prognosis ; T-Cell Antigen Receptor Specificity ; T-Lymphocytes, Cytotoxic/immunology ; Tumor Microenvironment/immunology
    Chemical Substances Antigens, Neoplasm ; Epitopes ; HLA Antigens ; Oligopeptides
    Language English
    Publishing date 2019-04-23
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 2399-3642
    ISSN (online) 2399-3642
    DOI 10.1038/s42003-019-0369-7
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Multimodal single-cell analysis reveals distinct radioresistant stem-like and progenitor cell populations in murine glioma.

    Alexander, Jes / LaPlant, Quincey C / Pattwell, Siobhan S / Szulzewsky, Frank / Cimino, Patrick J / Caruso, Francesca P / Pugliese, Pietro / Chen, Zhihong / Chardon, Florence / Hill, Andrew J / Spurrell, Cailyn / Ahrendsen, Dakota / Pietras, Alexander / Starita, Lea M / Hambardzumyan, Dolores / Iavarone, Antonio / Shendure, Jay / Holland, Eric C

    Glia

    2020  Volume 68, Issue 12, Page(s) 2486–2502

    Abstract: Radiation therapy is part of the standard of care for gliomas and kills a subset of tumor cells, while also altering the tumor microenvironment. Tumor cells with stem-like properties preferentially survive radiation and give rise to glioma recurrence. ... ...

    Abstract Radiation therapy is part of the standard of care for gliomas and kills a subset of tumor cells, while also altering the tumor microenvironment. Tumor cells with stem-like properties preferentially survive radiation and give rise to glioma recurrence. Various techniques for enriching and quantifying cells with stem-like properties have been used, including the fluorescence activated cell sorting (FACS)-based side population (SP) assay, which is a functional assay that enriches for stem-like tumor cells. In these analyses, mouse models of glioma have been used to understand the biology of this disease and therapeutic responses, including the radiation response. We present combined SP analysis and single-cell RNA sequencing of genetically-engineered mouse models of glioma to show a time course of cellular response to radiation. We identify and characterize two distinct tumor cell populations that are inherently radioresistant and also distinct effects of radiation on immune cell populations within the tumor microenvironment.
    MeSH term(s) Animals ; Brain Neoplasms/radiotherapy ; Glioma ; Mice ; Neoplastic Stem Cells ; Single-Cell Analysis ; Stem Cells ; Tumor Microenvironment
    Language English
    Publishing date 2020-07-04
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 639414-0
    ISSN 1098-1136 ; 0894-1491
    ISSN (online) 1098-1136
    ISSN 0894-1491
    DOI 10.1002/glia.23866
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Temporospatial genomic profiling in glioblastoma identifies commonly altered core pathways underlying tumor progression.

    Blomquist, Mylan R / Ensign, Shannon Fortin / D'Angelo, Fulvio / Phillips, Joanna J / Ceccarelli, Michele / Peng, Sen / Halperin, Rebecca F / Caruso, Francesca P / Garofano, Luciano / Byron, Sara A / Liang, Winnie S / Craig, David W / Carpten, John D / Prados, Michael D / Trent, Jeffrey M / Berens, Michael E / Iavarone, Antonio / Dhruv, Harshil / Tran, Nhan L

    Neuro-oncology advances

    2020  Volume 2, Issue 1, Page(s) vdaa078

    Abstract: Background: Tumor heterogeneity underlies resistance and disease progression in glioblastoma (GBM), and tumors most commonly recur adjacent to the surgical resection margins in contrast non-enhancing (NE) regions. To date, no targeted therapies have ... ...

    Abstract Background: Tumor heterogeneity underlies resistance and disease progression in glioblastoma (GBM), and tumors most commonly recur adjacent to the surgical resection margins in contrast non-enhancing (NE) regions. To date, no targeted therapies have meaningfully altered overall patient survival in the up-front setting. The aim of this study was to characterize intratumoral heterogeneity in recurrent GBM using bulk samples from primary resection and recurrent samples taken from contrast-enhancing (EN) and contrast NE regions.
    Methods: Whole exome and RNA sequencing were performed on matched bulk primary and multiple recurrent EN and NE tumor samples from 16 GBM patients who received standard of care treatment alone or in combination with investigational clinical trial regimens.
    Results: Private mutations emerge across multi-region sampling in recurrent tumors. Genomic clonal analysis revealed increased enrichment in gene alterations regulating the G2M checkpoint, Kras signaling, Wnt signaling, and DNA repair in recurrent disease. Subsequent functional studies identified augmented PI3K/AKT transcriptional and protein activity throughout progression, validated by phospho-protein levels. Moreover, a mesenchymal transcriptional signature was observed in recurrent EN regions, which differed from the proneural signature in recurrent NE regions.
    Conclusions: Subclonal populations observed within bulk resected primary GBMs transcriptionally evolve across tumor recurrence (EN and NE regions) and exhibit aberrant gene expression of common signaling pathways that persist despite standard or targeted therapy. Our findings provide evidence that there are both adaptive and clonally mediated dependencies of GBM on key pathways, such as the PI3K/AKT axis, for survival across recurrences.
    Language English
    Publishing date 2020-06-19
    Publishing country England
    Document type Journal Article
    ZDB-ID 3009682-0
    ISSN 2632-2498 ; 2632-2498
    ISSN (online) 2632-2498
    ISSN 2632-2498
    DOI 10.1093/noajnl/vdaa078
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Integrated molecular and multiparametric MRI mapping of high-grade glioma identifies regional biologic signatures.

    Hu, Leland S / D'Angelo, Fulvio / Weiskittel, Taylor M / Caruso, Francesca P / Fortin Ensign, Shannon P / Blomquist, Mylan R / Flick, Matthew J / Wang, Lujia / Sereduk, Christopher P / Meng-Lin, Kevin / De Leon, Gustavo / Nespodzany, Ashley / Urcuyo, Javier C / Gonzales, Ashlyn C / Curtin, Lee / Lewis, Erika M / Singleton, Kyle W / Dondlinger, Timothy / Anil, Aliya /
    Semmineh, Natenael B / Noviello, Teresa / Patel, Reyna A / Wang, Panwen / Wang, Junwen / Eschbacher, Jennifer M / Hawkins-Daarud, Andrea / Jackson, Pamela R / Grunfeld, Itamar S / Elrod, Christian / Mazza, Gina L / McGee, Sam C / Paulson, Lisa / Clark-Swanson, Kamala / Lassiter-Morris, Yvette / Smith, Kris A / Nakaji, Peter / Bendok, Bernard R / Zimmerman, Richard S / Krishna, Chandan / Patra, Devi P / Patel, Naresh P / Lyons, Mark / Neal, Matthew / Donev, Kliment / Mrugala, Maciej M / Porter, Alyx B / Beeman, Scott C / Jensen, Todd R / Schmainda, Kathleen M / Zhou, Yuxiang / Baxter, Leslie C / Plaisier, Christopher L / Li, Jing / Li, Hu / Lasorella, Anna / Quarles, C Chad / Swanson, Kristin R / Ceccarelli, Michele / Iavarone, Antonio / Tran, Nhan L

    Nature communications

    2023  Volume 14, Issue 1, Page(s) 6066

    Abstract: Sampling restrictions have hindered the comprehensive study of invasive non-enhancing (NE) high-grade glioma (HGG) cell populations driving tumor progression. Here, we present an integrated multi-omic analysis of spatially matched molecular and multi- ... ...

    Abstract Sampling restrictions have hindered the comprehensive study of invasive non-enhancing (NE) high-grade glioma (HGG) cell populations driving tumor progression. Here, we present an integrated multi-omic analysis of spatially matched molecular and multi-parametric magnetic resonance imaging (MRI) profiling across 313 multi-regional tumor biopsies, including 111 from the NE, across 68 HGG patients. Whole exome and RNA sequencing uncover unique genomic alterations to unresectable invasive NE tumor, including subclonal events, which inform genomic models predictive of geographic evolution. Infiltrative NE tumor is alternatively enriched with tumor cells exhibiting neuronal or glycolytic/plurimetabolic cellular states, two principal transcriptomic pathway-based glioma subtypes, which respectively demonstrate abundant private mutations or enrichment in immune cell signatures. These NE phenotypes are non-invasively identified through normalized K2 imaging signatures, which discern cell size heterogeneity on dynamic susceptibility contrast (DSC)-MRI. NE tumor populations predicted to display increased cellular proliferation by mean diffusivity (MD) MRI metrics are uniquely associated with EGFR amplification and CDKN2A homozygous deletion. The biophysical mapping of infiltrative HGG potentially enables the clinical recognition of tumor subpopulations with aggressive molecular signatures driving tumor progression, thereby informing precision medicine targeting.
    MeSH term(s) Humans ; Brain Neoplasms/diagnostic imaging ; Brain Neoplasms/genetics ; Brain Neoplasms/pathology ; Multiparametric Magnetic Resonance Imaging ; Homozygote ; Sequence Deletion ; Glioma/diagnostic imaging ; Glioma/genetics ; Glioma/pathology ; Magnetic Resonance Imaging/methods ; Biological Products
    Chemical Substances Biological Products
    Language English
    Publishing date 2023-09-28
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-023-41559-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Transcriptional regulatory networks of tumor-associated macrophages that drive malignancy in mesenchymal glioblastoma.

    Sa, Jason K / Chang, Nakho / Lee, Hye Won / Cho, Hee Jin / Ceccarelli, Michele / Cerulo, Luigi / Yin, Jinlong / Kim, Sung Soo / Caruso, Francesca P / Lee, Mijeong / Kim, Donggeon / Oh, Young Taek / Lee, Yeri / Her, Nam-Gu / Min, Byeongkwi / Kim, Hye-Jin / Jeong, Da Eun / Kim, Hye-Mi / Kim, Hyunho /
    Chung, Seok / Woo, Hyun Goo / Lee, Jeongwu / Kong, Doo-Sik / Seol, Ho Jun / Lee, Jung-Il / Kim, Jinho / Park, Woong-Yang / Wang, Qianghu / Sulman, Erik P / Heimberger, Amy B / Lim, Michael / Park, Jong Bae / Iavarone, Antonio / Verhaak, Roel G W / Nam, Do-Hyun

    Genome biology

    2020  Volume 21, Issue 1, Page(s) 216

    Abstract: Background: Glioblastoma (GBM) is a complex disease with extensive molecular and transcriptional heterogeneity. GBM can be subcategorized into four distinct subtypes; tumors that shift towards the mesenchymal phenotype upon recurrence are generally ... ...

    Abstract Background: Glioblastoma (GBM) is a complex disease with extensive molecular and transcriptional heterogeneity. GBM can be subcategorized into four distinct subtypes; tumors that shift towards the mesenchymal phenotype upon recurrence are generally associated with treatment resistance, unfavorable prognosis, and the infiltration of pro-tumorigenic macrophages.
    Results: We explore the transcriptional regulatory networks of mesenchymal-associated tumor-associated macrophages (MA-TAMs), which drive the malignant phenotypic state of GBM, and identify macrophage receptor with collagenous structure (MARCO) as the most highly differentially expressed gene. MARCO
    Conclusions: Collectively, our study characterizes the global transcriptional profile of TAMs driving mesenchymal GBM pathogenesis, providing potential therapeutic targets for improving the effectiveness of GBM immunotherapy.
    Language English
    Publishing date 2020-08-26
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2040529-7
    ISSN 1474-760X ; 1465-6906
    ISSN (online) 1474-760X
    ISSN 1465-6906
    DOI 10.1186/s13059-020-02140-x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article: Transcriptional regulatory networks of tumor-associated macrophages that drive malignancy in mesenchymal glioblastoma

    Sa, Jason K / Chang, Nakho / Lee, Hye Won / Cho, Hee Jin / Ceccarelli, Michele / Cerulo, Luigi / Yin, Jinlong / Kim, Sung Soo / Caruso, Francesca P / Lee, Mijeong / Kim, Donggeon / Oh, Young Taek / Lee, Yeri / Her, Nam-Gu / Min, Byeongkwi / Kim, Hye-Jin / Jeong, Da Eun / Kim, Hye-Mi / Kim, Hyunho /
    Chung, Seok / Woo, Hyun Goo / Lee, Jeongwu / Kong, Doo-Sik / Seol, Ho Jun / Lee, Jung-Il / Kim, Jinho / Park, Woong-Yang / Wang, Qianghu / Sulman, Erik P / Heimberger, Amy B / Lim, Michael / Park, Jong Bae / Iavarone, Antonio / Verhaak, Roel G. W / Nam, Do-Hyun

    Genome biology. 2020 Dec., v. 21, no. 1

    2020  

    Abstract: BACKGROUND: Glioblastoma (GBM) is a complex disease with extensive molecular and transcriptional heterogeneity. GBM can be subcategorized into four distinct subtypes; tumors that shift towards the mesenchymal phenotype upon recurrence are generally ... ...

    Abstract BACKGROUND: Glioblastoma (GBM) is a complex disease with extensive molecular and transcriptional heterogeneity. GBM can be subcategorized into four distinct subtypes; tumors that shift towards the mesenchymal phenotype upon recurrence are generally associated with treatment resistance, unfavorable prognosis, and the infiltration of pro-tumorigenic macrophages. RESULTS: We explore the transcriptional regulatory networks of mesenchymal-associated tumor-associated macrophages (MA-TAMs), which drive the malignant phenotypic state of GBM, and identify macrophage receptor with collagenous structure (MARCO) as the most highly differentially expressed gene. MARCOʰⁱᵍʰ TAMs induce a phenotypic shift towards mesenchymal cellular state of glioma stem cells, promoting both invasive and proliferative activities, as well as therapeutic resistance to irradiation. MARCOʰⁱᵍʰ TAMs also significantly accelerate tumor engraftment and growth in vivo. Moreover, both MA-TAM master regulators and their target genes are significantly correlated with poor clinical outcomes and are often associated with genomic aberrations in neurofibromin 1 (NF1) and phosphoinositide 3-kinases/mammalian target of rapamycin/Akt pathway (PI3K-mTOR-AKT)-related genes. We further demonstrate the origination of MA-TAMs from peripheral blood, as well as their potential association with tumor-induced polarization states and immunosuppressive environments. CONCLUSIONS: Collectively, our study characterizes the global transcriptional profile of TAMs driving mesenchymal GBM pathogenesis, providing potential therapeutic targets for improving the effectiveness of GBM immunotherapy.
    Keywords blood ; gene expression regulation ; genes ; genomics ; glioblastoma ; immunosuppression ; immunotherapy ; irradiation ; macrophages ; mammals ; neoplasm cells ; pathogenesis ; phenotype ; phenotypic plasticity ; phosphatidylinositol 3-kinase ; prognosis ; rapamycin ; stem cells ; transcription (genetics)
    Language English
    Dates of publication 2020-12
    Size p. 216.
    Publishing place BioMed Central
    Document type Article
    ZDB-ID 2040529-7
    ISSN 1474-760X ; 1465-6906
    ISSN (online) 1474-760X
    ISSN 1465-6906
    DOI 10.1186/s13059-020-02140-x
    Database NAL-Catalogue (AGRICOLA)

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  8. Article ; Online: The molecular landscape of glioma in patients with Neurofibromatosis 1.

    D'Angelo, Fulvio / Ceccarelli, Michele / Tala / Garofano, Luciano / Zhang, Jing / Frattini, Véronique / Caruso, Francesca P / Lewis, Genevieve / Alfaro, Kristin D / Bauchet, Luc / Berzero, Giulia / Cachia, David / Cangiano, Mario / Capelle, Laurent / de Groot, John / DiMeco, Francesco / Ducray, François / Farah, Walid / Finocchiaro, Gaetano /
    Goutagny, Stéphane / Kamiya-Matsuoka, Carlos / Lavarino, Cinzia / Loiseau, Hugues / Lorgis, Véronique / Marras, Carlo E / McCutcheon, Ian / Nam, Do-Hyun / Ronchi, Susanna / Saletti, Veronica / Seizeur, Romuald / Slopis, John / Suñol, Mariona / Vandenbos, Fanny / Varlet, Pascale / Vidaud, Dominique / Watts, Colin / Tabar, Viviane / Reuss, David E / Kim, Seung-Ki / Meyronet, David / Mokhtari, Karima / Salvador, Hector / Bhat, Krishna P / Eoli, Marica / Sanson, Marc / Lasorella, Anna / Iavarone, Antonio

    Nature medicine

    2018  Volume 25, Issue 1, Page(s) 176–187

    Abstract: Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome in which glioma is one of the prevalent tumors. Gliomagenesis in NF1 results in a heterogeneous spectrum of low- to high-grade neoplasms occurring during the entire lifespan of ... ...

    Abstract Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome in which glioma is one of the prevalent tumors. Gliomagenesis in NF1 results in a heterogeneous spectrum of low- to high-grade neoplasms occurring during the entire lifespan of patients. The pattern of genetic and epigenetic alterations of glioma that develops in NF1 patients and the similarities with sporadic glioma remain unknown. Here, we present the molecular landscape of low- and high-grade gliomas in patients affected by NF1 (NF1-glioma). We found that the predisposing germline mutation of the NF1 gene was frequently converted to homozygosity and the somatic mutational load of NF1-glioma was influenced by age and grade. High-grade tumors harbored genetic alterations of TP53 and CDKN2A, frequent mutations of ATRX associated with Alternative Lengthening of Telomere, and were enriched in genetic alterations of transcription/chromatin regulation and PI3 kinase pathways. Low-grade tumors exhibited fewer mutations that were over-represented in genes of the MAP kinase pathway. Approximately 50% of low-grade NF1-gliomas displayed an immune signature, T lymphocyte infiltrates, and increased neo-antigen load. DNA methylation assigned NF1-glioma to LGm6, a poorly defined Isocitrate Dehydrogenase 1 wild-type subgroup enriched with ATRX mutations. Thus, the profiling of NF1-glioma defined a distinct landscape that recapitulates a subset of sporadic tumors.
    MeSH term(s) Adolescent ; Adult ; Antigens, Neoplasm/metabolism ; Brain Neoplasms/complications ; Brain Neoplasms/genetics ; Brain Neoplasms/immunology ; Child ; Child, Preschool ; Cohort Studies ; DNA Methylation/genetics ; Female ; Germ-Line Mutation/genetics ; Glioma/complications ; Glioma/genetics ; Glioma/immunology ; Humans ; Male ; Middle Aged ; Neurofibromatosis 1/complications ; Neurofibromatosis 1/genetics ; Neurofibromin 1/genetics ; Reproducibility of Results ; T-Lymphocytes/immunology ; Transcriptome/genetics ; X-linked Nuclear Protein/genetics ; Young Adult
    Chemical Substances Antigens, Neoplasm ; NF1 protein, human ; Neurofibromin 1 ; ATRX protein, human (EC 3.6.4.12) ; X-linked Nuclear Protein (EC 3.6.4.12)
    Language English
    Publishing date 2018-12-10
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1220066-9
    ISSN 1546-170X ; 1078-8956
    ISSN (online) 1546-170X
    ISSN 1078-8956
    DOI 10.1038/s41591-018-0263-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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