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  1. Article ; Online: Novel coronavirus treatment with ribavirin: Groundwork for an evaluation concerning COVID-19.

    Khalili, Jahan S / Zhu, Hai / Mak, Nga Sze Amanda / Yan, Yongqi / Zhu, Yi

    Journal of medical virology

    2020  Volume 92, Issue 7, Page(s) 740–746

    Abstract: Confronting the challenge of the outbreak of COVID-19 should sharpen our focus on global drug access as a key issue in antiviral therapy testing. The testing and adoption of effective therapies for novel coronaviruses are hampered by the challenge of ... ...

    Abstract Confronting the challenge of the outbreak of COVID-19 should sharpen our focus on global drug access as a key issue in antiviral therapy testing. The testing and adoption of effective therapies for novel coronaviruses are hampered by the challenge of conducting controlled studies during a state of emergency. The access to direct antiviral drugs, such as ribavirin, that have an existing inventory and reliable supply chain may be a priority consideration for therapies developed for the 2019-nCoV infection outbreaks and any strain variants that may emerge. On the basis of the direct antiviral activity of ribavirin against 2019-nCoV in vitro and evidence for potency enhancement strategies developed during the prior SARS and MERS outbreaks, ribavirin may significantly impact our ability to end the lingering outbreaks in China and slow outbreaks in other countries. The apparent COVID-19 pandemic provides an opportunity to follow dosage guidelines for treatment with ribavirin, test new therapeutic concepts, and conduct controlled testing to apply the scientific rigor required to address the controversy around this mainstay of antiviral therapy.
    MeSH term(s) Antiviral Agents/therapeutic use ; Betacoronavirus/drug effects ; Betacoronavirus/genetics ; Betacoronavirus/pathogenicity ; COVID-19 ; Clinical Trials as Topic ; Coronavirus Infections/drug therapy ; Coronavirus Infections/epidemiology ; Coronavirus Infections/virology ; Disease Progression ; Drug Administration Schedule ; Gene Expression Regulation, Viral ; Humans ; Pandemics ; Pneumonia, Viral/drug therapy ; Pneumonia, Viral/epidemiology ; Pneumonia, Viral/virology ; RNA, Viral/antagonists & inhibitors ; RNA, Viral/biosynthesis ; RNA, Viral/genetics ; Ribavirin/therapeutic use ; SARS-CoV-2 ; Signal Transduction
    Chemical Substances Antiviral Agents ; RNA, Viral ; Ribavirin (49717AWG6K)
    Keywords covid19
    Language English
    Publishing date 2020-04-10
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 752392-0
    ISSN 1096-9071 ; 0146-6615
    ISSN (online) 1096-9071
    ISSN 0146-6615
    DOI 10.1002/jmv.25798
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  2. Article ; Online: Novel coronavirus treatment with ribavirin

    Khalili, Jahan S. / Zhu, Hai / Mak, Nga Sze Amanda / Yan, Yongqi / Zhu, Yi

    Journal of Medical Virology

    Groundwork for an evaluation concerning COVID‐19

    2020  Volume 92, Issue 7, Page(s) 740–746

    Keywords Virology ; Infectious Diseases ; covid19
    Language English
    Publisher Wiley
    Publishing country us
    Document type Article ; Online
    ZDB-ID 752392-0
    ISSN 1096-9071 ; 0146-6615
    ISSN (online) 1096-9071
    ISSN 0146-6615
    DOI 10.1002/jmv.25798
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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    Zs.A 1320: Show issues Location:
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  3. Article ; Online: ACE2-Fc fusion protein overcomes viral escape by potently neutralizing SARS-CoV-2 variants of concern.

    Tsai, Tsung-I / Khalili, Jahan S / Gilchrist, Mark / Waight, Andrew B / Cohen, Daniella / Zhuo, Shi / Zhang, Yong / Ding, Muran / Zhu, Hai / Mak, Amanda Nga-Sze / Zhu, Yi / Goulet, Dennis R

    Antiviral research

    2022  Volume 199, Page(s) 105271

    Abstract: COVID-19, an infectious disease caused by the SARS-CoV-2 virus, emerged globally in early 2020 and has remained a serious public health issue. To date, although several preventative vaccines have been approved by FDA and EMA, vaccinated individuals ... ...

    Abstract COVID-19, an infectious disease caused by the SARS-CoV-2 virus, emerged globally in early 2020 and has remained a serious public health issue. To date, although several preventative vaccines have been approved by FDA and EMA, vaccinated individuals increasingly suffer from breakthrough infections. Therapeutic antibodies may provide an alternative strategy to neutralize viral infection and treat serious cases; however, the clinical data and our experiments show that some FDA-approved monoclonal antibodies lose function against COVID-19 variants such as Omicron. Therefore, in this study, we present a novel therapeutic agent, SI-F019, an ACE2-Fc fusion protein whose neutralization efficiency is not compromised, but actually strengthened, by the mutations of dominant variants including Omicron. Comprehensive biophysical analyses revealed the mechanism of increased inhibition to be enhanced interaction of SI-F019 with all the tested spike variants, in contrast to monoclonal antibodies which tended to show weaker binding to some variants. The results imply that SI-F019 may be a broadly useful agent for treatment of COVID-19.
    MeSH term(s) Angiotensin-Converting Enzyme 2 ; Antibodies, Neutralizing ; Antibodies, Viral/therapeutic use ; Humans ; SARS-CoV-2/genetics ; Spike Glycoprotein, Coronavirus ; COVID-19 Drug Treatment
    Chemical Substances Antibodies, Neutralizing ; Antibodies, Viral ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
    Language English
    Publishing date 2022-02-28
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 306628-9
    ISSN 1872-9096 ; 0166-3542
    ISSN (online) 1872-9096
    ISSN 0166-3542
    DOI 10.1016/j.antiviral.2022.105271
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1627: Show issues Location:
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    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  4. Article: Forging a link between oncogenic signaling and immunosuppression in melanoma.

    Khalili, Jahan S / Hwu, Patrick / Lizée, Gregory

    Oncoimmunology

    2013  Volume 2, Issue 2, Page(s) e22745

    Abstract: Immunosuppressive tumor microenvironments limit the efficacy of T cell-based immunotherapy. We have recently demonstrated that the inhibition of ... ...

    Abstract Immunosuppressive tumor microenvironments limit the efficacy of T cell-based immunotherapy. We have recently demonstrated that the inhibition of BRAF
    Language English
    Publishing date 2013-02-28
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2645309-5
    ISSN 2162-402X ; 2162-4011
    ISSN (online) 2162-402X
    ISSN 2162-4011
    DOI 10.4161/onci.22745
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: Novel coronavirus treatment with ribavirin: Groundwork for an evaluation concerning COVID-19

    Khalili, Jahan S / Zhu, Hai / Mak, Nga Sze Amanda / Yan, Yongqi / Zhu, Yi

    J Med Virol

    Abstract: Confronting the challenge of the outbreak of COVID-19 should sharpen our focus on global drug access as a key issue in antiviral therapy testing. The testing and adoption of effective therapies for novel coronaviruses are hampered by the challenge of ... ...

    Abstract Confronting the challenge of the outbreak of COVID-19 should sharpen our focus on global drug access as a key issue in antiviral therapy testing. The testing and adoption of effective therapies for novel coronaviruses are hampered by the challenge of conducting controlled studies during a state of emergency. The access to direct antiviral drugs, such as ribavirin, that have an existing inventory and reliable supply chain may be a priority consideration for therapies developed for the 2019-nCoV infection outbreaks and any strain variants that may emerge. On the basis of the direct antiviral activity of ribavirin against 2019-nCoV in vitro and evidence for potency enhancement strategies developed during the prior SARS and MERS outbreaks, ribavirin may significantly impact our ability to end the lingering outbreaks in China and slow outbreaks in other countries. The apparent COVID-19 pandemic provides an opportunity to follow dosage guidelines for treatment with ribavirin, test new therapeutic concepts, and conduct controlled testing to apply the scientific rigor required to address the controversy around this mainstay of antiviral therapy.
    Keywords covid19
    Publisher WHO
    Document type Article
    Note WHO #Covidence: #87806
    Database COVID19

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  6. Article ; Online: Human forebrain endothelial cell therapy for psychiatric disorders.

    Datta, Debkanya / Subburaju, Sivan / Kaye, Sarah / Baruah, Jugajyoti / Choi, Yong Kee / Nian, Yeqi / Khalili, Jahan S / Chung, Sangmi / Elkhal, Abdallah / Vasudevan, Anju

    Molecular psychiatry

    2020  Volume 26, Issue 9, Page(s) 4864–4883

    Abstract: Abnormalities of or reductions in GABAergic interneurons are implicated in the pathology of severe neuropsychiatric disorders, for which effective treatments are still elusive. Transplantation of human stem cell-derived interneurons is a promising cell- ... ...

    Abstract Abnormalities of or reductions in GABAergic interneurons are implicated in the pathology of severe neuropsychiatric disorders, for which effective treatments are still elusive. Transplantation of human stem cell-derived interneurons is a promising cell-based therapy for treatment of these disorders. In mouse xenograft studies, human stem cell-derived-interneuron precursors could differentiate in vivo, but required a prolonged time of four to seven months to migrate from the graft site and integrate with the host tissue. This poses a serious roadblock for clinical translation of this approach. For transplantation to be effective, grafted neurons should migrate to affected areas at a faster rate. We have previously shown that endothelial cells of the periventricular vascular network are the natural substrates for GABAergic interneurons in the developing mouse forebrain, and provide valuable guidance cues for their long-distance migration. In addition, periventricular endothelial cells house a GABA signaling pathway with direct implications for psychiatric disease origin. In this study we translated this discovery into human, with significant therapeutic implications. We generated human periventricular endothelial cells, using human pluripotent stem cell technology, and extensively characterized its molecular, cellular, and functional properties. Co-culture of human periventricular endothelial cells with human interneurons significantly accelerated interneuron migration in vitro and led to faster migration and wider distribution of grafted interneurons in vivo, compared to neuron-only transplants. Furthermore, the co-transplantation strategy was able to rescue abnormal behavioral symptoms in a pre-clinical model of psychiatric disorder, within 1 month after transplantation. We anticipate this strategy to open new doors and facilitate exciting advances in angiogenesis-mediated treatment of psychiatric disorders.
    MeSH term(s) Animals ; Cell Movement ; Endothelial Cells ; GABAergic Neurons ; Humans ; Interneurons ; Mental Disorders/therapy ; Mice ; Prosencephalon
    Language English
    Publishing date 2020-07-13
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1330655-8
    ISSN 1476-5578 ; 1359-4184
    ISSN (online) 1476-5578
    ISSN 1359-4184
    DOI 10.1038/s41380-020-0839-9
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    Zs.A 4812: Show issues Location:
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    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  7. Article: In silico prediction of tumor antigens derived from functional missense mutations of the cancer gene census.

    Khalili, Jahan S / Hanson, Russell W / Szallasi, Zoltan

    Oncoimmunology

    2012  Volume 1, Issue 8, Page(s) 1281–1289

    Abstract: Antigen-specific immune responses against peptides derived from missense gene mutations have been identified in multiple cancers. The application of personalized peptide vaccines based on the tumor mutation repertoire of each cancer patient is a near- ... ...

    Abstract Antigen-specific immune responses against peptides derived from missense gene mutations have been identified in multiple cancers. The application of personalized peptide vaccines based on the tumor mutation repertoire of each cancer patient is a near-term clinical reality. These peptides can be identified for pre-validation by leveraging the results of massive gene sequencing efforts in cancer. In this study, we utilized NetMHC 3.2 to predict nanomolar peptide binding affinity to 57 human HLA-A and B alleles. All peptides were derived from 5,685 missense mutations in 312 genes annotated as functionally relevant in the Cancer Genome Project. Of the 26,672,189 potential 8-11 mer peptide-HLA pairs evaluated, 0.4% (127,800) display binding affinities < 50 nM, predicting high affinity interactions. These peptides can be segregated into two groups based on the binding affinity to HLA proteins relative to germline-encoded sequences: peptides for which both the mutant and wild-type forms are high affinity binders, and peptides for which only the mutant form is a high affinity binder. Current evidence directs the attention to mutations that increase HLA binding affinity, as compared with cognate wild-type peptide sequences, as these potentially are more relevant for vaccine development from a clinical perspective. Our analysis generated a database including all predicted HLA binding peptides and the corresponding change in binding affinity as a result of point mutations. Our study constitutes a broad foundation for the development of personalized peptide vaccines that hone-in on functionally relevant targets in multiple cancers in individuals with diverse HLA haplotypes.
    Language English
    Publishing date 2012-11-28
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2645309-5
    ISSN 2162-402X ; 2162-4011
    ISSN (online) 2162-402X
    ISSN 2162-4011
    DOI 10.4161/onci.21511
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: B-Raf regulation of integrin α4β1-mediated resistance to shear stress through changes in cell spreading and cytoskeletal association in T cells.

    Brown, Wells S / Khalili, Jahan S / Rodriguez-Cruz, Tania G / Lizee, Greg / McIntyre, Bradley W

    The Journal of biological chemistry

    2014  Volume 289, Issue 33, Page(s) 23141–23153

    Abstract: The regulation of integrin-mediated adhesion is of vital importance to adaptive and innate immunity. Integrins are versatile proteins and mediate T cell migration and trafficking by binding to extracellular matrix or other cells as well as initiating ... ...

    Abstract The regulation of integrin-mediated adhesion is of vital importance to adaptive and innate immunity. Integrins are versatile proteins and mediate T cell migration and trafficking by binding to extracellular matrix or other cells as well as initiating intracellular signaling cascades promoting survival or activation. The MAPK pathway is known to be downstream from integrins and to regulate survival, differentiation, and motility. However, secondary roles for canonical MAPK pathway members are being discovered. We show that chemical inhibition of RAF by sorafenib or shRNA-mediated knockdown of B-Raf reduces T cell resistance to shear stress to α4β1 integrin ligands vascular cell adhesion molecule 1 (VCAM-1) and fibronectin, whereas inhibition of MEK/ERK by U0126 had no effect. Microscopy showed that RAF inhibition leads to significant inhibition of T cell spreading on VCAM-1. The association of α4β1 integrin with the actin cytoskeleton was shown to be dependent on B-Raf activity or expression, whereas α4β1 integrin affinity for soluble VCAM-1 was not. These effects were shown to be specific for α4β1 integrin and not other integrins, such as α5β1 or LFA-1, or a variety of membrane proteins. We demonstrate a novel role for B-Raf in the selective regulation of α4β1 integrin-mediated adhesion.
    MeSH term(s) Cell Adhesion/drug effects ; Cell Adhesion/physiology ; Cytoskeleton/genetics ; Cytoskeleton/metabolism ; Gene Knockdown Techniques ; Humans ; Integrin alpha4beta1/genetics ; Integrin alpha4beta1/metabolism ; Jurkat Cells ; Lymphocyte Function-Associated Antigen-1/genetics ; Lymphocyte Function-Associated Antigen-1/metabolism ; Niacinamide/analogs & derivatives ; Niacinamide/pharmacology ; Phenylurea Compounds/pharmacology ; Protein Kinase Inhibitors/pharmacology ; Proto-Oncogene Proteins B-raf/antagonists & inhibitors ; Proto-Oncogene Proteins B-raf/genetics ; Proto-Oncogene Proteins B-raf/metabolism ; Receptors, Vitronectin/genetics ; Receptors, Vitronectin/metabolism ; Shear Strength/drug effects ; Shear Strength/physiology ; Sorafenib ; Stress, Physiological/drug effects ; Stress, Physiological/physiology ; T-Lymphocytes/cytology ; T-Lymphocytes/metabolism ; Vascular Cell Adhesion Molecule-1/genetics ; Vascular Cell Adhesion Molecule-1/metabolism
    Chemical Substances Integrin alpha4beta1 ; Lymphocyte Function-Associated Antigen-1 ; Phenylurea Compounds ; Protein Kinase Inhibitors ; Receptors, Vitronectin ; Vascular Cell Adhesion Molecule-1 ; integrin alphavbeta1 ; Niacinamide (25X51I8RD4) ; Sorafenib (9ZOQ3TZI87) ; BRAF protein, human (EC 2.7.11.1) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1)
    Language English
    Publishing date 2014-06-16
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.M114.562918
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    Uc I Zs.108: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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  9. Article ; Online: Endothelial cell-derived GABA signaling modulates neuronal migration and postnatal behavior.

    Li, Suyan / Kumar T, Peeyush / Joshee, Sampada / Kirschstein, Timo / Subburaju, Sivan / Khalili, Jahan S / Kloepper, Jonas / Du, Chuang / Elkhal, Abdallah / Szabó, Gábor / Jain, Rakesh K / Köhling, Rüdiger / Vasudevan, Anju

    Cell research

    2017  Volume 28, Issue 2, Page(s) 221–248

    Abstract: The cerebral cortex is essential for integration and processing of information that is required for most behaviors. The exquisitely precise laminar organization of the cerebral cortex arises during embryonic development when neurons migrate successively ... ...

    Abstract The cerebral cortex is essential for integration and processing of information that is required for most behaviors. The exquisitely precise laminar organization of the cerebral cortex arises during embryonic development when neurons migrate successively from ventricular zones to coalesce into specific cortical layers. While radial glia act as guide rails for projection neuron migration, pre-formed vascular networks provide support and guidance cues for GABAergic interneuron migration. This study provides novel conceptual and mechanistic insights into this paradigm of vascular-neuronal interactions, revealing new mechanisms of GABA and its receptor-mediated signaling via embryonic forebrain endothelial cells. With the use of two new endothelial cell specific conditional mouse models of the GABA pathway (Gabrb3
    MeSH term(s) Animals ; Behavior, Animal ; Cell Movement ; Cerebral Cortex/blood supply ; Cerebral Cortex/cytology ; Cerebral Cortex/embryology ; Endothelial Cells/metabolism ; Female ; GABAergic Neurons/physiology ; Gene Expression Profiling ; Interneurons/physiology ; Male ; Mice ; Mice, Knockout ; Mice, Transgenic ; Models, Animal ; Neurodevelopmental Disorders/etiology ; Neurodevelopmental Disorders/physiopathology ; Neurogenesis/physiology ; Phenotype ; Pregnancy ; RNA/genetics ; Receptors, GABA-A/physiology ; Vesicular Inhibitory Amino Acid Transport Proteins/metabolism ; gamma-Aminobutyric Acid/metabolism
    Chemical Substances Gabrb3 protein, mouse ; Receptors, GABA-A ; Vesicular Inhibitory Amino Acid Transport Proteins ; Viaat protein, mouse ; gamma-Aminobutyric Acid (56-12-2) ; RNA (63231-63-0)
    Language English
    Publishing date 2017-10-31
    Publishing country England
    Document type Journal Article
    ZDB-ID 1319303-x
    ISSN 1748-7838 ; 1001-0602
    ISSN (online) 1748-7838
    ISSN 1001-0602
    DOI 10.1038/cr.2017.135
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    Zs.A 5283: Show issues Location:
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  10. Article ; Online: Aurora kinase inhibition sensitizes melanoma cells to T-cell-mediated cytotoxicity.

    Punt, Simone / Malu, Shruti / McKenzie, Jodi A / Manrique, Soraya Zorro / Doorduijn, Elien M / Mbofung, Rina M / Williams, Leila / Silverman, Deborah A / Ashkin, Emily L / Dominguez, Ana Lucía / Wang, Zhe / Chen, Jie Qing / Maiti, Sourindra N / Tieu, Trang N / Liu, Chengwen / Xu, Chunyu / Forget, Marie-Andrée / Haymaker, Cara / Khalili, Jahan S /
    Satani, Nikunj / Muller, Florian / Cooper, Laurence J N / Overwijk, Willem W / Amaria, Rodabe N / Bernatchez, Chantale / Heffernan, Timothy P / Peng, Weiyi / Roszik, Jason / Hwu, Patrick

    Cancer immunology, immunotherapy : CII

    2020  Volume 70, Issue 4, Page(s) 1101–1113

    Abstract: Although immunotherapy has achieved impressive durable clinical responses, many cancers respond only temporarily or not at all to immunotherapy. To find novel, targetable mechanisms of resistance to immunotherapy, patient-derived melanoma cell lines were ...

    Abstract Although immunotherapy has achieved impressive durable clinical responses, many cancers respond only temporarily or not at all to immunotherapy. To find novel, targetable mechanisms of resistance to immunotherapy, patient-derived melanoma cell lines were transduced with 576 open reading frames, or exposed to arrayed libraries of 850 bioactive compounds, prior to co-culture with autologous tumor-infiltrating lymphocytes (TILs). The synergy between the targets and TILs to induce apoptosis, and the mechanisms of inhibiting resistance to TILs were interrogated. Gene expression analyses were performed on tumor samples from patients undergoing immunotherapy for metastatic melanoma. Finally, the effect of inhibiting the top targets on the efficacy of immunotherapy was investigated in multiple preclinical models. Aurora kinase was identified as a mediator of melanoma cell resistance to T-cell-mediated cytotoxicity in both complementary screens. Aurora kinase inhibitors were validated to synergize with T-cell-mediated cytotoxicity in vitro. The Aurora kinase inhibition-mediated sensitivity to T-cell cytotoxicity was shown to be partially driven by p21-mediated induction of cellular senescence. The expression levels of Aurora kinase and related proteins were inversely correlated with immune infiltration, response to immunotherapy and survival in melanoma patients. Aurora kinase inhibition showed variable responses in combination with immunotherapy in vivo, suggesting its activity is modified by other factors in the tumor microenvironment. These data suggest that Aurora kinase inhibition enhances T-cell cytotoxicity in vitro and can potentiate antitumor immunity in vivo in some but not all settings. Further studies are required to determine the mechanism of primary resistance to this therapeutic intervention.
    MeSH term(s) Animals ; Apoptosis ; Aurora Kinase A/antagonists & inhibitors ; Aurora Kinase A/genetics ; Aurora Kinase A/metabolism ; Aurora Kinase B/antagonists & inhibitors ; Aurora Kinase B/genetics ; Aurora Kinase B/metabolism ; Cell Proliferation ; Drug Resistance, Neoplasm/immunology ; Female ; Humans ; Immunotherapy/methods ; Lymphocytes, Tumor-Infiltrating/immunology ; Melanoma/genetics ; Melanoma/immunology ; Melanoma/metabolism ; Melanoma/therapy ; Mice ; Prognosis ; Survival Rate ; T-Lymphocytes, Cytotoxic/immunology ; T-Lymphocytes, Cytotoxic/transplantation ; Tumor Cells, Cultured ; Tumor Microenvironment/immunology ; Xenograft Model Antitumor Assays
    Chemical Substances AURKA protein, human (EC 2.7.11.1) ; AURKB protein, human (EC 2.7.11.1) ; Aurora Kinase A (EC 2.7.11.1) ; Aurora Kinase B (EC 2.7.11.1)
    Language English
    Publishing date 2020-10-29
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 195342-4
    ISSN 1432-0851 ; 0340-7004
    ISSN (online) 1432-0851
    ISSN 0340-7004
    DOI 10.1007/s00262-020-02748-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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