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  1. Article ; Online: Targeting the activated microenvironment with endosialin (CD248)-directed CAR-T cells ablates perivascular cells to impair tumor growth and metastasis.

    Ash, Sarah L / Orha, Rebecca / Mole, Holly / Dinesh-Kumar, Meg / Lee, Steven P / Turrell, Frances K / Isacke, Clare M

    Journal for immunotherapy of cancer

    2024  Volume 12, Issue 2

    Abstract: Background: Targeting of solid cancers with chimeric antigen receptor (CAR)-T cells is limited by the lack of suitable tumor-specific antigens and the immunosuppressive, desmoplastic tumor microenvironment that impedes CAR-T cell infiltration, activity ... ...

    Abstract Background: Targeting of solid cancers with chimeric antigen receptor (CAR)-T cells is limited by the lack of suitable tumor-specific antigens and the immunosuppressive, desmoplastic tumor microenvironment that impedes CAR-T cell infiltration, activity and persistence. We hypothesized that targeting the endosialin (CD248) receptor, strongly expressed by tumor-associated pericytes and perivascular cancer-associated fibroblasts, would circumvent these challenges and offer an exciting antigen for CAR-T cell therapy due to the close proximity of target cells to the tumor vasculature, the limited endosialin expression in normal tissues and the lack of phenotype observed in endosialin knockout mice.
    Methods: We generated endosialin-directed E3K CAR-T cells from three immunocompetent mouse strains, BALB/c, FVB/N and C57BL/6. E3K CAR-T cell composition (CD4
    Results: E3K CAR-T cells were active in vitro against both mouse and human endosialin
    Conclusions: Together these data highlight endosialin as a viable antigen for CAR-T cell therapy and that targeting stromal cells closely associated with the tumor vasculature avoids CAR-T cells having to navigate the harsh immunosuppressive tumor microenvironment. Further, the ability of E3K CAR-T cells to recognize and target both mouse and human endosialin
    MeSH term(s) Humans ; Mice ; Animals ; Pericytes/metabolism ; Receptors, Chimeric Antigen/genetics ; Receptors, Chimeric Antigen/metabolism ; Mice, Inbred C57BL ; Neoplasms/metabolism ; T-Lymphocytes/metabolism ; Mice, Knockout ; Tumor Microenvironment ; Antigens, Neoplasm/metabolism ; Antigens, CD/metabolism
    Chemical Substances Receptors, Chimeric Antigen ; CD248 protein, human ; Antigens, Neoplasm ; Antigens, CD ; CD248 protein, mouse
    Language English
    Publishing date 2024-02-27
    Publishing country England
    Document type Journal Article
    ZDB-ID 2719863-7
    ISSN 2051-1426 ; 2051-1426
    ISSN (online) 2051-1426
    ISSN 2051-1426
    DOI 10.1136/jitc-2023-008608
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Multi-level interaction between HIF and AHR transcriptional pathways in kidney carcinoma.

    Lafleur, Véronique N / Halim, Silvia / Choudhry, Hani / Ratcliffe, Peter J / Mole, David R

    Life science alliance

    2023  Volume 6, Issue 4

    Abstract: Hypoxia-inducible factor (HIF) and aryl hydrocarbon receptor (AHR) are members of the bHLH-PAS family of transcription factors that underpin cellular responses to oxygen and to endogenous and exogenous ligands, respectively, and have central roles in the ...

    Abstract Hypoxia-inducible factor (HIF) and aryl hydrocarbon receptor (AHR) are members of the bHLH-PAS family of transcription factors that underpin cellular responses to oxygen and to endogenous and exogenous ligands, respectively, and have central roles in the pathogenesis of renal cancer. Composed of heterodimers, they share a common HIF-1β/ARNT subunit and similar DNA-binding motifs, raising the possibility of crosstalk between the two transcriptional pathways. Here, we identify both general and locus-specific mechanisms of interaction between HIF and AHR that act both antagonistically and cooperatively. Specifically, we observe competition for the common HIF-1β/ARNT subunit, in cis synergy for chromatin binding, and overlap in their transcriptional targets. Recently, both HIF and AHR inhibitors have been developed for the treatment of solid tumours. However, inhibition of one pathway may promote the oncogenic effects of the other. Therefore, our work raises important questions as to whether combination therapy targeting both of these pro-tumourigenic pathways might show greater efficacy than targeting each system independently.
    MeSH term(s) Humans ; Receptors, Aryl Hydrocarbon/genetics ; Receptors, Aryl Hydrocarbon/metabolism ; Cell Hypoxia/physiology ; Carcinoma, Renal Cell/genetics ; Kidney Neoplasms/genetics ; Kidney/metabolism
    Chemical Substances Receptors, Aryl Hydrocarbon
    Language English
    Publishing date 2023-02-01
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2575-1077
    ISSN (online) 2575-1077
    DOI 10.26508/lsa.202201756
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  3. Article ; Online: Competing itinerant and local spin interactions in kagome metal FeGe.

    Chen, Lebing / Teng, Xiaokun / Tan, Hengxin / Winn, Barry L / Granroth, Garrett E / Ye, Feng / Yu, D H / Mole, R A / Gao, Bin / Yan, Binghai / Yi, Ming / Dai, Pengcheng

    Nature communications

    2024  Volume 15, Issue 1, Page(s) 1918

    Abstract: The combination of a geometrically frustrated lattice, and similar energy scales between degrees of freedom endows two-dimensional Kagome metals with a rich array of quantum phases and renders them ideal for studying strong electron correlations and band ...

    Abstract The combination of a geometrically frustrated lattice, and similar energy scales between degrees of freedom endows two-dimensional Kagome metals with a rich array of quantum phases and renders them ideal for studying strong electron correlations and band topology. The Kagome metal, FeGe is a noted example of this, exhibiting A-type collinear antiferromagnetic (AFM) order at T
    Language English
    Publishing date 2024-03-01
    Publishing country England
    Document type Journal Article
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-023-44190-2
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  4. Article ; Online: Pan-cancer analysis of tissue and single-cell HIF-pathway activation using a conserved gene signature.

    Lombardi, Olivia / Li, Ran / Halim, Silvia / Choudhry, Hani / Ratcliffe, Peter J / Mole, David R

    Cell reports

    2022  Volume 41, Issue 7, Page(s) 111652

    Abstract: Activation of cellular hypoxia pathways, orchestrated by HIF (hypoxia-inducible factor) transcription factors, is a common feature of multiple tumor types, resulting from microenvironment factors and oncogenic mutation. Although they help drive many of ... ...

    Abstract Activation of cellular hypoxia pathways, orchestrated by HIF (hypoxia-inducible factor) transcription factors, is a common feature of multiple tumor types, resulting from microenvironment factors and oncogenic mutation. Although they help drive many of the "hallmarks" of cancer and are associated with poor outcome and resistance to therapy, the transcriptional targets of HIF vary considerably depending on the cell type. By integrating 72 genome-wide assays of HIF binding and transcriptional regulation from multiple cancer types, we define a consensus set of 48 HIF target genes that is highly conserved across cancer types and cell lineages. These genes provide an effective marker of HIF activation in bulk and single-cell transcriptomic analyses across a wide range of cancer types and in malignant and stromal cell types. This allows the tissue-orchestrated responses to the hypoxic tumor microenvironment and to oncogenic HIF activation to be deconvoluted at the tumor and single-cell level.
    MeSH term(s) Humans ; Neoplasms/genetics ; Transcription Factors/metabolism ; Tumor Microenvironment/genetics ; Cell Hypoxia/genetics ; Hypoxia/metabolism
    Chemical Substances Transcription Factors
    Language English
    Publishing date 2022-11-15
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2022.111652
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  5. Article ; Online: Radiotherapy transiently reduces the sensitivity of cancer cells to lymphocyte cytotoxicity.

    Tuomela, Karoliina / Mukherjee, Debayan / Ambrose, Ashley R / Harikrishnan, Ashish / Mole, Holly / Hurlstone, Adam / Önfelt, Björn / Honeychurch, Jamie / Davis, Daniel M

    Proceedings of the National Academy of Sciences of the United States of America

    2022  Volume 119, Issue 3

    Abstract: ... as for antibody-dependent cellular cytotoxicity. Resistance appeared 72 h postirradiation and persisted for 2 wk. Resistance could also occur ...

    Abstract The impact of radiotherapy on the interaction between immune cells and cancer cells is important not least because radiotherapy can be used alongside immunotherapy as a cancer treatment. Unexpectedly, we found that X-ray irradiation of cancer cells induced significant resistance to natural killer (NK) cell killing. This was true across a wide variety of cancer-cell types as well as for antibody-dependent cellular cytotoxicity. Resistance appeared 72 h postirradiation and persisted for 2 wk. Resistance could also occur independently of radiotherapy through pharmacologically induced cell-cycle arrest. Crucially, multiple steps in NK-cell engagement, synapse assembly, and activation were unaffected by target cell irradiation. Instead, radiotherapy caused profound resistance to perforin-induced calcium flux and lysis. Resistance also occurred to a structurally similar bacterial toxin, streptolysin O. Radiotherapy did not affect the binding of pore-forming proteins at the cell surface or membrane repair. Rather, irradiation instigated a defect in functional pore formation, consistent with phosphatidylserine-mediated perforin inhibition. In vivo, radiotherapy also led to a significant reduction in NK cell-mediated clearance of cancer cells. Radiotherapy-induced resistance to perforin also constrained chimeric antigen receptor T-cell cytotoxicity. Together, these data establish a treatment-induced resistance to lymphocyte cytotoxicity that is important to consider in the design of radiotherapy-immunotherapy protocols.
    MeSH term(s) Antibody-Dependent Cell Cytotoxicity ; Bacterial Proteins ; Cell Line, Tumor ; Cell Membrane/metabolism ; Cytotoxicity, Immunologic ; Humans ; Immunotherapy ; Killer Cells, Natural/immunology ; Neoplasms/metabolism ; Perforin/metabolism ; Radiotherapy ; Receptors, Antigen, T-Cell/metabolism ; Receptors, Chimeric Antigen/metabolism ; Streptolysins
    Chemical Substances Bacterial Proteins ; Receptors, Antigen, T-Cell ; Receptors, Chimeric Antigen ; Streptolysins ; streptolysin O ; Perforin (126465-35-8)
    Language English
    Publishing date 2022-01-19
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2111900119
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1148: Show issues Location:
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  6. Article ; Online: Corrigendum: Contrasting effects on HIF-1α regulation by disease-causing pVHL mutations correlate with patterns of tumourigenesis in von Hippel-Lindau disease.

    Clifford, Steven C / Cockman, Matthew E / Smallwood, Alan C / Mole, David R / Woodward, Emma R / Maxwell, Patrick H / Ratcliffe, Peter J / Maher, Eamonn R

    Human molecular genetics

    2021  Volume 30, Issue 9, Page(s) 844–845

    Language English
    Publishing date 2021-03-24
    Publishing country England
    Document type Published Erratum
    ZDB-ID 1108742-0
    ISSN 1460-2083 ; 0964-6906
    ISSN (online) 1460-2083
    ISSN 0964-6906
    DOI 10.1093/hmg/ddab037
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    Zs.A 3469: Show issues Location:
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  7. Book: THE EFFECTS ON POPULATIONS OF EXPOSURE TO LOW LEVELS OF IONISING RADIATION

    MOLE, R. H.

    (BEIR III) ; A REV. OF THE REP. BY THE COMM. ON THE BIOL. EFFECTS OF IONISING RADIATIONS, DIVISION OF MEDICAL SCIENCES, ASSEMBLY OF LIFE SCIENCES, ... WASHINGTON D.C., 1980

    (RADIOLOGICAL PROTECTION BULLETIN ; 38 : SUPPL.)

    1981  

    Title variant EFFECTS ON POPULATIONS OF EXPOSURE TO LOW LEVELS OF IONISING RADIATION
    Author's details AN INV. REV. BY R. H. MOLE
    Series title RADIOLOGICAL PROTECTION BULLETIN ; 38 : SUPPL.
    Radiological protection bulletin
    Collection Radiological protection bulletin
    Keywords RADIATION EFFECTS ; RADIATION MONITORING
    Size 10 S.
    Publisher CASTLE HOUSE PUBL
    Publishing place TUNBRIDGE WELLS
    Document type Book
    HBZ-ID HT002504439
    Database Catalogue ZB MED Medicine, Health

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    Shelf markLoan statusLocation
    ZS B 2430 -38,SUPPL.- verfügbar in Königswinter Königswinter

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  8. Article: The diagnostic value of the Widal test in the inoculated.

    MOLE, R H

    The Journal of hygiene

    2008  Volume 46, Issue 1, Page(s) 98–100

    MeSH term(s) Humans ; Immunologic Tests ; Typhoid Fever ; Typhoid-Paratyphoid Vaccines
    Chemical Substances Typhoid-Paratyphoid Vaccines
    Language English
    Publishing date 2008-10-15
    Publishing country England
    Document type Journal Article
    ZDB-ID 218215-4
    ISSN 0022-1724
    ISSN 0022-1724
    DOI 10.1017/s0022172400036147
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  9. Article ; Online: Hypoxic regulation of the noncoding genome and NEAT1.

    Choudhry, Hani / Mole, David R

    Briefings in functional genomics

    2015  Volume 15, Issue 3, Page(s) 174–185

    Abstract: Activation of hypoxia pathways is both associated with and contributes to an aggressive phenotype across multiple types of solid cancers. The regulation of gene transcription by hypoxia-inducible factor (HIF) is a key element in this response. HIF ... ...

    Abstract Activation of hypoxia pathways is both associated with and contributes to an aggressive phenotype across multiple types of solid cancers. The regulation of gene transcription by hypoxia-inducible factor (HIF) is a key element in this response. HIF directly upregulates the expression of many hundreds of protein-coding genes, which act to both improve oxygen delivery and to reduce oxygen demand. However, it is now becoming apparent that many classes of noncoding RNAs are also regulated by hypoxia, with several (e.g. micro RNAs, long noncoding RNAs and antisense RNAs) under direct transcriptional regulation by HIF. These hypoxia-regulated, noncoding RNAs may act as effectors of the indirect response to HIF by acting on specific coding transcripts or by affecting generic RNA-processing pathways. In addition, noncoding RNAs may also act as modulators of the HIF pathway, either by integrating other physiological responses or, in the case of HIF-regulated, noncoding RNAs, by providing negative or positive feedback and feedforward loops that affect upstream or downstream components of the HIF cascade. These hypoxia-regulated, noncoding transcripts play important roles in the aggressive hypoxic phenotype observed in cancer.
    MeSH term(s) Gene Expression Regulation, Neoplastic ; Genome, Human ; Humans ; Hypoxia/physiopathology ; Neoplasms/genetics ; Neoplasms/pathology ; RNA, Long Noncoding/genetics
    Chemical Substances NEAT1 long non-coding RNA, human ; RNA, Long Noncoding
    Language English
    Publishing date 2015-11-20
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2540916-5
    ISSN 2041-2657 ; 2041-2649 ; 2041-2647
    ISSN (online) 2041-2657
    ISSN 2041-2649 ; 2041-2647
    DOI 10.1093/bfgp/elv050
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  10. Article: The relative humidity of the skin.

    Mole, R H

    The Journal of physiology

    2006  Volume 107, Issue 4, Page(s) 399–411

    Language English
    Publishing date 2006-09-21
    Publishing country England
    Document type Journal Article
    ZDB-ID 3115-x
    ISSN 1469-7793 ; 0022-3751
    ISSN (online) 1469-7793
    ISSN 0022-3751
    DOI 10.1113/jphysiol.1948.sp004284
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