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  • 1
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    Online Resource
    FOXC2 Promotes Vasculogenic Mimicry in Ovarian Cancer
    MDPI AG ; 2022
    In:  Cancers Vol. 14, No. 19 ( 2022-10-04), p. 4851-
    Details
    In: Cancers, MDPI AG, Vol. 14, No. 19 ( 2022-10-04), p. 4851-
    Abstract: FOXC2 is a forkhead family transcription factor that plays a critical role in specifying mesenchymal cell fate during embryogenesis. FOXC2 expression is associated with increased metastasis and poor survival in various solid malignancies. Using in vitro and in vivo assays in mouse ovarian cancer cell lines, we confirmed the previously reported mechanisms by which FOXC2 could promote cancer growth, metastasis, and drug resistance, including epithelial-mesenchymal transition, stem cell-like differentiation, and resistance to anoikis. In addition, we showed that FOXC2 expression is associated with vasculogenic mimicry in mouse and human ovarian cancers. FOXC2 overexpression increased the ability of human ovarian cancer cells to form vascular-like structures in vitro, while inhibition of FOXC2 had the opposite effect. Thus, we present a novel mechanism by which FOXC2 might contribute to cancer aggressiveness and poor patient survival.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers14194851
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
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  • 2
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    Abstract 2681: Co-detection of a tumor-infiltrating lymphocyte immunofluorescence (IF) panel and cytokine RNA in-situ hybridization (ISH) markers in non-small cell lung cancer (NSCLC) tumor microenvironment using combined MultiOmyx and RNAscope platforms
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 2681-2681
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 2681-2681
    Abstract: Co-detection of RNA and protein can greatly expand the data output from a single specimen, providing critical information such as the source of secreted proteins (e.g. cytokines) or cell type specific transcript levels. MultiOmyx is a proprietary immunofluorescence (IF) platform for the visualization and characterization of up to 60 protein biomarkers in a single formalin-fixed paraffin-embedded (FFPE) section. RNAscope Multiplex is a highly sensitive fluorescent in-situ hybridization (ISH) assay that can detect up to 3 RNA markers in a single FFPE section. Combination of MultiOmyx IF with RNAscope Multiplex ISH would therefore provide a novel and powerful platform to co-detect multiple RNA and protein markers in a single slide/sample. However, the RNAscope Multiplex assay includes a protease pretreatment step, which may compromise downstream antibody-antigen interaction and thereby the IF signal. This study is a validation of the sensitivity, specificity, reproducibility, and repeatability of an integrated MultiOmyx IF and RNAscope ISH assay. Depending on the context, cytokines interleukin-10 (IL10) and interferon gamma (IFNγ) have both been shown to either induce immunosuppression and favor tumor growth or promote an anti-tumor response. The mechanisms and cues determining the pro- or anti-tumor activity of IL10 and IFNγ are still poorly understood. Spatiotemporal characterization of IFNG and IL10 is therefore critical to help define the dynamic relationship of cytokines and the immune system within the tumor microenvironment. Therefore, for validation of the integrated MultiOmyx-RNAscope platform, RNA ISH markers for IL10 and IFNγ were combined with the MultiOmyx 12 marker tumor infiltrating lymphocyte (TIL) panel (CD3, CD4, CD8, CD20, CD68, CD56, CD45RO, PD-1, PD-L1, CTLA4, FOXP3, and tumor marker PanCK) on FFPE human NSCLC samples. This combined MultiOmyx-RNAscope workflow was performed for three individual runs using triplicate NSCLC samples for each run. Intensity and cell classification for each ISH and TIL marker was quantified using the proprietary MultiOmyx Analytics pipeline. The results demonstrate that the integrated assay maintains sensitivity and specificity of the TIL IF markers in the integrated workflow when benchmarked to an IF alone workflow. Furthermore, these results can be used to characterize expression of IL10 and IFNγ within immune cell subsets represented by the TIL IF panel (e.g. T cells, NK cells, macrophages). This integrated approach can be used to spatially correlate the distribution of cytokine and immune cell expression within the tumor microenvironment. Therefore, the RNAscope-MultiOmyx IF assay provides a robust and powerful platform to simultaneously co-detect RNA with protein IF in a single specimen. Citation Format: Courtney Todorov, Maricel Gozo, Harry Nunns, Erinn Parnell, Judy Kuo, Eric Leones, Mate Nagy, Qingyan Au. Co-detection of a tumor-infiltrating lymphocyte immunofluorescence (IF) panel and cytokine RNA in-situ hybridization (ISH) markers in non-small cell lung cancer (NSCLC) tumor microenvironment using combined MultiOmyx and RNAscope platforms [abstract] . In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2681.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-2681
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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    detail.hit.zdb_id: 410466-3
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  • 3
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    Abstract 434: Characterizing viral mRNA and immuno-protein expression in head and neck squamous cell carcinoma using a novel automated RNAscope™/Polaris™ integrated assay
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 434-434
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 434-434
    Abstract: Background: Chronic viral infection can generate inflammatory microenvironments leading to neoplastic growth and cancer development. Cancer patients with chronic viral infection have been shown to exhibit worse outcomes compared to non-infected individuals. One such cohort, head and neck squamous cell carcinoma (HNSCC) patients infected with chronic human cytomegalovirus (CMV), have increased risk of death when receiving radiotherapy or radiochemotherapy. This is clinically significant as HNSCC already carries a high mortality rate and low response to surgery and chemotherapeutic treatment. The ability to detect and localize viral infection and immune response in the same patient tissues has been historically under-developed and may assist in stratifying patients for therapeutic intervention. Methods: Immune infiltrate to tumor in CMV infected and non-infected samples was assessed in HNSCC patient tissue using RNAscope in-situ hybridization (ISH) probe to detect CMV mRNA and Vectra® Polaris™ automated multiplex protein detection of CD8, PD-L1, CD68 and panCK with OPAL dyes. Results: We developed a novel automated RNAscope™/Vectra® Polaris™ integrated multiplex immunofluorescence (IF) assay with OPAL detection and quantification of signal using Indica HALO® algorithms. The results include quantitative and reproducible RNAscope fluorescent ISH counting, cell-by-cell expression profiles, multiplex protein quantification and whole-slide image analysis. Conclusion: NeoGenomics Laboratories RNAscope™/Polaris™ integrated assay detects and quantifies CMV viral infection and protein expression of PD-L1 positive and negative cytotoxic T cells and macrophages within and adjacent to HNSCC tumor regions. Citation Format: Sara Pollan, Arezoo Hanifi, Mate Nagy, Nicholas Stavrou, Erinn Parnell, Maricel Gozo, Nickolas Attanasio, Josette William, Qingyan Au. Characterizing viral mRNA and immuno-protein expression in head and neck squamous cell carcinoma using a novel automated RNAscope™/Polaris™ integrated assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 434.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-434
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 4
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    Abstract 3881: Distinguishing dendritic cell subtypes in the tumor microenvironment using MultiOmyxTM
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 3881-3881
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 3881-3881
    Abstract: Dendritic cells (DCs) are key initiators and regulators of the innate and adaptive immune responses. An emerging interest in cancer therapies is the capability to activate endogenous DCs to induce antigen specific T cell responses and thereby generate DC-based immunotherapies. Understanding the function and diversity of DC subsets in the tumor environment will help improve therapies developed for cancer treatment. DC subpopulations have been recognized in humans and categorized based on their phenotype and functional criteria. These DC subsets are classified based on biomarker expressions and include CD123+ plasmacytoid dendritic cells (pDCs), two types of classical dendritic cells CD141+Clec9A+CD11c+ HLADR+ conventional type 1 dendritic cells (cDC1), CD1c+CD11c+HLADR+ conventional type 2 dendritic cells (cDC2) and CD14+CD11c+CD209+ monocyte derived dendritic cells (Mo-DCs). To help understand the complexity of distinct subsets of DCs, their spatial distribution within the tumor microenvironment (TME), and correlation with other immune cells, multiplex immunohistochemistry using a panel of antibodies broad enough to differentiate and characterize multiple DC subsets and T cell populations will be used. MultiOmyxTM, a novel hyperplexed multi ”omic” technology, enables visualization and characterization of multiple biomarkers across multiple assays on a single 4μm tissue section. MultiOmyx protein immunofluorescence (IF) assays utilize a pair of directly conjugated Cyanine dye-labeled (Cy3, Cy5) antibodies per round of staining. Each round of staining is imaged and followed by novel dye inactivation chemistry, enabling repeated rounds of staining and deactivation for up to 60 protein biomarkers. In this study, a MultiOmyx hyperplexed IF assay will be utilized to distinguish different DC subset within a tumor. Biomarkers including CD11c, CD123, CD141, CleC9A, CD1c, DC-Lamp, DC-sign, HLADR, CD14, CD68, CD163, CD3, CD4, CD8, FOXP3 and PanCK protein expression from a single 4 µm FFPE section in order to identify different subsets of DCs in tumor tissue from patients with Melanoma, a cancer type in which immunotherapeutic treatment has had a transformative effect and become the dominant therapeutic approach. Hopefully, a greater understanding of the phenotypes and functions of dendritic cells subsets will result in new cancer immunotherapy strategies. Citation Format: Maricel C. Gozo, Vivek Reddy, Mate Nagy, Nickolas Attanasio, Naiyun Zhou, Sara Pollan, Erinn Parnell, Eric Leones, Judy Kuo, Anna Juncker-Jensen, Josette William Ragheb, Qingyan Au. Distinguishing dendritic cell subtypes in the tumor microenvironment using MultiOmyxTM [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3881.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-3881
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 5
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    HOXB13 controls cell state through super-enhancers
    Elsevier BV ; 2020
    In:  Experimental Cell Research Vol. 393, No. 1 ( 2020-08), p. 112039-
    Details
    In: Experimental Cell Research, Elsevier BV, Vol. 393, No. 1 ( 2020-08), p. 112039-
    Type of Medium: Online Resource
    ISSN: 0014-4827
    URL: Article
    DOI: 10.1016/j.yexcr.2020.112039
    RVK:
    WA 15000
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
    detail.hit.zdb_id: 1466780-0
    SSG: 12
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  • 6
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    A Pilot Feasibility Study of Yttrium-90 Liver Radioembolization Followed by Durvalumab and Tremelimumab in Patients with Microsatellite Stable Colorectal Cancer Liver Metastases
    Oxford University Press (OUP) ; 2020
    In:  The Oncologist Vol. 25, No. 5 ( 2020-05-01), p. 382-e776
    Details
    In: The Oncologist, Oxford University Press (OUP), Vol. 25, No. 5 ( 2020-05-01), p. 382-e776
    Abstract: Click here to access other published clinical trials. Lessons Learned Radioembolization with yttrium-90 resin microspheres can be combined safely with full doses of durvalumab and tremelimumab in patients with metastatic colorectal cancer. Regional radioembolization with yttrium-90 resin microspheres did not result in any hepatic or extrahepatic responses to a combination of durvalumab and tremelimumab. The lack of immunomodulatory responses to yttrium-90 on biopsies before and after treatment rules out a potential role for this strategy in converting a “cold tumor” into an “inflamed,” immune responsive tumor. Background PD-1 inhibitors have been ineffective in microsatellite stable (MSS) metastatic colorectal cancer (CRC). Preclinical models suggest that radiation therapy may sensitize MSS CRC to PD-1 blockade. Methods Patients with MSS metastatic CRC with liver-predominant disease who progressed following at least one prior line of treatment were treated with yttrium-90 (Y90) radioembolization to the liver (SIR-Spheres; Sirtex, Woburn, MA) followed 2–3 weeks later by the combination of durvalumab and tremelimumab. A Simon two-stage design was implemented, with a planned expansion to 18 patients if at least one response was noted in the first nine patients. Results Nine patients enrolled in the first stage of the study, all with progressive disease (PD) during or after their first two cycles of treatment. Per preplanned design, the study was closed because of futility. No treatment-related grade 3 or greater toxicities were recorded. Correlative studies with tumor biopsies showed low levels of tumor-infiltrating lymphocyte (TIL) infiltration in tumor cancer islands before and after Y90 radioembolization. Conclusion Y90 radioembolization can be added safely to durvalumab and tremelimumab but did not promote tumor-directed immune responses against liver-metastasized MSS CRC.
    Type of Medium: Online Resource
    ISSN: 1083-7159 , 1549-490X
    URL: Article
    DOI: 10.1634/theoncologist.2019-0924
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
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  • 7
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    GB5121, a Brain-Penetrant, Irreversible BTK Inhibitor, Demonstrates Potent Anti-Tumor Activity in a Novel Mouse Model of Intracranial Lymphoma
    American Society of Hematology ; 2022
    In:  Blood Vol. 140, No. Supplement 1 ( 2022-11-15), p. 8878-8879
    Details
    In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 8878-8879
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2022-159088
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2022
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 8
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    Abstract 2143: Profiling exhausted T cells using Vectra® Polaris™multiplex immunofluorescence assay in HNSCC
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 2143-2143
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 2143-2143
    Abstract: Background: Head and neck squamous cell carcinoma (HNSCC) is a cancer with the ability to modulate the immune system to evade detection. It is the sixth most frequently diagnosed cancer with 550,000 new cases and 300,000 lives lost worldwide per year. New treatments for HNSCC are urgently needed as patients continue to experience a high mortality rate and low response to surgery and chemotherapeutic treatments. Part of the reason why HNSCC is difficult to treat is it upregulates the expression of immune-checkpoint signaling molecule TIGIT (T cell immunoreceptor with Ig and ITIM domains) to inhibit T cell activation in vivo. Emerging evidence shows TIGIT overexpression in the CD8+ and CD4+ T cells that infiltrate the tumor cells of HNSCC patients. TIGIT expression is also associated with up-regulation of immune-checkpoint ligands PD-1 (programmed cell death protein 1) and LAG-3 (lymphocyte-activation gene 3 aka CD223), markers of T-cell exhaustion. Altogether, activation of the TIGIT/PD-1/LAG-3 axis correlates with an immunosuppressive microenvironment as well as cancer development and progression. Although there is ample evidence that the upregulation of TIGIT decreases the immune response in HNSCC, only limited studies have been published that address the location, expression and co-expression of TIGIT, LAG-3 and PD-1 in the HNSCC microenvironment. Methods: In this study, we sought to establish a robust report of immune cells in the tissue of patients with HNSCC. Using Vectra Polaris multiplex immunofluorescence (IF) assays, we studied T-cell exhaustion and T-cell expression in HNSCC patient tissue using a total of 9 markers essential in cancer immunology. Sequential tissue sections were stained in two panels of 6, an exhausted T cell panel comprised of TIGIT, PD-1, LAG-3, panCK, CD4 and CD8 and a T cell panel including CD3, FOXP3, CD45RO, panCK, CD4 and CD8. Results: Multiplexing IF staining revealed a HNSCC histologic landscape characteristic of immune suppression in this study. The data demonstrated abundant T cells with TIGIT overexpression in the tissue microenvironment of HNSCC samples. Using Indica Halo algorithms, we quantified exhausted T cells (TIGIT+PD1+LAG3+CD4+CD3+, TIGIT+PD1+LAG3+CD8+CD3+), T helper cells (CD3+CD4+), T cytotoxic cells (CD3+CD8+), T regulatory cells (CD3+CD4+FoxP3), memory T-cells (CD3+CD4+CD45RO) and anergic T-cells (PD1+CD8+) within the tumor and the stromal regions. Conclusion: Currently AB154, a fully humanized immunoglobulin G1 monoclonal antibody targeting human TIGIT is in phase I clinical trials in HNSCC patients and BGB-A1217, an anti-TIGIT monoclonal antibody in combination with anti-PD-1 monoclonal antibody Tislelizumab is in a Phase 1/1b clinical trial in patients with advanced solid tumors. The Vectra Polaris imaging reported in this study identifies T cell composition in the tumor microenvironment of patients facing high mortality. Citation Format: Sara Pollan, Arezoo Hanifi, Mate Nagy, Nicholas Stavrou, Erinn Parnell, Maricel Gozo, Nickolas Attanasio, Josette William, Qingyan Au. Profiling exhausted T cells using Vectra® Polaris™multiplex immunofluorescence assay in HNSCC [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2143.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-2143
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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    detail.hit.zdb_id: 410466-3
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