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  • 1
    Online Resource
    Online Resource
    Cellular and humoral immune responses to SARS-CoV-2 vaccination in patients after CD19.CAR T-cell therapy
    American Society of Hematology ; 2023
    In:  Blood Advances Vol. 7, No. 10 ( 2023-05-23), p. 2066-2069
    Details
    In: Blood Advances, American Society of Hematology, Vol. 7, No. 10 ( 2023-05-23), p. 2066-2069
    Type of Medium: Online Resource
    ISSN: 2473-9529 , 2473-9537
    URL: Article
    DOI: 10.1182/bloodadvances.2022007806
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2023
    detail.hit.zdb_id: 2876449-3
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  • 2
    Online Resource
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    Mathematical Modelling in Biomedicine: A Primer for the Curious and the Skeptic
    MDPI AG ; 2021
    In:  International Journal of Molecular Sciences Vol. 22, No. 2 ( 2021-01-07), p. 547-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 22, No. 2 ( 2021-01-07), p. 547-
    Abstract: In most disciplines of natural sciences and engineering, mathematical and computational modelling are mainstay methods which are usefulness beyond doubt. These disciplines would not have reached today’s level of sophistication without an intensive use of mathematical and computational models together with quantitative data. This approach has not been followed in much of molecular biology and biomedicine, however, where qualitative descriptions are accepted as a satisfactory replacement for mathematical rigor and the use of computational models is seen by many as a fringe practice rather than as a powerful scientific method. This position disregards mathematical thinking as having contributed key discoveries in biology for more than a century, e.g., in the connection between genes, inheritance, and evolution or in the mechanisms of enzymatic catalysis. Here, we discuss the role of computational modelling in the arsenal of modern scientific methods in biomedicine. We list frequent misconceptions about mathematical modelling found among biomedical experimentalists and suggest some good practices that can help bridge the cognitive gap between modelers and experimental researchers in biomedicine. This manuscript was written with two readers in mind. Firstly, it is intended for mathematical modelers with a background in physics, mathematics, or engineering who want to jump into biomedicine. We provide them with ideas to motivate the use of mathematical modelling when discussing with experimental partners. Secondly, this is a text for biomedical researchers intrigued with utilizing mathematical modelling to investigate the pathophysiology of human diseases to improve their diagnostics and treatment.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms22020547
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 3
    Online Resource
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    Data_Sheet_2.pdf
    Frontiers Media SA ; 2021
    In:  Frontiers in Microbiology Vol. 12 ( 2021-12-22)
    Details
    In: Frontiers in Microbiology, Frontiers Media SA, Vol. 12 ( 2021-12-22)
    Abstract: Merkel cell carcinoma (MCC) is a rare and highly aggressive cancer, which is mainly caused by genomic integration of the Merkel cell polyomavirus and subsequent expression of a truncated form of its large T antigen. The resulting primary tumor is known to be immunogenic and under constant pressure to escape immune surveillance. Because interferon gamma (IFNγ), a key player of immune response, is secreted by many immune effector cells and has been shown to exert both anti-tumoral and pro-tumoral effects, we studied the transcriptomic response of MCC cells to IFNγ. In particular, immune modulatory effects that may help the tumor evade immune surveillance were of high interest to our investigation. The effect of IFNγ treatment on the transcriptomic program of three MCC cell lines (WaGa, MKL-1, and MKL-2) was analyzed using single-molecule sequencing via the Oxford Nanopore platform. A significant differential expression of several genes was detected across all three cell lines. Subsequent pathway analysis and manual annotation showed a clear upregulation of genes involved in the immune escape of tumor due to IFNγ treatment. The analysis of selected genes on protein level underlined our sequencing results. These findings contribute to a better understanding of immune escape of MCC and may help in clinical treatment of MCC patients. Furthermore, we demonstrate that single-molecule sequencing can be used to assess characteristics of large eukaryotic transcriptomes and thus contribute to a broader access to sequencing data in the community due to its low cost of entry.
    Type of Medium: Online Resource
    ISSN: 1664-302X
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.3389/fmicb.2021.785662
    DOI: 10.3389/fmicb.2021.785662.s001
    DOI: 10.3389/fmicb.2021.785662.s002
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
    detail.hit.zdb_id: 2587354-4
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  • 4
    Online Resource
    Online Resource
    Network- and systems-based re-engineering of dendritic cells with non-coding RNAs for cancer immunotherapy
    Ivyspring International Publisher ; 2021
    In:  Theranostics Vol. 11, No. 3 ( 2021), p. 1412-1428
    Details
    In: Theranostics, Ivyspring International Publisher, Vol. 11, No. 3 ( 2021), p. 1412-1428
    Type of Medium: Online Resource
    ISSN: 1838-7640
    URL: Article
    DOI: 10.7150/thno.53092
    Language: English
    Publisher: Ivyspring International Publisher
    Publication Date: 2021
    detail.hit.zdb_id: 2592097-2
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  • 5
    Online Resource
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    Melanoma 2.0. Skin cancer as a paradigm for emerging diagnostic technologies, computational modelling and artificial intelligence
    Oxford University Press (OUP) ; 2022
    In:  Briefings in Bioinformatics Vol. 23, No. 6 ( 2022-11-19)
    Details
    In: Briefings in Bioinformatics, Oxford University Press (OUP), Vol. 23, No. 6 ( 2022-11-19)
    Abstract: We live in an unprecedented time in oncology. We have accumulated samples and cases in cohorts larger and more complex than ever before. New technologies are available for quantifying solid or liquid samples at the molecular level. At the same time, we are now equipped with the computational power necessary to handle this enormous amount of quantitative data. Computational models are widely used helping us to substantiate and interpret data. Under the label of systems and precision medicine, we are putting all these developments together to improve and personalize the therapy of cancer. In this review, we use melanoma as a paradigm to present the successful application of these technologies but also to discuss possible future developments in patient care linked to them. Melanoma is a paradigmatic case for disruptive improvements in therapies, with a considerable number of metastatic melanoma patients benefiting from novel therapies. Nevertheless, a large proportion of patients does not respond to therapy or suffers from adverse events. Melanoma is an ideal case study to deploy advanced technologies not only due to the medical need but also to some intrinsic features of melanoma as a disease and the skin as an organ. From the perspective of data acquisition, the skin is the ideal organ due to its accessibility and suitability for many kinds of advanced imaging techniques. We put special emphasis on the necessity of computational strategies to integrate multiple sources of quantitative data describing the tumour at different scales and levels.
    Type of Medium: Online Resource
    ISSN: 1467-5463 , 1477-4054
    URL: Article
    DOI: 10.1093/bib/bbac433
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2036055-1
    SSG: 12
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  • 6
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    Dendritic cell vaccination in metastatic uveal melanoma as compassionate treatment: Immunological and clinical responses.
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 15_suppl ( 2019-05-20), p. e21024-e21024
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. e21024-e21024
    Abstract: e21024 Background: Other than cutaneous melanoma, metastatic uveal melanoma (UM) is minimally responsive to checkpoint inhibitors. The prognosis remains very poor with mortality rates nearly unchanged over the last decades. The recently growing insight that immunotherapy significantly improves outcomes for cancer patients led to a re-emergence of vaccines including dendritic cell (DC) vaccines. Methods: We vaccinated an UM patient in a compassionate use setting and assessed the immunological and clinical responses. Based on this experience we performed individual compassionate treatments in other UM patients using DC loaded by peptide pulsing and/or mRNA transfection (autologous tumor RNA or RNA coding for tumor antigens). Results: The first patient was vaccinated in 2013 after a liver metastasis was resected and checkpoint blockade with ipilimumab was started. In 2014 the patient showed progression in the liver. We continued DC vaccination in shorter intervals and adapted antigen loading (with mRNA coding for an individual GNAQ driver mutation) accompanied by a further cycle of ipilimumab. Therapy resulted in complete remission of liver metastases, but the patient developed new skin metastases. Again the loading of DC was adapted (peptides of passenger mutations predicted after Next-Generation Sequencing) and infusions with pembrolizumab were started. Pathology from some regressing lesions showed a massive T cell infiltration and in parallel GNAQ mutation-specific T cells could be found in the patient’s blood. Skin metastases regressed and the patient is now free of detectable tumor after 65 months. Immune monitoring in the patient’s blood showed a vaccine-induced functional T cell response against the QNAQ-driver mutation. Three of other four patients are also still alive, one in complete remission under DC vaccination in combination with pembrolizumab, two of them showing measurable disease, and one deceased disease related after 28 months, resulting in a median OS of the five patients of 36.4 months. Immune monitoring in one of those patients showed a CD4+ and CD8+ INF-gamma T cell response against the autologous tumor RNA vaccine. No grade 3 or 4 toxicity occurred. Conclusions: The observed prolonged median OS and the fact that 2/5 patients remain disease-free is definitely encouraging. Vaccination immunotherapy with antigen-laden DC is a potential therapeutic option for patients with metastatic uveal melanoma. Combinations with checkpoint inhibitors proved promising, and should be further evaluated in clinical trials.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.15_suppl.e21024
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
    detail.hit.zdb_id: 2005181-5
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  • 7
    Online Resource
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    Curatopes Melanoma: A Database of Predicted T-cell Epitopes from Overly Expressed Proteins in Metastatic Cutaneous Melanoma
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 20 ( 2019-10-15), p. 5452-5456
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 20 ( 2019-10-15), p. 5452-5456
    Abstract: Therapeutic anticancer vaccination has been adapted as an immunotherapy in several solid tumors. However, the selection of promising candidates from the total quantity of possible epitopes poses a challenge to clinicians and bioinformaticians alike, and very few epitopes have been tested in experimental or clinical settings to validate their efficacy. Here, we present a comprehensive database of predicted nonmutated peptide epitopes derived from genes that are overly expressed in a group of 32 melanoma biopsies compared with healthy tissues and that were filtered against expression in a curated list of survival-critical tissues. We hypothesize that these "self-tolerant" epitopes have two desirable properties: they do not depend on mutations, being immediately applicable to a large patient collective, and they potentially cause fewer autoimmune reactions. To support epitope selection, we provide an aggregated score of expected therapeutic efficiency as a shortlist mechanism. The database has applications in facilitating epitope selection and trial design and is freely accessible at https://www.curatopes.com. Significance: A database is presented that predicts and scores antitumor T-cell epitopes, with a focus on tolerability and avoidance of severe autoimmunity, offering a supplementary epitope set for further investigation in immunotherapy.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-19-0296
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 8
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    The IKZF1–IRF4/IRF5 Axis Controls Polarization of Myeloma-Associated Macrophages
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Immunology Research Vol. 9, No. 3 ( 2021-03-01), p. 265-278
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 9, No. 3 ( 2021-03-01), p. 265-278
    Abstract: The bone marrow niche has a pivotal role in progression, survival, and drug resistance of multiple myeloma cells. Therefore, it is important to develop means for targeting the multiple myeloma bone marrow microenvironment. Myeloma-associated macrophages (MAM) in the bone marrow niche are M2 like. They provide nurturing signals to multiple myeloma cells and promote immune escape. Reprogramming M2-like macrophages toward a tumoricidal M1 phenotype represents an intriguing therapeutic strategy. This is especially interesting in view of the successful use of mAbs against multiple myeloma cells, as these therapies hold the potential to trigger macrophage-mediated phagocytosis and cytotoxicity. In this study, we observed that MAMs derived from patients treated with the immunomodulatory drug (IMiD) lenalidomide skewed phenotypically and functionally toward an M1 phenotype. Lenalidomide is known to exert its beneficial effects by modulating the CRBN-CRL4 E3 ligase to ubiquitinate and degrade the transcription factor IKAROS family zinc finger 1 (IKZF1). In M2-like MAMs, we observed enhanced IKZF1 levels that vanished through treatment with lenalidomide, yielding MAMs with a bioenergetic profile, T-cell stimulatory properties, and loss of tumor-promoting capabilities that resemble M1 cells. We also provide evidence that IMiDs interfere epigenetically, via degradation of IKZF1, with IFN regulatory factors 4 and 5, which in turn alters the balance of M1/M2 polarization. We validated our observations in vivo using the CrbnI391V mouse model that recapitulates the IMiD-triggered IKZF1 degradation. These data show a role for IKZF1 in macrophage polarization and can provide explanations for the clinical benefits observed when combining IMiDs with therapeutic antibodies. See related Spotlight on p. 254
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6066.CIR-20-0555
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2732517-9
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  • 9
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    Long-term risk of adverse outcomes according to atrial fibrillation type
    Springer Science and Business Media LLC ; 2022
    In:  Scientific Reports Vol. 12, No. 1 ( 2022-02-09)
    Details
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 12, No. 1 ( 2022-02-09)
    Abstract: Sustained forms of atrial fibrillation (AF) may be associated with a higher risk of adverse outcomes, but few if any long-term studies took into account changes of AF type and co-morbidities over time. We prospectively followed 3843 AF patients and collected information on AF type and co-morbidities during yearly follow-ups. The primary outcome was a composite of stroke or systemic embolism (SE). Secondary outcomes included myocardial infarction, hospitalization for congestive heart failure (CHF), bleeding and all-cause mortality. Multivariable adjusted Cox proportional hazards models with time-varying covariates were used to compare hazard ratios (HR) according to AF type. At baseline 1895 (49%), 1046 (27%) and 902 (24%) patients had paroxysmal, persistent and permanent AF and 3234 (84%) were anticoagulated. After a median (IQR) follow-up of 3.0 (1.9; 4.2) years, the incidence of stroke/SE was 1.0 per 100 patient-years. The incidence of myocardial infarction, CHF, bleeding and all-cause mortality was 0.7, 3.0, 2.9 and 2.7 per 100 patient-years, respectively. The multivariable adjusted (a) HRs (95% confidence interval) for stroke/SE were 1.13 (0.69; 1.85) and 1.27 (0.83; 1.95) for time-updated persistent and permanent AF, respectively. The corresponding aHRs were 1.23 (0.89, 1.69) and 1.45 (1.12; 1.87) for all-cause mortality, 1.34 (1.00; 1.80) and 1.30 (1.01; 1.67) for CHF, 0.91 (0.48; 1.72) and 0.95 (0.56; 1.59) for myocardial infarction, and 0.89 (0.70; 1.14) and 1.00 (0.81; 1.24) for bleeding. In this large prospective cohort of AF patients, time-updated AF type was not associated with incident stroke/SE.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    URL: Article
    DOI: 10.1038/s41598-022-05688-9
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2615211-3
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