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  • 1
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    Online Resource
    Pegylated Insulin-Like Growth Factor 1 attenuates Hair Cell Loss and promotes Presynaptic Maintenance of Medial Olivocochlear Cholinergic Fibers in the Cochlea of the Progressive Motor Neuropathy Mouse
    Frontiers Media SA ; 2022
    In:  Frontiers in Neurology Vol. 13 ( 2022-6-3)
    Details
    In: Frontiers in Neurology, Frontiers Media SA, Vol. 13 ( 2022-6-3)
    Abstract: The progressive motor neuropathy (PMN) mouse is a model of an inherited motor neuropathy disease with progressive neurodegeneration. Axon degeneration associates with homozygous mutations of the TBCE gene encoding the tubulin chaperone E protein. TBCE is responsible for the correct dimerization of alpha and beta-tubulin. Strikingly, the PMN mouse also develops a progressive hearing loss after normal hearing onset, characterized by degeneration of the auditory nerve and outer hair cell (OHC) loss. However, the development of this neuronal and cochlear pathology is not fully understood yet. Previous studies with pegylated insulin-like growth factor 1 (peg-IGF-1) treatment in this mouse model have been shown to expand lifespan, weight, muscle strength, and motor coordination. Accordingly, peg-IGF-1 was evaluated for an otoprotective effect. We investigated the effect of peg-IGF-1 on the auditory system by treatment starting at postnatal day 15 (p15). Histological analysis revealed positive effects on OHC synapses of medial olivocochlear (MOC) neuronal fibers and a short-term attenuation of OHC loss. Peg-IGF-1 was able to conditionally restore the disorganization of OHC synapses and maintain the provision of cholinergic acetyltransferase in presynapses. To assess auditory function, frequency-specific auditory brainstem responses and distortion product otoacoustic emissions were recorded in animals on p21 and p28. However, despite the positive effect on MOC fibers and OHC, no restoration of hearing could be achieved. The present work demonstrates that the synaptic pathology of efferent MOC fibers in PMN mice represents a particular form of “efferent auditory neuropathy.” Peg-IGF-1 showed an otoprotective effect by preventing the degeneration of OHCs and efferent synapses. However, enhanced efforts are needed to optimize the treatment to obtain detectable improvements in hearing performances.
    Type of Medium: Online Resource
    ISSN: 1664-2295
    URL: Article
    DOI: 10.3389/fneur.2022.885026
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2564214-5
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  • 2
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    Data_Sheet_1.docx
    Frontiers Media SA ; 2019
    In:  Frontiers in Oncology Vol. 9 ( 2019-4-16)
    Details
    In: Frontiers in Oncology, Frontiers Media SA, Vol. 9 ( 2019-4-16)
    Type of Medium: Online Resource
    ISSN: 2234-943X
    URL: Article
    URL: Article
    DOI: 10.3389/fonc.2019.00275
    DOI: 10.3389/fonc.2019.00275.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2019
    detail.hit.zdb_id: 2649216-7
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  • 3
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    DataSheet_1.pdf
    Frontiers Media SA ; 2021
    In:  Frontiers in Immunology Vol. 12 ( 2021-6-29)
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    In: Frontiers in Immunology, Frontiers Media SA, Vol. 12 ( 2021-6-29)
    Abstract: Chimeric antigen receptor (CAR) T cell performance against solid tumors in mouse models and clinical trials is often less effective than predicted by CAR construct selection in two-dimensional (2D) cocultures. Three-dimensional (3D) solid tumor architecture is likely to be crucial for CAR T cell efficacy. We used a three-dimensional (3D) bioprinting approach for large-scale generation of highly reproducible 3D human tumor models for the test case, neuroblastoma, and compared these to 2D cocultures for evaluation of CAR T cells targeting the L1 cell adhesion molecule, L1CAM. CAR T cells infiltrated the model, and both CAR T and tumor cells were viable for long-term experiments and could be isolated as single-cell suspensions for whole-cell assays quantifying CAR T cell activation, effector function and tumor cell cytotoxicity. L1CAM-specific CAR T cell activation by neuroblastoma cells was stronger in the 3D model than in 2D cocultures, but neuroblastoma cell lysis was lower. The bioprinted 3D neuroblastoma model is highly reproducible and allows detection and quantification of CAR T cell tumor infiltration, representing a superior in vitro analysis tool for preclinical CAR T cell characterization likely to better select CAR T cells for in vivo performance than 2D cocultures.
    Type of Medium: Online Resource
    ISSN: 1664-3224
    URL: Article
    URL: Article
    DOI: 10.3389/fimmu.2021.689697
    DOI: 10.3389/fimmu.2021.689697.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
    detail.hit.zdb_id: 2606827-8
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  • 4
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    Case Report: Rubella Virus-Induced Cutaneous Granulomas in Two Pediatric Patients With DNA Double Strand Breakage Repair Disorders – Outcome After Hematopoietic Stem Cell Transplantation
    Frontiers Media SA ; 2022
    In:  Frontiers in Immunology Vol. 13 ( 2022-6-2)
    Details
    In: Frontiers in Immunology, Frontiers Media SA, Vol. 13 ( 2022-6-2)
    Abstract: We report two patients with DNA repair disorders (Artemis deficiency, Ataxia telangiectasia) with destructive skin granulomas, presumably triggered by live-attenuated rubella vaccinations. Both patients showed reduced naïve T cells. Rapid resolution of skin lesions was observed following hematopoietic stem cell transplantation. However, the patient with AT died due to complications of severe hepatic veno-occlusive disease 6 month after HSCT. Dried blood spots obtained after birth were available from this patient and showed absent T-cell receptor excision circles (TRECs). Therefore, newborn screening may help to prevent patients with moderate T-cell deficiency from receiving live-attenuated rubella vaccine potentially causing granulomas.
    Type of Medium: Online Resource
    ISSN: 1664-3224
    URL: Article
    DOI: 10.3389/fimmu.2022.886540
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2606827-8
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  • 5
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    Table_6.xlsx
    Frontiers Media SA ; 2021
    In:  Frontiers in Oncology Vol. 11 ( 2021-5-7)
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    In: Frontiers in Oncology, Frontiers Media SA, Vol. 11 ( 2021-5-7)
    Abstract: MYCN gene amplification and upregulated expression are major hallmarks in the progression of high-risk neuroblastoma. MYCN expression and function in modulating gene synthesis in neuroblastoma is controlled at virtually every level, including poorly understood regulation at the post-transcriptional level. MYCN modulates the expression of various microRNAs including the miR-17-92 cluster. MYCN mRNA expression itself is subjected to the control by miRNAs, most prominently the miR-17-92 cluster that balances MYCN expression by feed-back regulation. This homeostasis seems disturbed in neuroblastoma where MYCN upregulation coincides with severely increased expression of the miR-17-92 cluster. In the presented study, we applied high-throughput next generation sequencing to unravel the miRNome in a cohort of 97 neuroblastomas, representing all clinical stages. Aiming to reveal the MYCN -dependent miRNome, we evaluate miRNA expression in MYCN -amplified as well as none amplified tumor samples. In correlation with survival data analysis of differentially expressed miRNAs, we present various putative oncogenic as well as tumor suppressive miRNAs in neuroblastoma. Using microRNA trapping by RNA affinity purification, we provide a comprehensive view of MYCN-regulatory miRNAs in neuroblastoma-derived cells, confirming a pivotal role of the miR-17-92 cluster and moderate association by the let-7 miRNA family. Attempting to decipher how MYCN expression escapes elevated expression of inhibitory miRNAs, we present evidence that RNA-binding proteins like the IGF2 mRNA binding protein 1 reduce miRNA-directed downregulation of MYCN in neuroblastoma. Our findings emphasize the potency of post-transcriptional regulation of MYCN in neuroblastoma and unravel new avenues to pursue inhibition of this potent oncogene.
    Type of Medium: Online Resource
    ISSN: 2234-943X
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.3389/fonc.2021.647737
    DOI: 10.3389/fonc.2021.647737.s001
    DOI: 10.3389/fonc.2021.647737.s002
    DOI: 10.3389/fonc.2021.647737.s003
    DOI: 10.3389/fonc.2021.647737.s004
    DOI: 10.3389/fonc.2021.647737.s005
    DOI: 10.3389/fonc.2021.647737.s006
    DOI: 10.3389/fonc.2021.647737.s007
    DOI: 10.3389/fonc.2021.647737.s008
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
    detail.hit.zdb_id: 2649216-7
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  • 6
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    Precision Nutrition in Chronic Inflammation
    Frontiers Media SA ; 2020
    In:  Frontiers in Immunology Vol. 11 ( 2020-11-23)
    Details
    In: Frontiers in Immunology, Frontiers Media SA, Vol. 11 ( 2020-11-23)
    Abstract: The molecular foundation of chronic inflammatory diseases (CIDs) can differ markedly between individuals. As our understanding of the biochemical mechanisms underlying individual disease manifestations and progressions expands, new strategies to adjust treatments to the patient’s characteristics will continue to profoundly transform clinical practice. Nutrition has long been recognized as an important determinant of inflammatory disease phenotypes and treatment response. Yet empirical work demonstrating the therapeutic effectiveness of patient-tailored nutrition remains scarce. This is mainly due to the challenges presented by long-term effects of nutrition, variations in inter-individual gastrointestinal microbiota, the multiplicity of human metabolic pathways potentially affected by food ingredients, nutrition behavior, and the complexity of food composition. Historically, these challenges have been addressed in both human studies and experimental model laboratory studies primarily by using individual nutrition data collection in tandem with large-scale biomolecular data acquisition (e.g. genomics, metabolomics, etc.). This review highlights recent findings in the field of precision nutrition and their potential implications for the development of personalized treatment strategies for CIDs. It emphasizes the importance of computational approaches to integrate nutritional information into multi-omics data analysis and to predict which molecular mechanisms may explain how nutrients intersect with disease pathways. We conclude that recent findings point towards the unexhausted potential of nutrition as part of personalized medicine in chronic inflammation.
    Type of Medium: Online Resource
    ISSN: 1664-3224
    URL: Article
    DOI: 10.3389/fimmu.2020.587895
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2020
    detail.hit.zdb_id: 2606827-8
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  • 7
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    Biomechanical Influences on Mesh-Related Complications in Incisional Hernia Repair
    Frontiers Media SA ; 2021
    In:  Frontiers in Surgery Vol. 8 ( 2021-10-29)
    Details
    In: Frontiers in Surgery, Frontiers Media SA, Vol. 8 ( 2021-10-29)
    Abstract: Aim: Hernia repair strengthens the abdominal wall with a textile mesh. Recurrence and pain indicate weak bonds between mesh and tissue. It remains a question which biomechanical factors strengthen the mesh-tissue interface, and whether surgeons can enhance the bond between mesh and tissue. Material and Methods: This study assessed the strength of the mesh-tissue interface by dynamic loads. A self-built bench test delivered dynamic impacts. The test simulated coughing. Porcine and bovine tissue were used for the bench test. Tissue quality, mesh adhesiveness, and fixation intensity influenced the retention power. The influences were condensed in a formula to assess the durability of the repair. The formula was applied to clinical work. The relative strength of reconstruction was related to the individual human abdominal wall. From computerized tomography at rest and during Valsalva's Maneuver, the tissue quality of the individual patient was determined before surgery. Results: The results showed that biomechanical parameters observed in porcine, bovine, and human tissue were in the same range. Tissues failed in distinct patterns. Sutures slackened or burst at vulnerable points. Both the load duration and the peak load increased destruction. Stress concentrations elevated failure rates. Regional areas of force contortions increased stress concentrations. Hernia repair improved strain levels. Measures for improvement included the closure of the defect, use of higher dynamic intermittent strain (DIS) class meshes, increased mesh overlap, and additional fixation. Surgeons chose the safety margin of the reconstruction as desired. Conclusion: The tissue quality has now been introduced into the concept of a critical and a gained resistance toward pressure-related impacts. A durable hernia repair could be designed from available coefficients. Using biomechanical principles, surgeons could minimize pain levels. Mesh-related complications such as hernia recurrence can potentially be avoided in incisional hernia repair.
    Type of Medium: Online Resource
    ISSN: 2296-875X
    URL: Article
    DOI: 10.3389/fsurg.2021.763957
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
    detail.hit.zdb_id: 2773823-1
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  • 8
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    DataSheet1.pdf
    Frontiers Media SA ; 2021
    In:  Frontiers in Molecular Biosciences Vol. 8 ( 2021-5-10)
    Details
    In: Frontiers in Molecular Biosciences, Frontiers Media SA, Vol. 8 ( 2021-5-10)
    Abstract: The highly infectious disease COVID-19 caused by the Betacoronavirus SARS-CoV-2 poses a severe threat to humanity and demands the redirection of scientific efforts and criteria to organized research projects. The international COVID19-NMR consortium seeks to provide such new approaches by gathering scientific expertise worldwide. In particular, making available viral proteins and RNAs will pave the way to understanding the SARS-CoV-2 molecular components in detail. The research in COVID19-NMR and the resources provided through the consortium are fully disclosed to accelerate access and exploitation. NMR investigations of the viral molecular components are designated to provide the essential basis for further work, including macromolecular interaction studies and high-throughput drug screening. Here, we present the extensive catalog of a holistic SARS-CoV-2 protein preparation approach based on the consortium’s collective efforts. We provide protocols for the large-scale production of more than 80% of all SARS-CoV-2 proteins or essential parts of them. Several of the proteins were produced in more than one laboratory, demonstrating the high interoperability between NMR groups worldwide. For the majority of proteins, we can produce isotope-labeled samples of HSQC-grade. Together with several NMR chemical shift assignments made publicly available on covid19-nmr.com , we here provide highly valuable resources for the production of SARS-CoV-2 proteins in isotope-labeled form.
    Type of Medium: Online Resource
    ISSN: 2296-889X
    URL: Article
    URL: Article
    DOI: 10.3389/fmolb.2021.653148
    DOI: 10.3389/fmolb.2021.653148.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
    detail.hit.zdb_id: 2814330-9
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  • 9
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    Image2.tiff
    Frontiers Media SA ; 2023
    In:  Transplant International Vol. 36 ( 2023-5-9)
    Details
    In: Transplant International, Frontiers Media SA, Vol. 36 ( 2023-5-9)
    Abstract: Early-on post kidney transplantation, there is a high risk of graft rejection and opportunistic viral infections. A low tacrolimus concentration/dose (C/D) ratio as a surrogate marker of fast tacrolimus metabolism has been established for risk stratification 3 months post-transplantation (M3). However, many adverse events occurring earlier might be missed, and stratification at 1 month post-transplantation (M1) has not been investigated. We retrospectively analyzed case data from 589 patients who had undergone kidney transplantation between 2011 and 2021 at three German transplant centers. Tacrolimus metabolism was estimated by use of the C/D ratio at M1, M3, M6, and M12. C/D ratios increased substantially during the year, particularly between M1 and M3. Many viral infections and most graft rejections occurred before M3. Neither at M1 nor at M3 was a low C/D ratio associated with susceptibility to BKV viremia or BKV nephritis. A low C/D ratio at M1 could not predict acute graft rejections or impaired kidney function, whereas at M3 it was significantly associated with subsequent rejections and impairment of kidney function. In summary, most rejections occur before M3, but a low C/D ratio at M1 does not identify patients at risk, limiting the predictive utility of this stratification approach.
    Type of Medium: Online Resource
    ISSN: 1432-2277
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.3389/ti.2023.11027
    DOI: 10.3389/ti.2023.11027.s001
    DOI: 10.3389/ti.2023.11027.s002
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2023
    detail.hit.zdb_id: 1463183-0
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  • 10
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    Image_1.pdf
    Frontiers Media SA ; 2023
    In:  Frontiers in Immunology Vol. 13 ( 2023-1-9)
    Details
    In: Frontiers in Immunology, Frontiers Media SA, Vol. 13 ( 2023-1-9)
    Abstract: Despite advances in treating high-risk neuroblastoma, 50-60% of patients still suffer relapse, necessitating new treatment options. Bispecific trifunctional antibodies (trAbs) are a promising new class of immunotherapy. TrAbs are heterodimeric IgG-like molecules that bind CD3 and a tumor-associated antigen simultaneously, whereby inducing a TCR-independent anti-cancer T cell response. Moreover, via their functional Fc region they recruit and activate cells of the innate immune system like antigen-presenting cells potentially enhancing induction of adaptive tumor-specific immune responses. Methods We used the SUREK trAb, which is bispecific for GD2 and murine Cd3. Tumor-blind trAb and the monoclonal ch14.18 antibody were used as controls. A co-culture model of murine dendritic cells (DCs), T cells and a neuroblastoma cell line was established to evaluate the cytotoxic effect and the T cell effector function in vitro. Expression of immune checkpoint molecules on tumor-infiltrating T cells and the induction of an anti-neuroblastoma immune response using a combination of whole cell vaccination and trAb therapy was investigated in a syngeneic immunocompetent neuroblastoma mouse model (NXS2 in A/J background). Finally, vaccinated mice were assessed for the presence of neuroblastoma-directed antibodies. We show that SUREK trAb-mediated effective killing of NXS2 cells in vitro was strictly dependent on the combined presence of DCs and T cells. Results Using a syngeneic neuroblastoma mouse model, we showed that vaccination with irradiated tumor cells combined with SUREK trAb treatment significantly prolonged survival of tumor challenged mice and partially prevent tumor outgrowth compared to tumor vaccination alone. Treatment led to upregulation of programmed cell death protein 1 (Pd-1) on tumor infiltrating T cells and combination with anti-Pd-1 checkpoint inhibition enhanced the NXS2-directed humoral immune response. Conclusion Here, we provide first preclinical evidence that a tumor vaccination combined with SUREK trAb therapy induces an endogenous anti-neuroblastoma immune response reducing tumor recurrence. Furthermore, a combination with anti-Pd-1 immune checkpoint blockade might even further improve this promising immunotherapeutic concept in order to prevent relapse in high-risk neuroblastoma patients.
    Type of Medium: Online Resource
    ISSN: 1664-3224
    URL: Article
    URL: Article
    DOI: 10.3389/fimmu.2022.1023206
    DOI: 10.3389/fimmu.2022.1023206.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2023
    detail.hit.zdb_id: 2606827-8
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