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  • 1
    In: Frontiers in Molecular Neuroscience, Frontiers Media SA, Vol. 15 ( 2022-9-14)
    Abstract: The prognosis of diffusely infiltrating glioma patients is dismal but varies greatly between individuals. While characterization of gliomas primarily relied on histopathological features, molecular markers increasingly gained importance and play a key role in the recently published 5 th edition of the World Health Organization (WHO) classification. Heme biosynthesis represents a crucial pathway due to its paramount importance in oxygen transport, energy production and drug metabolism. Recently, we described a “heme biosynthesis mRNA expression signature” that correlates with histopathological glioma grade and survival. The aim of the current study was to correlate this heme biosynthesis mRNA expression signature with diagnostic molecular markers and investigate its continued prognostic relevance. Materials and methods In this study, patient data were derived from the “The Cancer Genome Atlas” (TCGA) lower-grade glioma and glioblastoma cohorts. We identified diffusely infiltrating gliomas correlating molecular tumor diagnosis according to the most recent WHO classification with heme biosynthesis mRNA expression. The following molecular markers were analyzed: EGFR amplification, TERT promoter mutation, CDKN2A/B homozygous loss, chromosome 7 + /10- aneuploidy, MGMT methylation, IDH mutation, ATRX loss, p53 mutation and 1p19q codeletion. Subsequently, we calculated the heme biosynthesis mRNA expression signature for correlation with distinct molecular glioma markers/molecular subgroups and performed survival analyses. Results A total of 649 patients with available data on up-to-date molecular markers and heme biosynthesis mRNA expression were included. According to analysis of individual molecular markers, we found a significantly higher heme biosynthesis mRNA expression signature in gliomas with IDH wildtype ( p & lt; 0.0005), without 1p19q codeletion ( p & lt; 0.0005), with homozygous CDKN2A/B loss ( p & lt; 0.0005) and with EGFR amplification ( p = 0.001 ). Furthermore, we observed that the heme biosynthesis mRNA expression signature increased with molecular subgroup aggressiveness ( p & lt; 0.0005 ), being lowest in WHO grade 2 oligodendrogliomas and highest in WHO grade 4 glioblastomas. Finally, the heme biosynthesis mRNA expression signature was a statistically significant survival predictor after multivariate correction for all molecular markers ( p & lt; 0.0005). Conclusion Our data demonstrate a significant correlation between heme biosynthesis regulation and diagnostic molecular markers and a prognostic relevance independent of these established markers. Consequently, heme biosynthesis expression is a promising biomarker for glioma aggressiveness and might constitute a potential target for novel therapeutic approaches.
    Type of Medium: Online Resource
    ISSN: 1662-5099
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2452967-9
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  • 2
    In: Frontiers in Medicine, Frontiers Media SA, Vol. 9 ( 2022-5-18)
    Abstract: The intraoperative visualization of adult-type diffuse gliomas with 5-aminolevulinic acid (5-ALA) induced fluorescence is widely used in the neurosurgical field. While visible 5-ALA induced fluorescence is found in the majority of high-grade gliomas, most low-grade gliomas lack visible fluorescence during surgery. Recently, the heme biosynthesis pathway was identified as crucial influencing factor for presence of visible fluorescence since it metabolizes 5-ALA to fluorescing Protoporphyrin IX (PpIX). However, the exact alterations within the heme biosynthesis pathway resulting in visible 5-ALA induced fluorescence in gliomas are still unclear. The aim of the present study was thus to compare the mRNA and protein expression of promising intramitochondrial heme biosynthesis enzymes/transporters in glioma tissue samples of different fluorescence behavior. Methods A total of 19 strongly fluorescing and 21 non-fluorescing tissue samples from neurosurgical adult-type diffuse gliomas (WHO grades II-IV) were included in the current analysis. In these samples, we investigated the mRNA expression by quantitative real time PCR and protein expression using immunohistochemistry of the intramitochondrial heme biosynthesis enzymes Coproporphyrinogen Oxidase (CPOX), Protoporphyrinogen Oxidase (PPOX), Ferrochelatase (FECH), and the transporter ATP-binding Cassette Subfamily B Member 2 (ABCG2). Results Regarding mRNA expression analysis, we found a significantly decreased ABCG2 expression in fluorescing specimens compared to non-fluorescing samples ( p = 0.001), whereas no difference in CPOX, PPOX and FECH was present. With respect to protein expression, significantly higher levels of CPOX ( p = 0.005), PPOX ( p & lt; 0.01) and FECH ( p = 0.003) were detected in fluorescing samples. Similar to mRNA expression analysis, the protein expression of ABCG2 ( p = 0.001) was significantly lower in fluorescing samples. Conclusion Distinct alterations of the analyzed heme biosynthesis factors were found primarily on protein level. Our data indicate that heme biosynthesis pathway activity in general is enhanced in fluorescing gliomas with upregulation of PpIX generating enzymes and decreased ABCG2 mediated PpIX efflux outweighing the also increased further metabolization of PpIX to heme. Intramitochondrial heme biosynthesis factors thus constitute promising pharmacological targets to optimize intraoperative 5-ALA fluorescence visualization of usually non-fluorescing tumors such as low-grade gliomas.
    Type of Medium: Online Resource
    ISSN: 2296-858X
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2775999-4
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  • 3
    In: Frontiers in Physiology, Frontiers Media SA, Vol. 10 ( 2019-6-4)
    Type of Medium: Online Resource
    ISSN: 1664-042X
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2019
    detail.hit.zdb_id: 2564217-0
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  • 4
    Online Resource
    Online Resource
    Frontiers Media SA ; 2018
    In:  Frontiers in Molecular Neuroscience Vol. 11 ( 2018-5-24)
    In: Frontiers in Molecular Neuroscience, Frontiers Media SA, Vol. 11 ( 2018-5-24)
    Type of Medium: Online Resource
    ISSN: 1662-5099
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2018
    detail.hit.zdb_id: 2452967-9
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  • 5
    In: Frontiers in Surgery, Frontiers Media SA, Vol. 8 ( 2021-8-19)
    Abstract: Background: Sarcopenia describes a generalized loss of skeletal muscle mass, strength, or function. Determined by measuring the total psoas muscle area (tPMA) on cross-sectional imaging, sarcopenia is an independent marker for poor post-surgical outcomes in adults and children. Children with cancer are at high risk for sarcopenia due to immobility, chemotherapy, and cachexia. We hypothesize that sarcopenic children with neuroblastoma are at higher risk for poor post-operative outcomes. Patients and Methods: Retrospective analysis of children with neuroblastoma ages 1–15 years who were treated at our hospital from 2008 to 2016 with follow-up through March 2021. Psoas muscle area (PMA) was measured from cross-sectional images, using computed tomography (CT) and magnetic resonance imaging (MRI) scans at lumbar disc levels L3-4 and L4-5. tPMA is the sum of the left and right PMA. Z-scores were calculated using age- and gender-specific reference values. Sarcopenia was defined as a tPMA z-score below −2. A correlation of tPMA z-scores and sarcopenia with clinical variables and outcome was performed. Results: One hundred and sixty-four children with workup for neuroblastoma were identified, and 101 children fulfilled inclusion criteria for further analysis, with a mean age of 3.92 years (SD 2.71 years). Mean tPMA z-score at L4-5 was −2.37 (SD 1.02). Correlation of tPMA z-score at L4-5 with weight-for-age z-score was moderate ( r = 0.54; 95% CI, 0.38, 0.66). No association between sarcopenia and short-term outcome was observed. Sarcopenia had a sensitivity of 0.82 (95% CI, 0.62–0.93) and a specificity of 0.48 (95% CI 0.36–0.61) in predicting 5-year survival. In a multiple regression analysis, pre-operative sarcopenia, pre-operative chemotherapy in the NB2004 high-risk group, unfavorable tumor histology, and age at diagnosis were associated with 5-year survival after surgery, with hazard ratios of 4.18 (95% CI 1.01–17.26), 2.46 (95% CI 1.02–5.92), 2.39 (95% CI 1.03–5.54), and 1.01 (95% CI 1.00–1.03), respectively. Conclusion: In this study, the majority of children had low tPMA z-scores and sarcopenia was a risk factor for decreased 5-year survival in children with neuroblastoma. Therefore, we suggest measuring the tPMA from pre-surgical cross-sectional imaging as a biomarker for additional risk stratification in children with neuroblastoma.
    Type of Medium: Online Resource
    ISSN: 2296-875X
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
    detail.hit.zdb_id: 2773823-1
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  • 6
    In: Frontiers in Marine Science, Frontiers Media SA, Vol. 9 ( 2022-7-12)
    Abstract: The invasive Atlantic blue crab Callinectes sapidus has considerably extended its distribution along the Gulf of Cadiz and Moroccan coasts in the northeast Atlantic. This could indicate a new introduction event in the Gulf of Cadiz from the native area, in case of detectable genetic differences from the Mediterranean Sea populations. To test this and reconstruct the invasion, we assessed the genetic structure of crabs in the Gulf of Cadiz and Alboran Sea. We used sequences of the mitochondrial gene cytochrome c oxidase subunit I (COI), in almost its full length (1511 basepairs), of 149 individuals from three sites along the Spanish Mediterranean coast, two in the Alboran Sea, and two in the Gulf of Cadiz. Our data reveal low genetic variability, with only two haplotypes (here referred to as CSWM1 and CSWM2), compared to its known high genetic diversity in the native range, indicating a strong founder effect in the study region. Here we document an inversion of haplotype predominance between regions, haplotype CSWM2 being dominant in most of the Spanish Mediterranean coast, but less frequent in the Gulf of Cadiz and Alboran Sea. This suggests a secondary introduction of propagules into the investigated area, rather than a new introduction from the native area, nor a natural westward expansion with environmental selection of one haplotype over the other. Further studies with additional populations would help to better unveil the history of yet another invasive species in the Gulf of Cadiz.
    Type of Medium: Online Resource
    ISSN: 2296-7745
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2757748-X
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  • 7
    In: Frontiers in Synthetic Biology, Frontiers Media SA, Vol. 2 ( 2024-4-12)
    Abstract: Life exists at an interface. One of the key characteristics of biological cells is compartmentalization, which is facilitated by lipids that create a water-impenetrable barrier to control transport of materials across the hydrophilic-hydrophobic interface. Microbial systems utilize a rich diversity of surfactants beyond lipids to adapt to an environmental niche, modify the properties of an interface, facilitate solubilization of nutrients for metabolism and as antimicrobials. As such, they are a fascinating class of biomolecules to study in terms of how effectiveness in an application or niche environment depends on sequence, structure and chemical properties. Moreover, there is increasing appreciation of the negative health and environmental impacts petrochemical-based surfactants can have, such as soil erosion and toxicity to plants and aquatic life, as well as the carbon footprint and associated greenhouse gas emissions associated with petrochemical surfactant manufacturing. In this review, we discuss the properties of biosurfactants and applications, and highlight key glycolipid-, protein- and peptide-based surfactants described in literature as examples of biosurfactants with unique potential and applications. As society looks towards the transition to a circular bioeconomy, we are excited by the potential of synthetic biology to develop new materials such as biosurfactants to facilitate this important transition.
    Type of Medium: Online Resource
    ISSN: 2813-818X
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2024
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  • 8
    Online Resource
    Online Resource
    Frontiers Media SA ; 2020
    In:  Frontiers in Neurology Vol. 11 ( 2020-9-8)
    In: Frontiers in Neurology, Frontiers Media SA, Vol. 11 ( 2020-9-8)
    Type of Medium: Online Resource
    ISSN: 1664-2295
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2020
    detail.hit.zdb_id: 2564214-5
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  • 9
    Online Resource
    Online Resource
    Frontiers Media SA ; 2021
    In:  Frontiers in Pharmacology Vol. 11 ( 2021-1-13)
    In: Frontiers in Pharmacology, Frontiers Media SA, Vol. 11 ( 2021-1-13)
    Abstract: The tachykinin hemokinin-1 (HK-1) is involved in immune cell development and inflammation, but little is known about its function in pain. It acts through the NK1 tachykinin receptor, but several effects are mediated by a yet unidentified target. Therefore, we investigated the role and mechanism of action of HK-1 in arthritis models of distinct mechanisms with special emphasis on pain. Arthritis was induced by i.p. K/BxN serum (passive transfer of inflammatory cytokines, autoantibodies), intra-articular mast cell tryptase or Complete Freund’s Adjuvant (CFA, active immunization) in wild type, HK-1- and NK1-deficient mice. Mechanical- and heat hyperalgesia determined by dynamic plantar esthesiometry and increasing temperature hot plate, respectively, swelling measured by plethysmometry or micrometry were significantly reduced in HK-1-deleted, but not NK1-deficient mice in all models. K/BxN serum-induced histopathological changes (day 14) were also decreased, but early myeloperoxidase activity detected by luminescent in vivo imaging increased in HK-1-deleted mice similarly to the CFA model. However, vasodilation and plasma protein extravasation determined by laser Speckle and fluorescent imaging, respectively, were not altered by HK-1 deficiency in any models. HK-1 induced Ca 2+ -influx in primary sensory neurons, which was also seen in NK1-deficient cells and after pertussis toxin-pretreatment, but not in extracellular Ca 2+ -free medium. These are the first results showing that HK-1 mediates arthritic pain and cellular, but not vascular inflammatory mechanisms, independently of NK1 activation. HK-1 activates primary sensory neurons presumably via Ca 2+ channel-linked receptor. Identifying its target opens new directions to understand joint pain leading to novel therapeutic opportunities.
    Type of Medium: Online Resource
    ISSN: 1663-9812
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
    detail.hit.zdb_id: 2587355-6
    SSG: 15,3
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