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  • 1
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    Online Resource
    Efficacy and Treatment Satisfaction of Different Systemic Therapies in Children and Adolescents with Moderate-to-Severe Atopic Dermatitis: A Real-World Study
    MDPI AG ; 2023
    In:  Journal of Clinical Medicine Vol. 12, No. 3 ( 2023-02-01), p. 1175-
    Details
    In: Journal of Clinical Medicine, MDPI AG, Vol. 12, No. 3 ( 2023-02-01), p. 1175-
    Abstract: For the treatment of moderate-to-severe atopic dermatitis in children and adolescents, the monoclonal antibody dupilumab and the selective JAK-1 inhibitor upadacitinib are two modern systemic therapies approved for long-term treatment. Both drugs have demonstrated high efficacy in randomized controlled trials, although evidence from real-world data in the pediatric population is limited. In a prospective analysis over 24 weeks, we investigated the efficacy, safety and treatment satisfaction of both systemic therapies in 23 patients (16 patients treated with dupilumab; 7 patients treated with upadacitinib). The median age of the patients was 16 years, with a median EASI of 18.8. A significant improvement in the EASI, VAS-itch, CDLQI, POEM and DFIQ from baseline to week 24 was demonstrated for both treatment options. No significant difference was observed between dupilumab and upadacitinib in any of the assessed scores. Less adverse events were recorded in the real-world setting compared with clinical trials. Our results confirm the efficacy and safety of dupilumab and upadacitinib as equivalent treatment options in children and adolescents in a real-world setting.
    Type of Medium: Online Resource
    ISSN: 2077-0383
    URL: Article
    DOI: 10.3390/jcm12031175
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2662592-1
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  • 2
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    Online Resource
    Preferential Response of Basal-Like Head and Neck Squamous Cell Carcinoma Cell Lines to EGFR-Targeted Therapy Depending on EREG-Driven Oncogenic Addiction
    MDPI AG ; 2019
    In:  Cancers Vol. 11, No. 6 ( 2019-06-08), p. 795-
    Details
    In: Cancers, MDPI AG, Vol. 11, No. 6 ( 2019-06-08), p. 795-
    Abstract: The management of locally advanced head and neck squamous cell carcinoma (HNSCC) with Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), achieves only moderate response rates, and clinical trials that evaluated EGFR-blockade with tyrosine kinase inhibitors (TKI) yielded disappointing results. Inter-tumor heterogeneity may hinder the therapeutic efficiency of anti-EGFR treatments. HNSCC heterogeneity was addressed in several studies, which all converged towards the definition of molecular subgroups. They include the basal subgroup, defined by the deregulated expression of factors involved in the EGFR signaling pathway, including the epiregulin EGFR ligand encoded by the EREG gene. These observations indicate that basal tumors could be more sensitive to anti-EGFR treatments. To test this hypothesis, we performed a screen of a representative collection of basal versus non-basal HNSCC cell lines for their sensitivity to several anti-EGFR drugs (Cetuximab, Afatinib, and Gefitinib), tested as monotherapy or in combination with drugs that target closely-linked pathways [Mitogen-activated protein kinase kinase/extracellular signal–regulated kinases (MEK), mammalian Target of Rapamycine (mTOR) or Human Epidermal growth factor Receptor 2 (HER2)]. Basal-like cell lines were found to be more sensitive to EGFR blockade alone or in combination with treatments that target MEK, mTOR, or HER2. Strikingly, the basal-like status was found to be a better predictor of cell response to EGFR blockade than clinically relevant mutations [e.g., cyclin-dependent kinase Inhibitor 2A (CDKN2A)] . Interestingly, we show that EGFR blockade inhibits EREG expression, and that EREG knock-down decreases basal cell clonogenic survival, suggesting that EREG expression could be a predictive functional marker of sensitivity to EGFR blockade in basal-like HNSCC.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers11060795
    Language: English
    Publisher: MDPI AG
    Publication Date: 2019
    detail.hit.zdb_id: 2527080-1
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  • 3
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    Online Resource
    Decline of European Beech in Austria: Involvement of Phytophthora spp. and Contributing Biotic and Abiotic Factors
    MDPI AG ; 2020
    In:  Forests Vol. 11, No. 8 ( 2020-08-18), p. 895-
    Details
    In: Forests, MDPI AG, Vol. 11, No. 8 ( 2020-08-18), p. 895-
    Abstract: A severe decline and dieback of European beech (Fagus sylvatica L.) stands have been observed in Austria in recent decades. From 2008 to 2010, the distribution and diversity of Phytophthora species and pathogenic fungi and pests were surveyed in 34 beech forest stands in Lower Austria, and analyses performed to assess the relationships between Phytophthora presence and various parameters, i.e. root condition, crown damage, ectomycorrhizal abundance and site conditions. In total, 6464 trees were surveyed, and Phytophthora-associated collar rot and aerial bark cankers were detected on 133 trees (2.1%) in 25 stands (73.5%). Isolations tests were performed from 103 trees in 27 stands and seven Phytophthora species were isolated from bleeding bark cankers and/or from the rhizosphere soil of 49 trees (47.6%) in 25 stands (92.6%). The most common species were P. ×cambivora (16 stands) followed by P. plurivora (eight stands) and P. cactorum (four stands), while P. gonapodyides, P. syringae, P. psychrophila and P. tubulina were each found in only one stand. Geological substrate had a significant effect on the distribution of P. ×cambivora and P. plurivora while P. cactorum showed no site preferences. In addition, 21 fungal species were identified on beech bark, of which 19 and five species were associated with collar rot and aerial bark cankers, respectively. Four tested fine root parameters showed differences between declining and non-declining beech trees in both Phytophthora-infested and Phytophthora-free stands. In both stand categories, ectomycorrhizal frequency of fine root tips was significantly higher in non-declining than in declining trees. This study confirmed the involvement of Phytophthora species in European beech decline and underlines the need of more research on the root condition of beech stands and other biotic and abiotic factors interacting with Phytophthora infections or causing beech decline in absence of Phytophthora.
    Type of Medium: Online Resource
    ISSN: 1999-4907
    URL: Article
    DOI: 10.3390/f11080895
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2527081-3
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  • 4
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    Husbandry Conditions and Welfare Outcomes in Organic Egg Production in Eight European Countries
    MDPI AG ; 2020
    In:  Animals Vol. 10, No. 11 ( 2020-11-12), p. 2102-
    Details
    In: Animals, MDPI AG, Vol. 10, No. 11 ( 2020-11-12), p. 2102-
    Abstract: In the European research project HealthyHens, welfare indicators as well as husbandry and management conditions were recorded in 107 organic laying hen farms in eight countries. Farms were visited at peak and end of lay. Egg production was on average comparable to breeder specifications. A mean mortality of 5.7% and mean prevalences of footpad lesions of 30.5%, keel bone damage of 44.5%, 57.3% of flocks with on average 〉 200 Ascarid eggs per gram faeces and 28.2% of flocks with 〉 100 mites/trap were recorded. A large variation between flocks indicated options for improvement. Based on the results, the following measures can be recommended: (i) decreasing mite and worm infestation and (ii) providing an attractive covered veranda, because of their association with decreased mortality; (iii) maximising access to the free range, because of its relation to decreased A. galli infection and less injurious pecking; (iv) feeding sufficient protein levels and (v) providing adequate litter as preventive measure against feather pecking and cannibalism; (vi) ensuring that the birds have sufficient weight and (vii) preventing accidents by adequate hen house facilities and light conditions to reduce keel bone damage. These primarily management-based measures have the potential to improve bird welfare both in terms of behavioural and health aspects.
    Type of Medium: Online Resource
    ISSN: 2076-2615
    URL: Article
    DOI: 10.3390/ani10112102
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2606558-7
    SSG: 23
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  • 5
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    Online Resource
    Beverages Containing Plant-Derived Polyphenols Inhibit Growth and Biofilm Formation of Streptococcus mutans and Children’s Supragingival Plaque Bacteria
    MDPI AG ; 2021
    In:  Beverages Vol. 7, No. 3 ( 2021-06-28), p. 43-
    Details
    In: Beverages, MDPI AG, Vol. 7, No. 3 ( 2021-06-28), p. 43-
    Abstract: Objectives: Polyphenols in edible berries and tea plant (Camellia sinensis) suppressed virulence factors of oral pathogens. We investigated if the commercially marketed plant polyphenols-containing beverages inhibited growth and biofilm formation of Streptococcus mutans and children’s dental plaque. Methods: Supragingival plaque collected from 16 children (7–11 years) were suspended in TSB for testing. Test beverages included 26 marketed packaged teas, ready-to-drink bottled raspberry flavored teas and cranberry juice cocktails with and without added sugars. Their effects on in vitro growth and biofilm formation of S. mutans and children’s plaque bacteria were determined after 24–48 h at 37 °C anaerobically in CDM with or without sucrose. Results: Brewed infusions from black, green and cinnamon or raspberry flavored teas bags inhibited growth and biofilm formation of children’s plaque bacteria. Compared to controls, bottled raspberry flavored teas and cranberry juice cocktails significantly inhibited growth and biofilm formation of test bacteria. Added sugar did not significantly impact the inhibition (p 〉 0.05). Biofilms formed in these beverages were loosely attached and easily dislodged from surfaces. Conclusions: Beverages rich in antimicrobial plant polyphenols reduce plaque adherence, may benefit oral health and are preferred over other sugary beverages. The concept of oral diseases prevention using natural foods/diet is innovative, practical and acceptable.
    Type of Medium: Online Resource
    ISSN: 2306-5710
    URL: Article
    DOI: 10.3390/beverages7030043
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2785444-9
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  • 6
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    Online Resource
    Lactate versus Phosphate as Biomarkers to Aid Mechanical Circulatory Support Decisions in Patients with Out-of-Hospital Cardiac Arrest and Return of Spontaneous Circulation
    MDPI AG ; 2023
    In:  Diagnostics Vol. 13, No. 9 ( 2023-04-24), p. 1523-
    Details
    In: Diagnostics, MDPI AG, Vol. 13, No. 9 ( 2023-04-24), p. 1523-
    Abstract: Aims: Identifying patients who may benefit from mechanical circulatory support (MCS) after out-of-hospital cardiac arrest (OHCA) and return of spontaneous circulation (ROSC) remains challenging; thus, a search for helpful biomarkers is warranted. We aimed to evaluate phosphate and lactate levels on admission regarding their associations with survival with and without MCS. Methods: In 224 OHCA patients who achieved ROSC, the initial phosphate and lactate levels were investigated to discriminate in-hospital mortality by receiver operating characteristic (ROC) curves. According to the Youden Index (YI) from the respective ROC, the groups were risk stratified by both biomarkers, and 30-day mortality was analyzed in patients with and without MCS. Results: Within the entire collective, MCS was not associated with a better chance of survival. Both phosphate and lactate level elevations showed good yet comparable discriminations to predict mortality (areas under the curve: 0.80 vs. 0.79, p = 0.74). In patients with initial phosphate values 〉 2.2 mmol/L ( 〉 YI), 30-day mortality within the MCS cohort was lower (HR 2.3, 95% CI: 1.4–3.7; p = 0.0037). In patients with lower phosphate levels and groups stratified by lactate, 30-day mortality was similar in patients with and without MCS. Conclusions: We found a significant association between survival and MCS therapy in patients with phosphate levels above 2.2 mmol/L (Youden Index), and a similar discrimination of patient overall survival by lactate and phosphate. Prospective studies should assess the possible independent prognostic value of phosphate and its clearance for MCS efficiency.
    Type of Medium: Online Resource
    ISSN: 2075-4418
    URL: Article
    DOI: 10.3390/diagnostics13091523
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2662336-5
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  • 7
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    Generation and Characterization of a CRISPR/Cas9-Mediated SNAP29 Knockout in Human Fibroblasts
    MDPI AG ; 2021
    In:  International Journal of Molecular Sciences Vol. 22, No. 10 ( 2021-05-18), p. 5293-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 22, No. 10 ( 2021-05-18), p. 5293-
    Abstract: Loss-of-function mutations in the synaptosomal-associated protein 29 (SNAP29) lead to the rare autosomal recessive neurocutaneous cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma (CEDNIK) syndrome. SNAP29 is a soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein. So far, it has been shown to be involved in membrane fusion, epidermal differentiation, formation of primary cilia, and autophagy. Recently, we reported the successful generation of two mouse models for the human CEDNIK syndrome. The aim of this investigation was the generation of a CRISPR/Cas9-mediated SNAP29 knockout (KO) in an immortalized human cell line to further investigate the role of SNAP29 in cellular homeostasis and signaling in humans independently of animal models. Comparison of different methods of delivery for CRISPR/Cas9 plasmids into the cell revealed that lentiviral transduction is more efficient than transfection methods. Here, we reported to the best of our knowledge the first successful generation of a CRISPR/Cas9-mediated SNAP29 KO in immortalized human MRC5Vi fibroblasts (c.169_196delinsTTCGT) via lentiviral transduction.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms22105293
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 8
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    Ectodysplasin A1 Deficiency Leads to Osteopetrosis-like Changes in Bones of the Skull Associated with Diminished Osteoclastic Activity
    MDPI AG ; 2022
    In:  International Journal of Molecular Sciences Vol. 23, No. 20 ( 2022-10-13), p. 12189-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 23, No. 20 ( 2022-10-13), p. 12189-
    Abstract: Pathogenic variants of the gene Eda cause X-linked hypohidrotic ectodermal dysplasia (XLHED), which is characterized by structural abnormalities or lack of ectodermal appendages. Signs of dysplasia are not restricted to derivatives of the ectodermal layer, but mesodermal abnormalities, such as craniofacial dysmorphism, are also frequently observed, suggesting close reciprocal interactions between the ectoderm and mesoderm; however, a causal link has remained unsubstantiated. We investigated the functional impact of defective ectodysplasin A1 (Eda1) signaling on postnatal bone homeostasis in Eda1-deficient Tabby mice. Interestingly, Eda1 was detected in wild-type mouse calvariae throughout postnatal lifetime. In calvariae, bone-lining Osterix (Osx)+ osteoblasts stained positive for Eda1, and osteoclasts were revealed as Eda receptor (Edar)-positive. Moreover, adult Eda1-deficient calvarial bone showed osteopetrosis-like changes with significantly diminished marrow space, which was maintained during adulthood. Concomitantly with osteopetrosis-like changes, Tabby calvarial bone and Tabby bone marrow-derived osteoclasts had far less osteoclastic activity-associated co-enzymes including cathepsin K, Mmp9, Trap, and Tcirg1 (V-type proton ATPase a3 subunit) compared with wild-type calvariae in vivo or osteoclasts in vitro, indicating that Eda1 deficiency may affect the activity of osteoclasts. Finally, we confirmed that nuclear Nfatc1-positive osteoclasts were strongly diminished during mature osteoclastic differentiation under M-CSF and RANKL in the Tabby model, while Fc-EDA treatment of Tabby-derived osteoclasts significantly increased nuclear translocation of Nfatc1. Furthermore, we identified enhanced Nfatc1 and NF-κB transcriptional activity following Fc-EDA treatment in vitro using luciferase assays. Overall, the results indicate that diminished expressions of osteoclastic activity-associated co-enzymes may lead to disturbed bone homeostasis in Tabby calvariae postnatally.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms232012189
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 9
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    CD103+ Tissue Resident T-Lymphocytes Accumulate in Lung Metastases and Are Correlated with Poor Prognosis in ccRCC
    MDPI AG ; 2022
    In:  Cancers Vol. 14, No. 6 ( 2022-03-17), p. 1541-
    Details
    In: Cancers, MDPI AG, Vol. 14, No. 6 ( 2022-03-17), p. 1541-
    Abstract: Clear cell renal cell carcinoma (ccRCC) is a highly immunogenic tumor with variable responses to immune checkpoint therapy. The significance of the immune cell infiltrate in distant metastases, their association with the immune infiltrate in the primary tumors and their impact on prognosis are poorly described. We hypothesized that specific subtypes of immune cells may be involved in the control of metastases and may have an impact on the prognosis of ccRCC. We analyzed the immune microenvironment in ccRCC primary tumors with distant metastases, paired distant metastases and non-metastasized ccRCC (n = 25 each group) by immunohistochemistry. Confirmatory analyses for CD8+ and CD103+ cells were performed in a large ccRCC cohort (n = 241) using a TCGA-KIRC data set (ITGAE/CD103). High immune cell infiltration in primary ccRCC tumors was significantly correlated with the development of distant tumor metastasis (p 〈 0.05). A high density of CD103+ cells in ccRCC was more frequent in poorly differentiated tumors (p 〈 0.001). ccRCCs showed high levels of ITGAE/CD103 compared with adjacent non-neoplastic tissue. A higher density of CD103+ cells and a higher ITGAE/CD103 expression were significantly correlated with poor overall survival in ccRCC (log rank p 〈 0.05). Our results show a major prognostic value of the immune pattern, in particular CD103+ cell infiltration in ccRCC, and highlight the importance of the tumor immune microenvironment.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers14061541
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2527080-1
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  • 10
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    Online Resource
    Adverse Outcome Following Mild Traumatic Brain Injury Is Associated with Microstructure Alterations at the Gray and White Matter Boundary
    MDPI AG ; 2023
    In:  Journal of Clinical Medicine Vol. 12, No. 16 ( 2023-08-21), p. 5415-
    Details
    In: Journal of Clinical Medicine, MDPI AG, Vol. 12, No. 16 ( 2023-08-21), p. 5415-
    Abstract: The gray matter/white matter (GM/WM) boundary of the brain is vulnerable to shear strain associated with mild traumatic brain injury (mTBI). It is, however, unknown whether GM/WM microstructure is associated with long-term outcomes following mTBI. The diffusion and structural MRI data of 278 participants between 18 and 65 years of age with and without military background from the Department of Defense INTRuST study were analyzed. Fractional anisotropy (FA) was extracted at the GM/WM boundary across the brain and for each lobe. Additionally, two conventional analytic approaches were used: whole-brain deep WM FA (TBSS) and whole-brain cortical thickness (FreeSurfer). ANCOVAs were applied to assess differences between the mTBI cohort (n = 147) and the comparison cohort (n = 131). Associations between imaging features and post-concussive symptom severity, and functional and cognitive impairment were investigated using partial correlations while controlling for mental health comorbidities that are particularly common among military cohorts and were present in both the mTBI and comparison group. Findings revealed significantly lower whole-brain and lobe-specific GM/WM boundary FA (p 〈 0.011), and deep WM FA (p = 0.001) in the mTBI cohort. Whole-brain and lobe-specific GM/WM boundary FA was significantly negatively correlated with post-concussive symptoms (p 〈 0.039), functional (p 〈 0.016), and cognitive impairment (p 〈 0.049). Deep WM FA was associated with functional impairment (p = 0.002). Finally, no significant difference was observed in cortical thickness, nor between cortical thickness and outcome (p 〉 0.05). Findings from this study suggest that microstructural alterations at the GM/WM boundary may be sensitive markers of adverse long-term outcomes following mTBI.
    Type of Medium: Online Resource
    ISSN: 2077-0383
    URL: Article
    DOI: 10.3390/jcm12165415
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2662592-1
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