Recent Submissions

  • Journal Article

    COVID-19 Pandemic: Effect of Different Face Masks on Self-Perceived Dry Mouth and Halitosis 

    Kanzow, Philipp; Dylla, Viktoria; Mahler, Alannah Malina; Hrasky, Valentina; Rödig, Tina; Barre, Felix; Scheithauer, Simone; Wiegand, Annette
    Int J Environ Res Public Health 2021; 18(17): Art. 9180
    Due to the COVID-19 pandemic, the use of face masks has increased, resulting in potential health-related side-effects. Therefore, the study aimed to analyse the effect of wearing face masks on self-perceived dry mouth and halitosis. A questionnaire addressing the daily wearing time of different face masks (community masks, surgical/medical masks and KN95-/N95-/FFP2-masks) and self-perceived dry mouth and halitosis was given to adults attending or working at a university hospital. Statistical analysis was performed using Wilcoxon signed-rank test and multiple linear regression analysis (p < 0.05). 3750 participants (age: 50.4 ± 15.5 years; 60.0% female) were included. During the pandemic, face masks were used for 4.7 ± 3.8 h per day: community masks: 0.9 ± 2.0 h, medical/surgical masks: 1.9 ± 2.8 h and KN95-/N95-/FFP2-masks: 1.9 ± 2.5 h per day. The use of face masks significantly increased self-perceived dry mouth and halitosis (both p < 0.001). Self-perceived dry mouth and halitosis increased with increasing wearing time (community masks: dry mouth: p < 0.001, halitosis: p = 0.014; medical/surgical masks: both: p < 0.001; KN95-/N95-/FFP2-masks: dry mouth: p < 0.001, halitosis: p = 0.011). The perception of dry mouth and halitosis was increased in females compared to males (both: p < 0.001). Participants used to wearing face masks prior to the pandemic perceived dry mouth to a higher extent (p = 0.043). Self-perceived halitosis was lower in older than in younger participants (p < 0.001). Due to the increased perception of dry mouth and halitosis, people might abstain from wearing face masks. Further studies need to analyse measurable changes in dry mouth or halitosis.
    View Document Abstract
  • Journal Article

    On weakly informative prior distributions for the heterogeneity parameter in Bayesian random-effects meta-analysis. 

    Röver, Christian; Bender, Ralf; Dias, Sofia; Schmid, Christopher H; Schmidli, Heinz; Sturtz, Sibylle; Weber, Sebastian; Friede, Tim
    Research Synthesis Methods 2021; 12(4) p.448-474
    The normal-normal hierarchical model (NNHM) constitutes a simple and widely used framework for meta-analysis. In the common case of only few studies contributing to the meta-analysis, standard approaches to inference tend to perform poorly, and Bayesian meta-analysis has been suggested as a potential solution. The Bayesian approach, however, requires the sensible specification of prior distributions. While noninformative priors are commonly used for the overall mean effect, the use of weakly informative priors has been suggested for the heterogeneity parameter, in particular in the setting of (very) few studies. To date, however, a consensus on how to generally specify a weakly informative heterogeneity prior is lacking. Here we investigate the problem more closely and provide some guidance on prior specification.
    View Document Abstract
  • Journal Article

    Survival of direct composite restorations placed under general anesthesia in adult patients with intellectual and/or physical disabilities. 

    Maes, Mona Shaghayegh; Kanzow, Philipp; Hrasky, Valentina; Wiegand, Annette
    Clin Oral Investig 2021; 25(7) p.4563-4569
    Objectives: This study aimed to assess the survival of direct composite restorations placed under general anesthesia in adult patients with intellectual and/or physical disabilities. Materials and methods: Survival of composite restorations placed under general anesthesia in adult patients with intellectual and/or physical disabilities was retrospectively analyzed. Failure was defined as the need for replacement of at least one surface of the original restoration or extraction of the tooth. Individual-, tooth-, and restoration-related factors were obtained from dental records. Five-year mean annual failure rate (mAFR) and median survival time were calculated (Kaplan-Meier statistics). The effect of potential risk factors on failure was tested using univariate log-rank tests and multivariate Cox-regression analysis (α = 5%). Results: A total of 728 restorations in 101 patients were included in the analysis. The survival after 5 years amounted to 67.7% (5-year mAFR: 7.5%) and median survival time to 7.9 years. Results of the multivariate Cox-regression analysis revealed physical disability (HR: 50.932, p = 0.001) and combined intellectual/physical disability (HR: 3.145, p = 0.016) compared with intellectual disability only, presence of a removable partial denture (HR: 3.013, p < 0.001), and restorations in incisors (HR: 2.281, p = 0.013) or molars (HR: 1.693, p = 0.017) compared with premolars to increase the risk for failure. Conclusion: Composite restorations placed under general anesthesia in adult patients with intellectual and/or physical disabilities showed a reasonable longevity as 67.7% survived at least 5 years. Clinical relevance: Survival of composite restorations depends on risk factors that need to be considered when planning restorative treatment in patients with intellectual and/or physical disabilities. NCT04407520.
    View Document Abstract
  • Journal Article

    Microglia: The Missing Link to Decipher and Therapeutically Control MS Progression? 

    Geladaris, Anastasia; Häusler, Darius; Weber, Martin S.
    International Journal of Molecular Sciences 2021; 22(7): Art. 3461
    Therapeutically controlling chronic progression in multiple sclerosis (MS) remains a major challenge. MS progression is defined as a steady loss of parenchymal and functional integrity of the central nervous system (CNS), occurring independent of relapses or focal, magnetic resonance imaging (MRI)-detectable inflammatory lesions. While it clinically surfaces in primary or secondary progressive MS, it is assumed to be an integral component of MS from the very beginning. The exact mechanisms causing progression are still unknown, although evolving evidence suggests that they may substantially differ from those driving relapse biology. To date, progression is assumed to be caused by an interplay of CNS-resident cells and CNS-trapped hematopoietic cells. On the CNS-resident cell side, microglia that are phenotypically and functionally related to cells of the monocyte/macrophage lineage may play a key role. Microglia function is highly transformable. Depending on their molecular signature, microglia can trigger neurotoxic pathways leading to neurodegeneration, or alternatively exert important roles in promoting neuroprotection, downregulation of inflammation, and stimulation of repair. Accordingly, to understand and to possibly alter the role of microglial activation during MS disease progression may provide a unique opportunity for the development of suitable, more effective therapeutics. This review focuses on the current understanding of the role of microglia during disease progression of MS and discusses possible targets for therapeutic intervention.
    View Document Abstract
  • Journal Article

    Characterization of Methacrylate-Based Resins Containing Methacryl-Polyhedral Oligomeric Silsesquioxanes (MA-POSS-8) 

    Kreutz, Marietta; Wiegand, Annette; Stawarczyk, Bogna; Lümkemann, Nina; Rizk, Marta
    Materials 2021; 14(7): Art. 1680
    The use of functionalized dental adhesives that might prevent degradation of the dentin hybrid layer has been proposed. The aim of the study was to characterize the physicochemical properties and the potential to induce mineral precipitation of methacrylate-based resins containing methacryl-functionalized polyhedral oligomeric silsesquioxane (MA-POSS-8). In total, six different compositions of resins based on bisphenol A glycerolate dimethacrylate (BisGMA, 40 to 60 wt.%), triethylene glycol dimethacrylate (TEGDMA, 5 to 35 wt.%) and 2-hydroxyethyl methacrylate (HEMA, 25 or 35 wt.%) were prepared and infiltrated with 5 wt.% MA-POSS-8. Unfilled resins served as control. Degree of conversion, viscosity, Martens hardness, indentation modulus, water sorption, and sol fraction were investigated. Polymerized specimens were examined by SEM/EDX for the presence of Ca/P precipitates after immersion in artificial saliva for 28 days at 37 °C. Statistical analysis was performed with two-way ANOVA and Tukey’s post-hoc test (p < 0.05). The degree of conversion ranged from 55.0 to 59.8% and was not affected by the addition of MA-POSS-8. Viscosity ranged from 60.0 to 422.3 mPa*s and was not affected by MA-POSS-8 except for one methacrylate-based resin with 60 wt.% BisGMA. Martens hardness and indentation modulus ranged from 161.3 to 138.1 N/mm2 and 4.2 to 3.9 kN/mm2 and were affected by MA-POSS-8 in only one resin (50 wt.% BisGMA, 25 wt.% TEGDMA, 25 wt.% HEMA). Water sorption was not affected by MA-POSS-8; sol fraction was below the detection limit. Formation of Ca/P precipitates was observed on all specimens of test and control groups. Material properties were not affected adversly by MA-POSS-8 except for slight differences in Martens Hardness, indentation modulus, viscosity, in some groups.
    View Document Abstract
  • Journal Article

    Evaluation of ustekinumab trough levels during induction and maintenance therapy with regard to disease activity status in difficult to treat Crohn disease patients 

    Mechie, Nicolae-Catalin; Burmester, Merle; Mavropoulou, Eirini; Pilavakis, Yiannis; Kunsch, Steffen; Ellenrieder, Volker; Amanzada, Ahmad
    Medicine 2021; 100(11): Art. e25111
    Ustekinumab (UST) is approved for the treatment of moderate and severe Crohn disease (CD). Therapeutic drug monitoring (TDM) can help monitor the therapeutic effects of biologics. Therefore, the aim of this study was to evaluate the clinical outcomes of UST-treated CD patients and to determine the UST trough level in clinical and corticosteroid-free remission. This retrospective study included patients with moderate and severe active disease (AD) treated intravenously with a weight-adapted induction dose of UST. The maintenance therapy consisted of 90 mg UST subcutaneously at week 8 and thereafter every 8 or 12 weeks, depending on the clinical response. Clinical and corticosteroid-free remission, Harvey-Bradshaw-Index (HBI), UST trough level, and further laboratory parameters were measured just before the injection of UST at each follow-up evaluation until week 40. 37 CD patients with a median HBI of 9 at week 0 were included in the study. Starting from 24% at the beginning of the monitoring period, and 38% of patients at the end of the monitoring period were treated with an 8-week interval (P = .18). There was a significant improvement in clinical (P = .0004), corticosteroid-free remission (P = .03), and HBI (P < .0001) from week 0 until the end of the observation period. The serum UST trough level decreased significantly from 2.0 at week 8 to 0.3, in the maintenance therapy and 0.4 μg/ml at the end of the therapy (P < .0001). Neither UST trough level nor levels of C-reactive protein (CRP) or fecal calprotectin (FC) were associated with disease outcome. Concomitant immunomodulator therapy did not appear to affect the UST trough level or clinical course. UST is an effective treatment option for difficult-to-treat patients with CD. UST trough levels may not be associated with treatment efficacy or the prediction of treatment outcomes in patients with CD. Further prospective randomized trials should be conducted to evaluate whether UST trough levels are associated with treatment outcomes in patients with CD.
    View Document Abstract
  • Journal Article

    Case Report: Interferon-γ Restores Monocytic Human Leukocyte Antigen Receptor (mHLA-DR) in Severe COVID-19 With Acquired Immunosuppression Syndrome 

    Dickel, Steffen; Grimm, Clemens; Amschler, Katharina; Schnitzler, Sebastian Uwe; Schanz, Julie; Moerer, Onnen; Payen, Didier; Tampe, Bjoern; Winkler, Martin Sebastian
    Frontiers in Immunology 2021; 12: Art. 645124
    Background: The major histocompatibility complex (MHC) class II characterized by monocytes CD14+ expression of human leukocyte antigen receptors (HLA-DR), is essential for the synapse between innate and adaptive immune response in infectious disease. Its reduced expression is associated with a high risk of secondary infections in septic patients and can be safely corrected by Interferon-y (IFNy) injection. Coronavirus disease (COVID-19) induces an alteration of Interferon (IFN) genes expression potentially responsible for the observed low HLA-DR expression in circulating monocytes (mHLA-DR). Methods: We report a case of one-time INFy injection (100 mcg s.c.) in a superinfected 61-year-old man with COVID-19–associated acute respiratory distress syndrome (ARDS), with monitoring of mHLA-DR expression and clinical tolerance. Observations: Low mHLA-DR pretreatment expression (26.7%) was observed. IFNy therapy leading to a rapid increase in mHLA-DR expression (83.1%). Conclusions: Severe ARDS in a COVID-19 patient has a deep reduction in mHLA-DR expression concomitantly with secondary infections. The unique IFNy injection was safe and led to a sharp increase in the expression of mHLA-DR. Based on immune and infection monitoring, more cases of severe COVID-19 patients with low mHLA-DR should be treated by IFNy to test the clinical effectiveness.
    View Document Abstract
  • Journal Article

    Electrophysiology Echoes Brain Dynamics in Children and Adolescents With Tourette Syndrome—A Developmental Perspective 

    Rothenberger, Aribert; Heinrich, Hartmut
    Frontiers in Neurology 2021; 12: Art. 587097
    The development of the complex clinical picture of motor and vocal tics in children and adolescents with Tourette syndrome (TS) must be paralleled by changes in the underlying pathophysiology. Electrophysiological methods such as EEG and event-related potentials (ERPs) are non-invasive, safe and easy to apply and thus seem to provide an adequate means to investigate brain dynamics during this brain maturational period. Also, electrophysiology is characterized by a high time resolution and can reflect motor, sensory and cognitive aspects as well as sleep behavior. Hence, this narrative review focuses on how electrophysiology echoes brain dynamics during development of youngsters with TS and might be useful for the treatment of tics. A comprehensive picture of developmental brain dynamics could be revealed showing that electrophysiological parameters evolve concurrently with clinical characteristics of TS. Specifically, evidence for a maturational delay of motor inhibition related to cortico-spinal hyper-excitability and brain mechanisms for its cognitive compensation could be shown. Moreover, deviant sleep parameters and probably a stronger perception-action binding were reported. For neuromodulatory treatments (e.g., neurofeedback; repetitive transcranial magnetic stimulation, rTMS/transcranial direct current stimulation, tDCS) targeting neuronal deficits and/or strengthening compensatory brain mechanisms, pilot studies support the possibility of positive effects regarding tic reduction. Finally, attention-deficit/hyperactivity disorder (ADHD), as a highly frequent co-existing disorder with TS, has to be considered when using and interpreting electrophysiological measures in TS. In conclusion, application of electrophysiology seems to be promising regarding clinical and research aspects in youngsters with TS.
    View Document Abstract
  • Journal Article

    Different Forms of Tumor Vascularization and Their Clinical Implications Focusing on Vessel Co-option in Colorectal Cancer Liver Metastases 

    Haas, Gwendolyn; Fan, Shuang; Ghadimi, Michael; De Oliveira, Tiago; Conradi, Lena-Christin
    Frontiers in Cell and Developmental Biology 2021; 9: Art. 612774
    In modern anti-cancer therapy of metastatic colorectal cancer (mCRC) the anti-angiogenic treatment targeting sprouting angiogenesis is firmly established for more than a decade. However, its clinical benefits still remain limited. As liver metastases (LM) represent the most common metastatic site of colorectal cancer and affect approximately one-quarter of the patients diagnosed with this malignancy, its treatment is an essential aspect for patients' prognosis. Especially in the perioperative setting, the application of anti-angiogenic drugs represents a therapeutic option that may be used in case of high-risk or borderline resectable colorectal cancer liver metastases (CRCLM) in order to achieve secondary resectability. Regarding CRCLM, one reason for the limitations of anti-angiogenic treatment may be represented by vessel co-option (VCO), which is an alternative mechanism of blood supply that differs fundamentally from the well-known sprouting angiogenesis and occurs in a significant fraction of CRCLM. In this scenario, tumor cells hijack pre-existing mature vessels of the host organ independently from stimulating new vessels formation. This represents an escape mechanism from common anti-angiogenic anti-cancer treatments, as they primarily target the main trigger of sprouting angiogenesis, the vascular endothelial growth factor A. Moreover, the mechanism of blood supply in CRCLM can be deduced from their phenotypic histopathological growth pattern (HGP). For that, a specific guideline has already been implemented. These HGP vary not only regarding their blood supply, but also concerning their tumor microenvironment (TME), as notable differences in immune cell infiltration and desmoplastic reaction surrounding the CRCLM can be observed. The latter actually serves as one of the central criteria for the classification of the HGP. Regarding the clinically relevant effects of the HGP, it is still a topic of research whether the VCO-subgroup of CRCLM results in an impaired treatment response to anti-angiogenic treatment when compared to an angiogenic subgroup. However, it is well-proved, that VCO in CRCLM generally relates to an inferior survival compared to the angiogenic subgroup. Altogether the different types of blood supply result in a relevant influence on the patients' prognosis. This reinforces the need of an extended understanding of the underlying mechanisms of VCO in CRCLM with the aim to generate more comprehensive approaches which can target tumor vessels alternatively or even other components of the TME. This review aims to augment the current state of knowledge on VCO in CRCLM and other tumor entities and its impact on anti-angiogenic anti-cancer therapy.
    View Document Abstract
  • Journal Article

    Adipose‐derived mesenchymal stem cells reduce autophagy in stroke mice by extracellular vesicle transfer of miR‐25 

    Kuang, Yaoyun; Zheng, Xuan; Zhang, Lin; Ai, Xiaoyu; Venkataramani, Vivek; Kilic, Ertugrul; Hermann, Dirk M.; Majid, Arshad; Bähr, Mathias; Doeppner, Thorsten R.
    Journal of Extracellular Vesicles 2020; 10(1): Art. e12024
    Grafted mesenchymal stem cells (MSCs) yield neuroprotection in preclinical stroke models by secreting extracellular vesicles (EVs). The neuroprotective cargo of EVs, however, has not yet been identified. To investigate such cargo and its underlying mechanism, primary neurons were exposed to oxygen-glucose-deprivation (OGD) and cocultured with adipose-derived MSCs (ADMSCs) or ADMSC-secreted EVs. Under such conditions, both ADMSCs and ADMSC-secreted EVs significantly reduced neuronal death. Screening for signalling cascades being involved in the interaction between ADMSCs and neurons revealed a decreased autophagic flux as well as a declined p53-BNIP3 activity in neurons receiving either treatment paradigm. However, the aforementioned effects were reversed when ADMSCs were pretreated with the inhibitor of exosomal secretion GW4869 or when Hrs was knocked down. In light of miR-25-3p being the most highly expressed miRNA in ADMSC-EVs interacting with the p53 pathway, further in vitro work focused on this pathway. Indeed, a miR-25-3p oligonucleotide mimic reduced cell death, whereas the anti-oligonucleotide increased autophagic flux and cell death by modulating p53-BNIP3 signalling in primary neurons exposed to OGD. Likewise, native ADMSC-EVs but not EVs obtained from ADMSCs pretreated with the anti-miR-25-3p oligonucleotide (ADMSC-EVsanti-miR-25-3p) confirmed the aforementioned in vitro observations in C57BL/6 mice exposed to cerebral ischemia. The infarct size was reduced, and neurological recovery was increased in mice treated with native ADMSC-EVs when compared to ADMSC-EVsanti-miR-25-3p. ADMSCs induce neuroprotection by improved autophagic flux through secreted EVs containing miR-25-3p. Hence, our work uncovers a novel key factor in naturally secreted ADMSC-EVs for the regulation of autophagy and induction of neuroprotection in a preclinical stroke model.
    View Document Abstract
  • Journal Article

    Non‐invasive hemodynamic profile of early COVID‐19 infection 

    Busana, Mattia; Schiavone, Marco; Lanfranchi, Antonio; Battista Forleo, Giovanni; Ceriani, Elisa; Beatrice Cogliati, Chiara; Gasperetti, Alessio
    Physiological Reports 2020; 8(20): Art. e14628
    Introduction Little is known about the systemic and pulmonary macrohemodynamics in early COVID-19 infection. Echocardiography may provide useful insights into COVID-19 physiopathology. Methods Twenty-three COVID-19 patients were enrolled in a medical ward. Gas exchange, transthoracic echocardiographic, and hemodynamic variables were collected. Results Mean age was 57 ± 17 years. The patients were hypoxemic (PaO2/FiO2 = 273.0 ± 102.6 mmHg) and mildly hypocapnic (PaCO2 = 36.2 ± 6.3 mmHg, pH = 7.45 ± 0.03). Mean arterial pressure was decreased (86.7 [80.0–88.3] mmHg). Cardiac index was elevated (4.32 ± 0.90 L∙min-1∙m-2) and the resulting systemic vascular resistance index low (1,458 [1358–1664] dyn∙s∙cm-5∙m-2). The right heart was morphologically and functionally normal, with pulmonary artery pressure (PAPm, 18.0 ± 2.9 mmHg) and Total Pulmonary Resistances (TPR, 2.3 [2.1–2.7] mmHg∙l-1∙min-1) within normal limits. When stratifying for SVRI, patients with an SVRI value below the cohort median had also more severe oxygenation impairment and lower TPR, despite a similar degree of CXR infiltrates. Oxygen delivery index in this group resulted supranormal. Conclusions In the early stages of COVID-19 infection the hemodynamic profile is characterized by a hyperdynamic circulatory state with high CI and low SVRI, while the right heart is functionally unaffected. Our findings suggest that hypoxemia, viral sepsis or peripheral shunting are possible mechanisms for the vasodilation that dominates at this stage of the disease and may itself worsen the gas exchange.
    View Document Abstract
  • Journal Article

    Cardiotoxicity and Cardiovascular Biomarkers in Patients With Breast Cancer: Data From the GeparOcto‐GBG 84 Trial 

    Rüger, Alexandra Maria; Schneeweiss, Andreas; Seiler, Sabine; Tesch, Hans; van Mackelenbergh, Marion; Marmé, Frederik; Lübbe, Kristina; Sinn, Bruno; Karn, Thomas; Stickeler, Elmar; et al.
    Müller, VolkmarSchem, ChristianDenkert, CarstenFasching, Peter A.Nekljudova, ValentinaGarfias‐Macedo, TaniaHasenfuß, GerdHaverkamp, WilhelmLoibl, Sibyllevon Haehling, Stephan
    Journal of the American Heart Association 2020; 9(23): Art. e018143
    Background Patients with breast cancer can be affected by cardiotoxic reactions through cancer therapies. Cardiac biomarkers, like NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) and high‐sensitivity cardiac troponin T, might have predictive value. Methods and Results Echocardiography, ECG, hemodynamic parameters, NT‐proBNP and high‐sensitivity cardiac troponin T were assessed in 853 patients with early‐stage breast cancer randomized in the German Breast Group GeparOcto‐GBG 84 phase III trial. Patients received neo‐adjuvant dose‐dense, dose‐intensified epirubicin, paclitaxel, and cyclophosphamide (iddEPC group, n=424) or paclitaxel, non‐pegylated doxorubicin, and in triple negative breast cancer, (paclitaxel, non‐pegylated doxorubicin, carboplatin group, n=429) treatment for 18 weeks. Patients positive for human epidermal growth receptor 2 (n=354, 41.5%) received monoclonal antibodies on top of allocated therapy; 119 (12.9%) of all patients showed a cardiotoxic reaction during therapy (15 [1.8%] using a more strict definition). Presence of cardiotoxic reactions was irrespective of treatment allocation (P=0.31). Small but significant increases in NT‐proBNP developed early in patients with a cardiotoxic reaction as compared with those without in whom NT‐proBNP rose only towards the end of therapy (P=0.04). High‐sensitivity cardiac troponin T rose early in both groups. Logistic regression showed that NT‐proBNP (odds ratio [OR], 1.03; 95% CI, 1.008–1.055; P=0.01) and hemoglobin (OR, 1.31; 95% CI, 1.05–1.63; P=0.02) measured at 6 weeks after treatment initiation were significantly associated with cardiotoxic reactions. Conclusions NT‐proBNP and hemoglobin are significantly associated with cardiotoxic reactions in patients with early‐stage breast cancer undergoing dose‐dense and dose‐intensified chemotherapy, but high‐sensitivity cardiac troponin T is not.
    View Document Abstract
  • Journal Article

    Bounds for the weight of external data in shrinkage estimation. 

    Röver, Christian; Friede, Tim
    Biometrical journal. Biometrische Zeitschrift 2021-02-25; 63(5) p.1131-1143
    Shrinkage estimation in a meta-analysis framework may be used to facilitate dynamical borrowing of information. This framework might be used to analyze a new study in the light of previous data, which might differ in their design (e.g., a randomized controlled trial and a clinical registry). We show how the common study weights arise in effect and shrinkage estimation, and how these may be generalized to the case of Bayesian meta-analysis. Next we develop simple ways to compute bounds on the weights, so that the contribution of the external evidence may be assessed a priori. These considerations are illustrated and discussed using numerical examples, including applications in the treatment of Creutzfeldt-Jakob disease and in fetal monitoring to prevent the occurrence of metabolic acidosis. The target study's contribution to the resulting estimate is shown to be bounded below. Therefore, concerns of evidence being easily overwhelmed by external data are largely unwarranted.
    View Document Abstract
  • Journal Article

    Identification of drivers of breast cancer invasion by secretome analysis: insight into CTGF signaling 

    Hellinger, Johanna W.; Schömel, Franziska; Buse, Judith V.; Lenz, Christof; Bauerschmitz, Gerd; Emons, Günter; Gründker, Carsten
    Scientific Reports 2020; 10(1)
    An altered consistency of tumor microenvironment facilitates the progression of the tumor towards metastasis. Here we combine data from secretome and proteome analysis using mass spectrometry with microarray data from mesenchymal transformed breast cancer cells (MCF-7-EMT) to elucidate the drivers of epithelial-mesenchymal transition (EMT) and cell invasion. Suppression of connective tissue growth factor (CTGF) reduced invasion in 2D and 3D invasion assays and expression of transforming growth factor-beta-induced protein ig-h3 (TGFBI), Zinc finger E-box-binding homeobox 1 (ZEB1) and lysyl oxidase (LOX), while the adhesion of cell-extracellular matrix (ECM) in mesenchymal transformed breast cancer cells is increased. In contrast, an enhanced expression of CTGF leads to an increased 3D invasion, expression of fibronectin 1 (FN1), secreted protein acidic and cysteine rich (SPARC) and CD44 and a reduced cell ECM adhesion. Gonadotropin-releasing hormone (GnRH) agonist Triptorelin reduces CTGF expression in a Ras homolog family member A (RhoA)-dependent manner. Our results suggest that CTGF drives breast cancer cell invasion in vitro and therefore could be an attractive therapeutic target for drug development to prevent the spread of breast cancer.
    View Document Abstract
  • Journal Article

    A double-Flp-in method for stable overexpression of two genes 

    Jensen, Ole; Ansari, Salim; Gebauer, Lukas; Müller, Simon F.; Lowjaga, Kira A. A. T.; Geyer, Joachim; Tzvetkov, Mladen V.; Brockmöller, Jürgen
    Scientific Reports 2020; 10(1)
    Overexpression of single genes in mammalian cells is widely used to investigate protein function in basic and applied biosciences and in drug research. A better understanding of interactions of two proteins is an important next step in the advancement of our understanding of complex biological systems. However, simultaneous and robust overexpression of two or more genes is challenging. The Flp-In system integrates a vector into cell lines at a specific genomic locus, but has not been used for integration of more than one gene. Here we present a modification of the Flp-In system that enables the simultaneous targeted integration of two genes. We describe the modification and generation of the vectors required and give the complete protocol for transfection and validation of correct genomic integration and expression. We also provide results on the stability and reproducibility, and we functionally validated this approach with a pharmacologically relevant combination of a membrane transporter facilitating drug uptake and an enzyme mediating drug metabolism.
    View Document Abstract
  • Journal Article

    Continuous lengthening potential after four years of magnetically controlled spinal deformity correction in children with spinal muscular atrophy 

    Lorenz, Heiko M.; Hecker, Marina M.; Braunschweig, Lena; Badwan, Batoul; Tsaknakis, Konstantinos; Hell, Anna K.
    Scientific Reports 2020; 10(1)
    Magnetically controlled growing rods (MCGR) are commonly implanted for the treatment of early-onset scoliosis. While most authors report favorable short-term results, little is known about long-term deformity correction. This prospective cohort study assesses spinal deformity control in a homogeneous spinal muscular atrophy (SMA) patient group treated with MCGR implants, a standardized lengthening protocol and a minimum follow-up of four years. 17 SMA patients with progressive scoliosis were treated with MCGR implanted parallel to the spine with rib-to-pelvis fixation. Radiologic measurements were performed before and after MCGR implantation and during external lengthening procedures. These included measurements of the scoliotic curve, kyphosis, lordosis, pelvic obliquity and the spinal length. Additional clinical data of the complications were also analyzed. 17 children (mean age 7.4 years) were surgically treated and underwent a total of 376 lengthenings. Complication rates were 3.5% in respect to all interventions or 41% of the patients had complications during 3.5% of the lengthening sessions. The initial implantation significantly reduced the main scoliotic curve by 59%, with the correction remaining constant throughout the follow-up. Pelvic obliquity was also significantly and permanently corrected by 72%, whereas kyphosis and lordosis were not influenced. The spinal length could be significantly increased mostly during the first year of treatment. Bilateral implantation of MCGRs for correction of spinal deformity in children with SMA showed no decrease of the lengthening potential during a four-year follow-up. Therefore, the previously described ‘law of diminishing returns’ could not be applied to this patient population.
    View Document Abstract
  • Journal Article

    Accuracy of zero-heat-flux thermometry and bladder temperature measurement in critically ill patients 

    Bräuer, Anselm; Fazliu, Albulena; Perl, Thorsten; Heise, Daniel; Meissner, Konrad; Brandes, Ivo Florian
    Scientific Reports 2020; 10(1)
    Core temperature (TCore) monitoring is essential in intensive care medicine. Bladder temperature is the standard of care in many institutions, but not possible in all patients. We therefore compared core temperature measured with a zero-heat flux thermometer (TZHF) and with a bladder catheter (TBladder) against blood temperature (TBlood) as a gold standard in 50 critically ill patients in a prospective, observational study. Every 30 min TBlood, TBladder and TZHF were documented simultaneously. Bland–Altman statistics were used for interpretation. 7018 pairs of measurements for the comparison of TBlood with TZHF and 7265 pairs of measurements for the comparison of TBlood with TBladder could be used. TBladder represented TBlood more accurate than TZHF. In the Bland Altman analyses the bias was smaller (0.05 °C vs. − 0.12 °C) and limits of agreement were narrower (0.64 °C to − 0.54 °C vs. 0.51 °C to – 0.76 °C), but not in clinically meaningful amounts. In conclusion the results for zero-heat-flux and bladder temperatures were virtually identical within about a tenth of a degree, although TZHF tended to underestimate TBlood. Therefore, either is suitable for clinical use.
    View Document Abstract
  • Journal Article

    Memory guidance of value-based decision making at an abstract level of representation 

    Liashenko, Anna; Dizaji, Aslan S.; Melloni, Lucia; Schwiedrzik, Caspar M.
    Scientific Reports 2020; 10(1)
    Value-based decisions about alternatives we have never experienced can be guided by associations between current choice options and memories of prior reward. A critical question is how similar memories need to be to the current situation to effectively guide decisions. We address this question in the context of associative learning of faces using a sensory preconditioning paradigm. We find that memories of reward spread along established associations between faces to guide decision making. While memory guidance is specific for associated facial identities, it does not only occur for the specific images that were originally encountered. Instead, memory guidance generalizes across different images of the associated identities. This suggests that memory guidance does not rely on a pictorial format of representation but on a higher, view-invariant level of abstraction. Thus, memory guidance operates on a level of representation that neither over- nor underspecifies associative relationships in the context of obtaining reward.
    View Document Abstract
  • Journal Article

    Vimentin protects differentiating stem cells from stress 

    Pattabiraman, Sundararaghavan; Azad, Gajendra Kumar; Amen, Triana; Brielle, Shlomi; Park, Jung Eun; Sze, Siu Kwan; Meshorer, Eran; Kaganovich, Daniel
    Scientific Reports 2020; 10(1)
    Vimentin is one of the first cytoplasmic intermediate filaments to be expressed in mammalian cells during embryogenesis, but its role in cellular fitness has long been a mystery. Vimentin is acknowledged to play a role in cell stiffness, cell motility, and cytoplasmic organization, yet it is widely considered to be dispensable for cellular function and organismal development. Here, we show that Vimentin plays a role in cellular stress response in differentiating cells, by recruiting aggregates, stress granules, and RNA-binding proteins, directing their elimination and asymmetric partitioning. In the absence of Vimentin, pluripotent embryonic stem cells fail to differentiate properly, with a pronounced deficiency in neuronal differentiation. Our results uncover a novel function for Vimentin, with important implications for development, tissue homeostasis, and in particular, stress response.
    View Document Abstract
  • Journal Article

    X-ray diffraction and second harmonic imaging reveal new insights into structural alterations caused by pressure-overload in murine hearts 

    Nicolas, Jan-David; Khan, Amara; Markus, Andrea; Mohamed, Belal A.; Toischer, Karl; Alves, Frauke; Salditt, Tim
    Scientific Reports 2020; 10(1)
    We demonstrate a label-free imaging approach to study cardiac remodeling of fibrotic and hypertrophic hearts, bridging scales from the whole organ down to the molecular level. To this end, we have used mice subjected to transverse aortic constriction and imaged adjacent cardiac tissue sections by microfocus X-ray diffraction and second harmonic generation (SHG) imaging. In this way, the acto-myosin structure was probed in a spatially resolved manner for entire heart sections. From the recorded diffraction data, spatial maps of diffraction intensity, anisotropy and orientation were obtained, and fully automated analysis depicted the acto-myosin filament spacing and direction. X-ray diffraction presented an overview of entire heart sections and revealed that in regions of severe cardiac remodeling the muscle mass is partly replaced by connective tissue and the acto-myosin lattice spacing is increased at these regions. SHG imaging revealed sub-cellular structure of cardiac tissue and complemented the findings from X-ray diffraction by revealing micro-level distortion of myofibrils, immune cell infiltration at regions of cardiac remodeling and the development of fibrosis down to the scale of a single collagen fibril. Overall, our results show that both X-ray diffraction and SHG imaging can be used for label-free and high-resolution visualization of cardiac remodeling and fibrosis progression at different stages in a cardiac pressure-overload mouse model that cannot be achieved by conventional histology.
    View Document Abstract

View more