Recent Submissions

  • 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.
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  • 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.
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  • 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.
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  • 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.
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  • 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.
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  • 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.
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  • 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.
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  • 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.
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  • Journal Article

    Rapid direct detection of pathogens for diagnosis of joint infections by MALDI-TOF MS after liquid enrichment in the BacT/Alert blood culture system 

    Noll, Christine; Nasruddin-Yekta, Azadda; Sternisek, Pia; Weig, Michael; Groß, Uwe; Schilling, Arndt F.; Beil, Frank Timo; Bader, Oliver
    PLOS ONE 2020; 15(12)
    Pathogen identification is a critical step during diagnosis of infectious diseases. Matrix-Assisted Laser Desorption/Ionization Time-Of-Flight mass spectrometry (MALDI-TOF-MS) has become the gold standard for identification of microorganisms cultured on solid media in microbiology laboratories. Direct identification of microbes from liquid specimen, circumventing the need for the additional overnight cultivation step, has been successfully established for blood culture, urine and liquor. Here, we evaluate the ability of MALDI-TOF MS for direct identification of pathogens in synovial fluid after liquid enrichment in BacT/Alert blood culture bottles. Influence of synovial specimen quality on direct species identification with the MALDI BioTyper/Sepsityper was tested with samples inoculated from pretested native synovia with concomitant inoculation of blood or pus, or highly viscous fluid. Here, we achieved >90% concordance with culture on solid medium, and only mixed-species samples posed significant problems. Performance in routine diagnostics was tested prospectively on bottles inoculated by treating physicians on ward. There, we achieved >70% concordance with culture on solid media. The major contributors to test failure were the absence of a measurable mass signal and mixed-specimen samples. The Sepsityper workflow worked well on samples derived from BacT/Alert blood culture bottles inoculated with synovial fluid, giving concordant results to identification from solid media. Host remnant material in the inoculum, such as blood or pus, had no detrimental effect on identification score values of the BioTyper system after processing with the Sepsityper workflow, and neither had the initial viscosity of the synovial sample.
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  • Journal Article

    Comparison of the double loop knot stitch and Kessler stitch for Achilles tendon repair: A biomechanical cadaver study 

    Frosch, Stephan; Buchhorn, Gottfried; Hawellek, Thelonius; Walde, Tim Alexander; Lehmann, Wolfgang; Hubert, Jan
    PLOS ONE 2020; 15(12)
    Tendon elongation after Achilles tendon (AT) repair is associated with the clinical outcome. Reliable suture techniques are essential to reduce gap formations and to allow early mobilization. Cyclic loading conditions represent the repetitive loading in rehabilitation. The aim of this study was to compare the Kessler stitch and double loop knot stitch (DLKS) in a cyclic loading program focussing on gap formation. Sixteen human cadaveric ATs were transected and sutured using either the Kessler stitch or DLKS (eight matched pairs). The suture-tendon configurations were subjected to cyclic loading and additional ultimate load to failure testing using the Zwick 1446 universal testing machine. Each AT survived cyclic loading, with a mean gap formation less than 5 mm after 1000 cycles. The mechanical properties of the Kessler stitch and DLKS were not significantly different after cyclic loading with a mean displacement of 4.57 mm (± 1.16) for the Kessler stitch and 4.85 mm (± 1.14) for the DLKS (P = .76). There were no significant differences in the ultimate load testing (P = .85). Both bioprotective techniques prevent excessive gaping in cyclic testing when tendon loading is moderate. Our data and those from literature of gap formation in cyclic and ultimate loading allow the conclusion, that early aggressive AT loading after repair (e.g. full weightbearing) overstrain simple as well as complex suture configurations. Initial intraoperative tightening of the knots (preloading) before locking is important to decrease postoperative elongation.
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  • Journal Article

    Genetic structure of coast redwood (Sequoia sempervirens [D. Don] Endl.) populations in and outside of the natural distribution range based on nuclear and chloroplast microsatellite markers 

    Breidenbach, Natalie; Gailing, Oliver; Krutovsky, Konstantin V.
    PLOS ONE 2020; 15(12)
    Coast redwood (Sequoia sempervirens) naturally growing in southern Oregon and northern California is one of the few conifer tree species that are polyploid. Despite its unique ecological and economic importance, its population genetic structure is still insufficiently studied. To obtain additional data on its population genetic structure we genotyped 317 samples collected from populations in California (data set C) and 144 trees growing in a provenance trial in France (data set F) using 12 nuclear (five random nuclear genomic nSSRs and seven expressed sequence tag EST-SSRs) and six chloroplast (cpSSRs) microsatellite or simple sequence repeat (SSR) markers, respectively. These data sets were also used as reference to infer the origin of 147 coast redwood trees growing in Germany (data set G). Coast redwood was introduced to Europe, including Germany as an ornamental species, decades ago. Due to its fast growth and high timber quality, it could be considered as a potential commercial timber species, especially in perspective to climate warming that makes more regions in Germany suitable for its growing. The well performing trees in colder Germany could be potential frost resistant genotypes, but their genetic properties and origin are mostly unknown. Within the natural range in southern Oregon and northern California, only two relatively weak clusters were identified, one northern and one southern, separated by the San Francisco Bay. High genetic diversity, but low differentiation was found based on the 12 nuclear SSR markers for all three data sets F, C and G. We found that investigated 147 German trees represented only 37 different genotypes. They showed genetic diversity at the level less than diversity observed within the natural range in the northern or southern cluster, but more similar to the diversity observed in the southern cluster. It was difficult to assign German trees to the original single native populations using the six cpSSR markers, but rather to either the northern or southern cluster. The high number of haplotypes found in the data sets based on six cpSSR markers and low genetic differentiation based on 12 nuclear SSRs found in this study helps us study and better understand population genetic structure of this complex polyploid tree and supports the selection of potential genotypes for German forestry.
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  • 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)
    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.
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  • 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)
    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.
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  • 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)
    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.
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  • Journal Article

    Comparison of Grip Strength in Recreational Climbers and Non-Climbing Athletes—A Cross-Sectional Study 

    Assmann, Mara; Steinmetz, Gino; Schilling, Arndt Friedrich; Saul, Dominik
    International Journal of Environmental Research and Public Health 2021; 18(1)
    In recent years, climbing sports is on the rise making its Olympic debut in 2021. Physiological traits of professional rock climbers have been intensively studied, while recreational indoor climbers are less investigated, especially regarding grip strength and upper extremity proportions. In this cross-sectional study, we aimed to understand what discerns the recreational climber from disparate recreational athletes. Therefore, we analyzed 50 recreational climbing (30.3 ± 12.7 years, 1.76 ± 0.09 m and 67.0 ± 14.0 kg) and 50 non-climbing athletes (26.4 ± 9.1 years, 1.78 ± 0.09 m and 73.2 ± 12.6 kg) to detect differences in their finger grip strength of seven different pinches. In addition, the upper extremity proportions were measured. Even in recreational climbers, almost all analyzed grips were stronger compared to other athletes (p < 0.05 in all but non-dominant fist, small to moderate effect sizes). Only the grip strength of the whole non-dominant hand was not significantly different (p = 0.17). Interestingly, differences between the dominant and non-dominant hand appeared to be larger in the non-climbing (all p < 0.05, all but one with small effect size) compared to the climbing cohort (pinch I/IV and pinch I/II+III+IV not different and mostly trivial). Circumference measurements showed that 10 cm below the lateral epicondyle, climbers exhibited significantly greater perimeter compared to non-climbing athletes (p < 0.05, small effect size). Our results show that recreational climbers have higher measured grip strength, but less profound differences between the dominant and non-dominant hand.
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  • Journal Article

    Immunotherapy in Autoantibody-Associated Psychiatric Syndromes in Adults 

    Hansen, Niels; Timäus, Charles
    Frontiers in Psychiatry 2021; 12
    Background: Autoantibody-associated psychiatric syndromes are often distinct from, but might also be part of autoimmune encephalitis. Our article focuses on potential immunotherapy in these patients with a probable autoimmune origin of their psychiatric syndrome. Methods: We searched through PubMed for appropriate articles on immunotherapy in autoantibody-associated psychiatric syndromes between 2010 and 2020 for this narrative review. Results: In line with prior recommendations for autoimmune encephalitis and autoimmune psychosis, we suggest that in patients with a probable autoimmune-based psychiatric syndrome should be given early corticosteroids, intravenous immunoglobulins, or plasmapheresis as first line immunotherapy. If these therapeutic options fail, second-line immunotherapy should be applied within 1 month consisting of rituximab or cyclophosphamide. Maintenance therapy is best for those patients responding to steroids including mycofenolate mofetil or azathioprine. So far, there is evidence from a few retrospective cohort studies supporting the usage of first- and second-line, and maintenance immunotherapies for autoantibody-associated psychiatric syndromes. Some immunological agents are discussed that might exert an effect in autoimmune-based psychiatric syndromes, but the latest evidence is low and derived from case reports or series with autoimmune encephalitis patients. Conclusions: Taken together, the immunotherapeutic landscape for patients with autoantibody-associated psychiatric syndromes is delineated. Our suggestions rely on observational studies in autoantibody-associated psychiatric syndromes and a few placebo-controlled, randomized trials for patients with autoimmune encephalitis and psychosis. Thus, adequate powered, prospective as well as placebo-controlled clinical trials in patients with autoantibody-associated psychiatric syndromes are warranted in order to enlighten efficacy and safety aspects of current and novel therapy strategies.
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  • Journal Article

    Case Report: Findings Suggestive of Paraclinical Progressive Multifocal Leukoencephalopathy and Lung Cancer-Derived Brain Metastases in an MS Patient Treated With Fingolimod 

    Maass, Fabian; von Gottberg, Philipp; Franz, Jonas; Stadelmann, Christine; Bähr, Mathias; Weber, Martin S.
    Frontiers in Neurology 2021; 12
    Fingolimod represents a highly effective disease-modifying drug in patients with active relapsing-remitting multiple sclerosis (RRMS). Its immunosuppressive effects can mediate adverse events like increased risk of cancer development or appearance of opportunistic infections. Progressive multifocal leukoencephalopathy (PML)–representing a severe opportunistic infection–has been only infrequently described during Fingolimod treatment. Here, we present a case of a 63-year-old women with pre-diagnosed RRMS who presented with new multiple cerebral lesions in a routine MRI scan, also including a tumefactive lesion in the left parietal lobe, eventually leading to the diagnosis of brain metastases derived by an adenocarcinoma of the lung. Additionally, a JCV-DNA-PCR in the cerebrospinal fluid revealed positive results, corresponding to a paraclinical progressive multifocal leukoencephalopathy. In conclusion, adverse events potentially associated with immunosuppression can occur during Fingolimod treatment. In this context, the occurrence of cancer and opportunistic infections should be carefully monitored. Here, we report a case in which JCV-DNA-PCR in the cerebrospinal fluid suggests asymptomatic PML and simultaneously lung cancer brain metastases developed. While it is rather unlikely that either event occurred as an adverse event of fingolimod treatment, a contributing effect cannot be formally excluded.
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  • Journal Article

    Variable Expression of PD-L1 in Kidneys Independent of Immune Checkpoint Inhibition 

    Hakroush, Samy; Kopp, Sarah Birgit; Tampe, Désirée; Gersmann, Ann-Kathrin; Korsten, Peter; Zeisberg, Michael; Tampe, Björn
    Frontiers in Immunology 2021; 11
    Context: Due to recent advantages in cancer therapy, immune checkpoint inhibitors (ICIs) are new classes of drugs targeting programmed cell death protein 1 (PD-1) or its ligand programmed cell death protein 1-ligand 1 (PD-L1) used in many cancer therapies. Acute interstitial nephritis (AIN) is a potential and deleterious immune-related adverse events (irAE) in the kidney observed in patients receiving ICIs and the most common biopsy-proven diagnosis in patients who develop acute kidney injury (AKI). Based on previous reports, AIN in patients receiving ICIs is associated with tubular positivity for PD-L1, implicating that PD-L1 positivity reflects susceptibility to develop renal complications with these agents. It remains unclear if PD-L1 positivity is acquired specifically during ICI therapy or expressed independently in the kidney. Methods: PD-L1 was analyzed in experimental mouse models of ischemia-reperfusion injury (IRI), folic acid-induced nephropathy (FAN), unilateral ureteral obstruction (UUO), and nephrotoxic serum nephritis (NTN) by immunostaining, SDS-PAGE, and subsequent immunoblotting. In addition, we included a total number of 87 human kidney samples (six renal biopsies with AIN related to ICI therapy, 13 nephrectomy control kidneys, and 68 ICI-naïve renal biopsies with various underlying kidney diseases to describe PD-L1 expression. Results: We here report distinct PD-L1 expression in renal compartments in multiple murine models of kidney injury and human cases with various underlying kidney diseases, including ICI-related AIN and renal pathologies independent of ICI therapy. PD-L1 is frequently expressed in various renal pathologies independent of ICI therapy and could potentially be a pre-requisit for susceptibility to develop AKI and deleterious immune-related AIN. In addition, we provide evidence that tubular PD-L1 positivity in the kidney is associated with detection of urinary PD-L1+ tubular epithelial cells. Conclusion: Our study implicates that PD-L1 is frequently expressed in various renal pathologies independent of ICI therapy and could potentially be a pre-requisit for susceptibility to develop AKI and deleterious immune-related AIN. Because non-invasive detection of PD-L1+ cells in corresponding urine samples correlates with intrarenal PD-L1 positivity, it is attractive to speculate that further non-invasive detection of PD-L1+ cells may identify patients at risk for ICI-related AIN.
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  • Journal Article

    The Glucocorticoid Receptor in Intestinal Epithelial Cells Alleviates Colitis and Associated Colorectal Cancer in Mice 

    Muzzi, Chiara; Watanabe, Norika; Twomey, Eric; Meers, Garrit K.; Reichardt, Holger M.; Bohnenberger, Hanibal; Reichardt, Sybille D.
    Cellular and Molecular Gastroenterology and Hepatology 2021; 11(5) p.1505-1518
    BACKGROUND & AIMS: Inflammatory bowel disease is commonly treated by administration of glucocorticoids. While the importance of intestinal epithelial cells for the pathogenesis of this disorder is widely accepted, their role as target cells for glucocorticoids has not been explored. To address this issue, we induced colonic inflammation in GRvillin mice, which carry an inducible deletion of the glucocorticoid receptor in intestinal epithelial cells. METHODS: Colitis and colitis-associated colorectal cancer were induced by administration of dextran sulfate sodium and azoxymethane in mice. Clinical parameters, epithelial permeability and tumor development were monitored during disease progression. Colon tissue, lamina propria cells and intestinal epithelial cells were examined by gene expression analyses, flow cytometry, histopathology, and immunohistochemistry. RESULTS: The absence of the intestinal epithelial glucocorticoid receptor aggravated clinical symptoms and tissue damage, and compromised epithelial barrier integrity during colitis. Gene expression of chemokines, pattern recognition receptors and molecules controlling epithelial permeability was dysregulated in intestinal epithelial cells of GRvillin mice, leading to a reduced recruitment and a hyperactivation of leukocytes in the lamina propria of the colon. Importantly, the exaggerated inflammatory response in GRvillin mice also enhanced associated tumorigenesis, resulting in a higher number and larger size of tumors in the colon. CONCLUSIONS: Our results reveal an important role of intestinal epithelial cells as targets of glucocorticoid action in inflammatory bowel disease and suggest that the efficacy with which colitis is kept at bay directly affects the progression of colorectal cancer.
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  • Journal Article

    Pluripotent Stem Cell-Derived Mesenchymal Stem Cells Show Comparable Functionality to Their Autologous Origin 

    Jakob, Mark; Hambrecht, Mario; Spiegel, Jennifer L.; Kitz, Julia; Canis, Martin; Dressel, Ralf; Streckfuss-Bömeke, Katrin
    Cells 2021; 10(1)
    The HER2-positive breast cancer subtype (HER2+-BC) displays a particularly aggressive behavior. Anti-HER2 therapies have significantly improved the survival of patients with HER2+-BC. However, a large number of patients become refractory to current targeted therapies, necessitating the development of new treatment strategies. Epigenetic regulators are commonly misregulated in cancer and represent attractive molecular therapeutic targets. Monoubiquitination of histone 2B (H2Bub1) by the heterodimeric ubiquitin ligase complex RNF20/RNF40 has been described to have tumor suppressor functions and loss of H2Bub1 has been associated with cancer progression. In this study, we utilized human tumor samples, cell culture models, and a mammary carcinoma mouse model with tissue-specific Rnf40 deletion and identified an unexpected tumorsupportive role of RNF40 in HER2+-BC. We demonstrate that RNF40-driven H2B monoubiquitination is essential for transcriptional activation of RHO/ROCK/LIMK pathway components and proper actin-cytoskeleton dynamics through a trans-histone crosstalk with histone 3 lysine 4 trimethylation (H3K4me3). Collectively, this work demonstrates a previously unknown essential role of RNF40 in HER2+-BC, revealing the H2B monoubiquitination axis as a possible tumor contextdependent therapeutic target in breast cancer.
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