Recent Submissions

  • Journal Article

    MT‐102 prevents tissue wasting and improves survival in a rat model of severe cancer cachexia 

    Pötsch, Mareike S.; Ishida, Junichi; Palus, Sandra; Tschirner, Anika; Haehling, Stephan; Döhner, Wolfram; Anker, Stefan D.; Springer, Jochen
    Journal of Cachexia, Sarcopenia and Muscle
    BACKGROUND: Cachexia, a common manifestation of malignant cancer, is associated with wasting of skeletal muscle and fat tissue. In this study, we investigated the effects of a new first in class anabolic catabolic transforming agent on skeletal muscle in a rat model of cancer cachexia. METHODS: Young male Wistar Han rats were intraperitoneally inoculated with 108 Yoshida hepatoma AH-130 cells and once daily treated with 0.3 mg kg-1 , 3 mg kg-1 MT-102, or placebo by gavage. RESULTS: Three mg kg-1 d-1 MT-102 not only prevented progressive loss of fat mass (-6 ± 2 g vs -12 ± 1 g; P < 0.001); lean mass (+1 ± 10 g vs. -37 ± 2 g; P < 0.001) and body weight (+1 ± 13 g vs. -60 ± 2 g; P < 0.001) were remained. Quality of life was also improved as indicated by a higher food intake 12.9 ± 3.1 g and 4.3 ± 0.5 g, 3 mg kg-1 d-1 MT-102 vs. placebo, respectively, P < 0.001) and a higher spontaneous activity (52 369 ± 6521 counts/24 h and 29 509 ± 1775 counts/24 h, 3 mg·kg-1 d-1 MT-102 vs. placebo, respectively, P < 0.01) on Day 11. Most importantly, survival was improved (HR = 0.29; 95% CI: 0.16-0.51, P < 0.001). The molecular mechanisms behind these effects involve reduction of overall protein degradation and activation of protein synthesis, assessed by measurement of proteasome and caspase-6 activity or Western blot analysis, respectively. CONCLUSIONS: The present study shows that 3 mg kg-1 MT-102 reduces catabolism, while inducing anabolism in skeletal muscle leading to an improved survival.
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  • Journal Article

    High CD206 levels in Hodgkin lymphoma‐educated macrophages are linked to matrix‐remodeling and lymphoma dissemination 

    Arlt, Annekatrin; Bonin, Frederike; Rehberg, Thorsten; Perez‐Rubio, Paula; Engelmann, Julia C.; Limm, Katharina; Reinke, Sarah; Dullin, Christian; Sun, Xueni; Specht, Rieke; et al.
    Maulhardt, MarkusLinke, FranziskaBunt, GertrudeKlapper, WolframVockerodt, MartinaWilting, JörgPukrop, TobiasDettmer, KatjaGronwald, WolframOefner, Peter J.Spang, RainerKube, Dieter
    Molecular Oncology p.1-19
    Macrophages (Mφ) are abundantly present in the tumor microenvironment and may predict outcome in solid tumors and defined lymphoma subtypes. Mφ heterogeneity, the mechanisms of their recruitment, and their differentiation into lymphoma-promoting, alternatively activated M2-like phenotypes are still not fully understood. Therefore, further functional studies are required to understand biological mechanisms associated with human tumor-associated Mφ (TAM). Here, we show that the global mRNA expression and protein abundance of human Mφ differentiated in Hodgkin lymphoma (HL)-conditioned medium (CM) differ from those of Mφ educated by conditioned media from diffuse large B-cell lymphoma (DLBCL) cells or, classically, by macrophage colony-stimulating factor (M-CSF). Conditioned media from HL cells support TAM differentiation through upregulation of surface antigens such as CD40, CD163, CD206, and PD-L1. In particular, RNA and cell surface protein expression of mannose receptor 1 (MRC1)/CD206 significantly exceed the levels induced by classical M-CSF stimulation in M2-like Mφ; this is regulated by interleukin 13 to a large extent. Functionally, high CD206 enhances mannose-dependent endocytosis and uptake of type I collagen. Together with high matrix metalloprotease9 secretion, HL-TAMs appear to be active modulators of the tumor matrix. Preclinical in ovo models show that co-cultures of HL cells with monocytes or Mφ support dissemination of lymphoma cells via lymphatic vessels, while tumor size and vessel destruction are decreased in comparison with lymphoma-only tumors. Immunohistology of human HL tissues reveals a fraction of cases feature large numbers of CD206-positive cells, with high MRC1 expression being characteristic of HL-stage IV. In summary, the lymphoma-TAM interaction contributes to matrix-remodeling and lymphoma cell dissemination.
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  • Journal Article

    Biofunctionalized Polyelectrolyte Microcapsules Encoded with Fluorescent Semiconductor Nanocrystals for Highly Specific Targeting and Imaging of Cancer Cells 

    Nifontova, Galina; Kalenichenko, Daria; Baryshnikova, Maria; Ramos Gomes, Fernanda; Alves, Frauke; Karaulov, Alexander; Nabiev, Igor; Sukhanova, Alyona
    Photonics 2019; 6(4): Art. 117
    Fluorescent semiconductor nanocrystals or quantum dots (QDs) are characterized by unique optical properties, including a high photostability, wide absorption spectrum, and narrow, symmetric fluorescence spectrum. This makes them attractive fluorescent nanolabels for the optical encoding of microcarriers intended for targeted drug delivery, diagnosis, and imaging of transport processes on the body, cellular, and subcellular levels. Incorporation of QDs into carriers in the form of polyelectrolyte microcapsules through layer-by-layer adsorption of oppositely charged polyelectrolyte polymers yields microcapsules with a bright fluorescence signal and adaptable size, structure, and surface characteristics without using organic solvents. The easily modifiable surface of the microcapsules allows for its subsequent functionalization with capture molecules, such as antibodies, which ensures specific and selective interaction with cells, including tumor cells, with the use of the bioconjugation technique developed here. We obtained stable water-soluble nanolabels based on QDs whose surface was modified with polyethylene glycol (PEG) derivatives and determined their colloidal and optical characteristics. The obtained nanocrystals were used to encode polyelectrolyte microcapsules optically. The microcapsule surface was modified with humanized monoclonal antibodies (Abs) recognizing a cancer marker, epidermal growth factor receptor (EGFR). The possibility of effective, specific, and selective delivery of the microcapsules to tumor cells expressing EGFR has been demonstrated. The results show that the QD-encoded polyelectrolyte microcapsules functionalized with monoclonal Abs against EGFR can be used for targeted imaging and diagnosis.
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  • Journal Article

    Myoelectric Control for Upper Limb Prostheses 

    Igual, Carles; Pardo, Luis A.; Hahne, Jr.; Igual, Janne M.
    Electronics 2019; 8(11): Art. 1244
    State-of-the-art high-end prostheses are electro-mechanically able to provide a great variety of movements. Nevertheless, in order to functionally replace a human limb, it is essential that each movement is properly controlled. This is the goal of prosthesis control, which has become a growing research field in the last decades, with the ultimate goal of reproducing biological limb control. Therefore, exploration and development of prosthesis control are crucial to improve many aspects of an amputee’s life. Nowadays, a large divergence between academia and industry has become evident in commercial systems. Although several studies propose more natural control systems with promising results, basic one degree of freedom (DoF), a control switching system is the most widely used option in industry because of simplicity, robustness and inertia. A few classification controlled prostheses have emerged in the last years but they are still a low percentage of the used ones. One of the factors that generate this situation is the lack of robustness of more advanced control algorithms in daily life activities outside of laboratory conditions. Because of this, research has shifted towards more functional prosthesis control. This work reviews the most recent literature in upper limb prosthetic control. It covers commonly used variants of possible biological inputs, its processing and translation to actual control, mostly focusing on electromyograms as well as the problems it will have to overcome in near future
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  • Journal Article

    Responsibility in dealing with genetic risk information 

    Wöhlke, Sabine; Perry, Julia
    Social Theory & Health p.1-22
    Predictive testing information raises questions about risk communication, health responsibility, and about how to deal with the gap between knowledge of risks and options to act on this knowledge. For some diseases identified by predictive testing, specific treatments or interventions are available, while other diseases, thus far, remain untreatable or unpreventable; this triggers different forms of responsibility. Gender also often intersects with moral responsibility, regarding risk communication but also responsibilities of care which may become necessary with a family member’s onset of disease. The aim of the study was to analyze laypeople’s attitudes towards predictive testing with a special focus on forms of responsibility arising while dealing with uncertainty of risk information. We conducted seven focus groups with laypeople (n = 43) in four German cities in 2016. Participants were provided with different genetic testing scenarios (breast cancer, early-onset Alzheimer’s disease, pharmacogenetics in rectal cancer) for discussing their responsibilities and risk perceptions. We identified three different forms of responsibility: self-responsibility and self-care, family responsibility and care for others, and professional responsibility. For laypeople, the decision for predictive genetic testing seems voluntary and free from external constraint; however, both family and professional conditions influence an individual’s decision.
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  • Journal Article

    Comprehensive multimodality characterization of hemodynamically significant and non-significant coronary lesions using invasive and noninvasive measures 

    Engel, Leif-Christopher; Landmesser, Ulf; Abdelwahed, Youssef S.; Jaguszewski, Milosz; Gigengack, Kevin; Wurster, Thomas-Heinrich; Skurk, Carsten; Manes, Costantina; Schuster, Andreas; Noutsias, Michel; et al.
    Hamm, BerndBotnar, Rene M.Makowski, Marcus R.Bigalke, Boris
    PLOS ONE 2020; 15(1): Art. e0228292
    Background There is limited knowledge about morphological molecular-imaging-derived parameters to further characterize hemodynamically relevant coronary lesions. Objective The aim of this study was to describe and differentiate specific parameters between hemodynamically significant and non-significant coronary lesions using various invasive and non-invasive measures. Methods This clinical study analyzed patients with symptoms suggestive of coronary artery disease (CAD) who underwent native T1-weighted CMR and gadofosveset-enhanced CMR as well as invasive coronary angiography. OCT of the culprit vessel to determine the plaque type was performed in a subset of patients. Functional relevance of all lesions was examined using quantitative flow reserve (QFR-angiography). Hemodynamically significant lesions were defined as lesions with a QFR <0.8. Signal intensity (contrast-to-noise ratios; CNRs) on native T1-weighted CMR and gadofosveset-enhanced CMR was defined as a measure for intraplaque hemorrhage and endothelial permeability, respectively. Results Overall 29 coronary segments from 14 patients were examined. Segments containing lesions with a QFR <0.8 (n = 9) were associated with significantly higher signal enhancement on Gadofosveset-enhanced CMR as compared to segments containing a lesions without significant stenosis (lesion-QFR>0.8; n = 19) (5.32 (4.47–7.02) vs. 2.42 (1.04–5.11); p = 0.042). No differences in signal enhancement were seen on native T1-weighted CMR (2.2 (0.68–6.75) vs. 2.09 (0.91–6.57), p = 0.412). 66.7% (4 out of 6) of all vulnerable plaque and 33.3% (2 out of 6) of all non-vulnerable plaque (fibroatheroma) as assessed by OCT were hemodynamically significant lesions. Conclusion The findings of this pilot study suggest that signal enhancement on albumin-binding probe-enhanced CMR but not on T1-weighted CMR is associated with hemodynamically relevant coronary lesions
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  • Journal Article

    Differential Effect on Hippocampal Synaptic Facilitation by the Presynaptic Protein Mover 

    Viotti, Julio S.; Dresbach, Thomas
    Frontiers in Synaptic Neuroscience 2019; 11: Art. 30
    Neurotransmitter release relies on an evolutionarily conserved presynaptic machinery. Nonetheless, some proteins occur in certain species and synapses, and are absent in others, indicating that they may have modulatory roles. How such proteins expand the power or versatility of the core release machinery is unclear. The presynaptic protein Mover/TPRGL/SVAP30 is heterogeneously expressed among synapses of the rodent brain, suggesting that it may add special functions to subtypes of presynaptic terminals. Mover is a synaptic vesicle-attached phosphoprotein that binds to Calmodulin and the active zone scaffolding protein Bassoon. Here we use a Mover knockout mouse line to investigate the role of Mover in the hippocampal mossy fiber (MF) to CA3 pyramidal cell synapse and Schaffer collateral to CA1. While Schaffer collateral synapses were unchanged by the knockout, the MFs showed strongly increased facilitation. The effect of Mover knockout in facilitation was both calcium- and age-dependent, having a stronger effect at higher calcium concentrations and in younger animals. Increasing cyclic adenosine monophosphate (cAMP) levels by forskolin equally potentiated both wildtype and knockout MF synapses, but occluded the increased facilitation observed in the knockout. These discoveries suggest that Mover has distinct roles at different synapses. At MF terminals, it acts to constrain the extent of presynaptic facilitation.
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  • Journal Article

    The long noncoding RNA neuroLNC regulates presynaptic activity by interacting with the neurodegeneration-associated protein TDP-43 

    Keihani, S.; Kluever, V.; Mandad, S.; Bansal, V.; Rahman, R.; Fritsch, E.; Gomes, L. Caldi; Gärtner, A.; Kügler, S.; Urlaub, H.; et al.
    Wren, J. D.Bonn, S.Rizzoli, S. O.Fornasiero, E. F.
    Science Advances 2019; 5(12): Art. eaay2670
    The cellular and the molecular mechanisms by which long noncoding RNAs (lncRNAs) may regulate presynaptic function and neuronal activity are largely unexplored. Here, we established an integrated screening strategy to discover lncRNAs implicated in neurotransmitter and synaptic vesicle release. With this approach, we identified neuroLNC, a neuron-specific nuclear lncRNA conserved from rodents to humans. NeuroLNC is tuned by synaptic activity and influences several other essential aspects of neuronal development including calcium influx, neuritogenesis, and neuronal migration in vivo. We defined the molecular interactors of neuroLNC in detail using chromatin isolation by RNA purification, RNA interactome analysis, and protein mass spectrometry. We found that the effects of neuroLNC on synaptic vesicle release require interaction with the RNA-binding protein TDP-43 (TAR DNA binding protein-43) and the selective stabilization of mRNAs encoding for presynaptic proteins. These results provide the first proof of an lncRNA that orchestrates neuronal excitability by influencing presynaptic function.
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  • Journal Article

    Dynamically borrowing strength from another study through shrinkage estimation 

    Röver, Christian; Friede, Tim
    Statistical Methods in Medical Research 2020-01-22; 29(1) p.293-308
    Meta-analytic methods may be used to combine evidence from different sources of information. Quite commonly, the normal-normal hierarchical model (NNHM) including a random-effect to account for between-study heterogeneity is utilized for such analyses. The same modeling framework may also be used to not only derive a combined estimate, but also to borrow strength for a particular study from another by deriving a shrinkage estimate. For instance, a small-scale randomized controlled trial could be supported by a non-randomized study, e.g. a clinical registry. This would be particularly attractive in the context of rare diseases. We demonstrate that a meta-analysis still makes sense in this extreme case, effectively based on a synthesis of only two studies, as illustrated using a recent trial and a clinical registry in Creutzfeld-Jakob disease. Derivation of a shrinkage estimate within a Bayesian random-effects meta-analysis may substantially improve a given estimate even based on only a single additional estimate while accounting for potential effect heterogeneity between the studies. Alternatively, inference may equivalently be motivated via a model specification that does not require a common overall mean parameter but considers the treatment effect in one study, and the difference in effects between the studies. The proposed approach is quite generally applicable to combine different types of evidence originating, e.g. from meta-analyses or individual studies. An application of this more general setup is provided in immunosuppression following liver transplantation in children.
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  • Journal Article

    Chronic hyponatremia in patients with proximal femoral fractures after low energy trauma: A retrospective study in a level-1 trauma center 

    Hoffmann, Daniel Bernd; Popescu, Christian; Komrakova, Marina; Welte, Lena; Saul, Dominik; Lehmann, Wolfgang; Hawellek, Thelonius; Beil, Frank Timo; Dakna, Mohammed; Sehmisch, Stephan
    Bone Reports 2020; 12: Art. 100234
    Introduction: We evaluated the prevalence and influence of chronic hyponatremia in patients with low energy trauma. We also investigated the influence of medication and diseases on hyponatremia. Material and methods: This retrospective study included 314 cases of proximal femoral fracture due to low energy trauma. Patients were treated in the University Medical Center Goettingen within 3 years. Hyponatremia was defined as serum sodium <135 mmol/L at admission. Results: Overall, 15.6% of patients in the low energy trauma group had hyponatremia. Among patients older than 80 years, women showed distinctly higher rates of hyponatremia (female: 16.4%; male: 5.9%). In contrast only 4.7% of patients who underwent elective hip arthroplasty showed hyponatremia. Patients on sartanes and aldosterone antagonists showed significantly higher rates of hyponatremia. Alcoholism was significantly associated with hyponatremia. Conclusions: We confirmed a high prevalence of chronic hyponatremia in patients with fractures due to low energy trauma. Our data underscore chronic hyponatremia as a contributing factor to hip fractures. Women older than 80 have a higher risk of developing hyponatremia. Sartanes, aldosterone antagonists, and alcohol disease are associated with hyponatremia. Treating hyponatremia may decrease the risk of fracture after low energy trauma. Therefore, physicians of different specialties should focus on treatment of chronic hyponatremia to reduce the fracture rate associated with low energy trauma.
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  • Journal Article

    The HPQ-Development and First Administration of a Questionnaire for Hypoparathyroid Patients 

    Wilde, Deborah; Wilken, Lara; Stamm, Bettina; Blaschke, Martina; Heppner, Christina; Chavanon, Mira-Lynn; Leha, Andreas; Herrmann-Lingen, Christoph; Siggelkow, Heide
    JBMR Plus 2019; 4(1): Art. e10245
    Hypoparathyroidism patients suffer a variety of complaints often leading to reduced quality of life. Currently, no specific standard instrument exists to measure corresponding disease manifestations. We therefore aimed to develop a disease-characteristic questionnaire for hypoparathyroid patients. We used an analytical-empirical approach for questionnaire construction based on retrospective analysis of four well-established but non-disease-specific questionnaires (Symptom Checklist 90, revised [SCL-90-R]; Giessen Complaint List [GBB]; Short-Form-36 Health Survey [SF-36]; von Zerssen Symptom List [B-L Zerssen]) and two additional unpublished or local questionnaires (SHGdQ and GPQ) in a German hypoparathyroidism self-help group (n = 60). Retrospective data were compared with corresponding general population norms. The new questionnaire was administered prospectively over 1 year to patients with postoperative hypoparathyroidism and two control groups to validate specificity. Exploratory factor analysis (EFA) and reliability testing were applied to identify relevant scales and reduce overlapping items. In the self-help group, SCL-90-R revealed elevated symptom load in four complaint areas (p = 0.003 to p < 0.001). The SF-36 mental summary score (p < 0.001) and further scales were lowered. In the GBB, four of five scales (p = 0.009 to p < 0.001) were elevated. In the B-L Zerssen, 6 of 24 items revealed complaint areas. Based on these findings, the new 40-item "Hypoparathyroid Patient Questionnaire" (HPQ 40) was developed, tested prospectively, and further analyzed. EFA revealed five scales (pain and cramps, gastrointestinal symptoms, depression and anxiety, neurovegetative symptoms, loss of vitality), all with Cronbach's alpha >0.7. The questionnaire was revised accordingly and shortened to 28 questions to avoid redundancy. We present a new disease-characteristic questionnaire for hypoparathyroidism patients. Prospective testing revealed five major complaint areas and promising psychometric properties. This questionnaire can be tested for usefulness in further clinical trials. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
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  • Journal Article

    Regeneration competent satellite cell niches in rat engineered skeletal muscle 

    Tiburcy, Malte; Markov, Alex; Kraemer, Lena K.; Christalla, Peter; Rave‐Fraenk, Margret; Fischer, Henrike J.; Reichardt, Holger M.; Zimmermann, Wolfram‐Hubertus
    FASEB BioAdvances 2019; 1(12) p.731-746
    Satellite cells reside in defined niches and are activated upon skeletal muscle injury to facilitate regeneration. Mechanistic studies of skeletal muscle regeneration are hampered by the inability to faithfully simulate satellite cell biology in vitro. We sought to overcome this limitation by developing tissue engineered skeletal muscle (ESM) with (1) satellite cell niches and (2) the capacity to regenerate after injury. ESMs contained quiescent Pax7‐positive satellite cells in morphologically defined niches. Satellite cells could be activated to repair (i) cardiotoxin and (ii) mechanical crush injuries. Activation of the Wnt‐pathway was essential for muscle regeneration. Finally, muscle progenitors from the engineered niche developed de novo ESM in vitro and regenerated skeletal muscle after cardiotoxin‐induced injury in vivo. We conclude that ESM with functional progenitor niches reminiscent of the in vivo satellite cell niches can be engineered in vitro. ESM may ultimately be exploited in disease modeling, drug screening, or muscle regeneration.
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  • Journal Article

    Are There Any Biomarkers for Pedophilia and Sexual Child Abuse? A Review 

    Jordan, Kirsten; Wild, Tamara Sheila Nadine; Fromberger, Peter; Müller, Isabel; Müller, Jürgen Leo
    Frontiers in Psychiatry 2020; 10: Art. 940
    The use of biomarkers in medicine is a common and valuable approach in several clinical fields. Understanding the relationship between measurable biological processes and clinical outcomes not only is indispensable in the face of understanding physiological processes in healthy as well as in diseased organisms but also for understanding and evaluating treatment effects. Therefore, also in the context of forensic psychiatry, biomarkers and their potentially beneficial effects are of growing interest. The objective of this review is to examine if there are biomarkers that may serve as a tool to support diagnostic process, treatment evaluation, and risk assessment of pedophilic individuals and child sexual offenders. In the first part, we present an overview of the current neurobiological, as well as physiological and psychophysiological approaches to characterize pedophilia and child sexual offending. Secondly, we discuss and evaluate the impact of these approaches on the development of biomarkers for diagnosis, therapy, and risk assessment in pedophilic subjects and child sexual offenders. We conclude that a lot of research has already enhanced our neurobiological knowledge about pedophilia and child sexual offending. Although there surely exist promising parameters and approaches, in our view currently none of these is ready yet to serve as a clinically applicable diagnostic, response, or predictive biomarker for pedophilia and child sexual offending. Therefore, further work remains to be done. The development of a composite diagnostic biomarker to assess deviant sexual interest, combining several measures like functional magnetic resonance imaging, electroencephalogram, eye tracking, and behavioral approaches seems to be most promising. A valid and reliable measurement of deviant sexual interest, insensitive to manipulations could significantly support clinical diagnostic process. Similarly, regarding therapy evaluation and risk assessment, a composite biomarker to assess inhibitory control functions seems to be promising. Furthermore, the application of the Research Domain Criteria-approach, a new approach for investigating and classifying mental disorders, offers the possibility to take research to a new level.
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  • Journal Article

    DCAF1 (VprBP): emerging physiological roles for a unique dual-service E3 ubiquitin ligase substrate receptor 

    Schabla, N Max; Mondal, Koushik; Swanson, Patrick C
    Journal of Molecular Cell Biology 2018; 11(9) p.725-735
    Cullin-RING ligases (CRLs) comprise a large group of modular eukaryotic E3 ubiquitin ligases. Within this family, the CRL4 ligase (consisting of the Cullin4 [CUL4] scaffold protein, the Rbx1 RING finger domain protein, the DNA damage-binding protein 1 [DDB1], and one of many DDB1-associated substrate receptor proteins) has been intensively studied in recent years due to its involvement in regulating various cellular processes, its role in cancer development and progression, and its subversion by viral accessory proteins. Initially discovered as a target for hijacking by the human immunodeficiency virus accessory protein r, the normal targets and function of the CRL4 substrate receptor protein DDB1-Cul4-associated factor 1 (DCAF1; also known as VprBP) had remained elusive, but newer studies have begun to shed light on these questions. Here, we review recent progress in understanding the diverse physiological roles of this DCAF1 in supporting various general and cell type-specific cellular processes in its context with the CRL4 E3 ligase, as well as another HECT-type E3 ligase with which DCAF1 also associates, called EDD/UBR5. We also discuss emerging questions and areas of future study to uncover the dynamic roles of DCAF1 in normal physiology.
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  • Journal Article

    Adjuvant Radiotherapy and/or Chemotherapy for Endometrial Cancer, Status as at 2019 

    Emons, Günter; Tempfer, Clemens; Battista, Marco Johannes; Mustea, Alexander; Vordermark, Dirk
    Geburtshilfe und Frauenheilkunde 2019; 79(12) p.1273-1277
    The role of adjuvant radiotherapy and/or chemotherapy in the primary treatment of endometrial cancer with a high risk of recurrence has still not been conclusively determined. The results of 3 large randomized controlled studies on different aspects of this issue have been published in full in recent months, and the relevant results are analyzed here.
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  • Journal Article

    Variations in concerns reported on the patient concerns inventory in patients with head and neck cancer from different health settings across the world 

    Rogers, Simon N.; Alvear, Alvaro; Anesi, Alexandre; Babin, Emmanuel; Balik, Ali; Batstone, Martin; Brockmeyer, Phillipp; Carrasco, Claudia Celedon; Chien, Chih‐Yen; Chirila, Magdalena; et al.
    Dholam, Kanchan P.Doss, Jennifer G.Finizia, CaterinaGhani, Wan M. NabilahGurav, Sandeep V.Kadir, KathreenaKolator, MateuszLima, RobertoLin, Yu‐TsaiNhongo, SimonOzdemir‐Karatas, MeltemPeker, KadriyePesic, ZoranRansy, PierreSantos, IzabellaSchliephake, HenningShah, KetanSouza, FernandaSunil, GeethuThankappan, KrishnakumarEhrsson, Ylva TiblomTiple, CristinaTuomi, LisaValerini, SaraLara, Pablo VasquezZatoński, TomaszLowe, Derek
    Head & Neck p.1-15
    BACKGROUND: The aim was to collate and contrast patient concerns from a range of different head and neck cancer follow-up clinics around the world. Also, we sought to explore the relationship, if any, between responses to the patient concerns inventory (PCI) and overall quality of life (QOL). METHODS: Nineteen units participated with intention of including 100 patients per site as close to a consecutive series as possible in order to minimize selection bias. RESULTS: There were 2136 patients with a median total number of PCI items selected of 5 (2-10). "Fear of the cancer returning" (39%) and "dry mouth" (37%) were most common. Twenty-five percent (524) reported less than good QOL. CONCLUSION: There was considerable variation between units in the number of items selected and in overall QOL, even after allowing for case-mix variables. There was a strong progressive association between the number of PCI items and QOL.
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  • Journal Article

    Dose-dependent effect of cannabinoid WIN-55,212-2 on myelin repair following a demyelinating insult 

    Tomas-Roig, J.; Agbemenyah, H. Y.; Celarain, N.; Quintana, E.; Ramió-Torrentà, Ll.; Havemann-Reinecke, U.
    Scientific Reports 2020; 10(1): Art. 590
    Dysfunctions in the endocannabinoid system have been associated with experimental animal models and multiple sclerosis patients. Interestingly, the endocannabinoid system has been reported to confer neuroprotection against demyelination. The present study aims to assess the effects of the cannabinoid agonist WIN-55,212-2 in cuprizone fed animals on myelin repair capacity. Animals exposed to cuprizone were simultaneously treated withWIN-55,212-2, behaviorally tested and finally the corpus callosum was exhaustively studied by Western blotting, qRT-PCR and a myelin staining procedure. We report that the long-term administration of WIN-55,212-2 reduced the global amount of CB1 protein. Histological analysis revealed clear demyelination after being fed cuprizone for three weeks. However, cuprizone-fed mice subjected to 0.5 mg/Kg of WIN-55,212-2 displayed no differences when compared to controls during demyelination, although there was a robust increase in the myelinated axons during the remyelination phase. These animals displayed better performance on contextual fear conditioning which was in turn non-attributable to an antinociceptive effect. In contrast, a 1 mg/Kg dosage caused a remarkable demyelination accompanied by limited potential for myelin repair. Upon drug administration while mice ongoing demyeliniation, the expression of Aif1 (microglia) and Gfap (astrocytes) followed a dose-dependent manner whereas the expression of both markers was apparently attenuated during remyelination. Treatment with vehicle or 0.5 mg/Kg of the drug during demyelination increased the expression of Pdgfra (oligodendrocyte precursor cells) but this did not occur when 1 mg/Kg was administered. In conclusion, the drug at 0.5 mg/Kg did not alter myelin architecture while 1 mg/Kg had a deleterious effect in this model.
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  • Journal Article

    Pathway-, layer- and cell-type-specific thalamic input to mouse barrel cortex 

    Sermet, B .Semihcan; Truschow, Pavel; Feyerabend, Michael; Mayrhofer, Johannes M.; Oram, Tess B.; Yizhar, Ofer; Staiger, Jochen F.; Petersen, Carl C.H.
    eLife 2019; 8: Art. e52665
    Mouse primary somatosensory barrel cortex (wS1) processes whisker sensory information, receiving input from two distinct thalamic nuclei. The first-order ventral posterior medial (VPM) somatosensory thalamic nucleus most densely innervates layer 4 (L4) barrels, whereas the higher-order posterior thalamic nucleus (medial part, POm) most densely innervates L1 and L5A. We optogenetically stimulated VPM or POm axons, and recorded evoked excitatory postsynaptic potentials (EPSPs) in different cell-types across cortical layers in wS1. We found that excitatory neurons and parvalbumin-expressing inhibitory neurons received the largest EPSPs, dominated by VPM input to L4 and POm input to L5A. In contrast, somatostatin-expressing inhibitory neurons received very little input from either pathway in any layer. Vasoactive intestinal peptide-expressing inhibitory neurons received an intermediate level of excitatory input with less apparent layer-specificity. Our data help understand how wS1 neocortical microcircuits might process and integrate sensory and higher-order inputs.
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  • Journal Article

    Impaired lysosomal acidification triggers iron deficiency and inflammation in vivo 

    Yambire, King Faisal; Rostosky, Christine; Watanabe, Takashi; Pacheu-Grau, David; Torres-Odio, Sylvia; Sanchez-Guerrero, Angela; Senderovich, Ola; Meyron-Holtz, Esther G; Milosevic, Ira; Frahm, Jens; et al.
    West, A PhillipRaimundo, Nuno
    eLife 2019; 8: Art. e51031
    Lysosomal acidification is a key feature of healthy cells. Inability to maintain lysosomal acidic pH is associated with aging and neurodegenerative diseases. However, the mechanisms elicited by impaired lysosomal acidification remain poorly understood. We show here that inhibition of lysosomal acidification triggers cellular iron deficiency, which results in impaired mitochondrial function and non-apoptotic cell death. These effects are recovered by supplying iron via a lysosome-independent pathway. Notably, iron deficiency is sufficient to trigger inflammatory signaling in cultured primary neurons. Using a mouse model of impaired lysosomal acidification, we observed a robust iron deficiency response in the brain, verified by in vivo magnetic resonance imaging. Furthermore, the brains of these mice present a pervasive inflammatory signature associated with instability of mitochondrial DNA (mtDNA), both corrected by supplementation of the mice diet with iron. Our results highlight a novel mechanism linking impaired lysosomal acidification, mitochondrial malfunction and inflammation in vivo
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  • Journal Article

    IVIVC Assessment of Two Mouse Brain Endothelial Cell Models for Drug Screening 

    Puscas, Ina; Bernard-Patrzynski, Florian; Jutras, Martin; Lécuyer, Marc-André; Bourbonnière, Lyne; Prat, Alexandre; Leclair, Grégoire; Roullin, V. Gaëlle
    Pharmaceutics 2019; 11(11): Art. 587
    Since most preclinical drug permeability assays across the blood-brain barrier (BBB) are still evaluated in rodents, we compared an in vitro mouse primary endothelial cell model to the mouse b.End3 and the acellular parallel artificial membrane permeability assay (PAMPA) models for drug screening purposes. The mRNA expression of key feature membrane proteins of primary and bEnd.3 mouse brain endothelial cells were compared. Transwell® monolayer models were further characterized in terms of tightness and integrity. The in vitro in vivo correlation (IVIVC) was obtained by the correlation of the in vitro permeability data with log BB values obtained in mice for seven drugs. The mouse primary model showed higher monolayer integrity and levels of mRNA expression of BBB tight junction (TJ) proteins and membrane transporters (MBRT), especially for the efflux transporter Pgp. The IVIVC and drug ranking underlined the superiority of the primary model (r2 = 0.765) when compared to the PAMPA-BBB (r2 = 0.391) and bEnd.3 cell line (r2 = 0.019) models. The primary monolayer mouse model came out as a simple and reliable candidate for the prediction of drug permeability across the BBB. This model encompasses a rapid set-up, a fair reproduction of BBB tissue characteristics, and an accurate drug screening.
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