Recent Submissions

  • Journal Article

    Cardiac cachexia 

    Lena, Alessia; Ebner, Nicole; Anker, Markus S.
    European Heart Journal Supplements 2019; 21(Supplement_L) p.L24-L27
    Cachexia is a multifactorial disease characterized by a pathologic shift of metabolism towards a more catabolic state. It frequently occurs in patients with chronic diseases such as chronic heart failure and is especially common in the elderly. In patients at risk, cardiac cachexia is found in about 10% of heart failure patients. The negative impact of cardiac cachexia on mortality, morbidity, and quality of life demonstrates the urgent need to find new effective therapies against cardiac cachexia. Furthermore, exercise training and nutritional support can help patients with cardiac cachexia. Despite ongoing efforts to find new therapies for cachexia treatment, also new preventive strategies are needed.
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  • Journal Article

    Sarcopaenia complicating heart failure 

    Fonseca, Guilherme Wesley Peixoto da; von Haehling, Stephan
    European Heart Journal Supplements 2019; 21(Supplement_L) p.L20-L23
    Sarcopaenia is defined as reduced skeletal muscle mass associated with either a decline in muscle strength or low physical performance. It has been shown to affect 17.5% of people worldwide, with a prevalence of 20% or higher in patients with heart failure (HF). Sarcopaenia has severe impact on mortality, physical capacity, and quality of life. Even though several mechanisms, such as autonomic imbalance, reduced muscle blood flow, increased inflammation, hormonal alterations, increased apoptosis, and autophagy have been proposed to fuel the pathogenesis of sarcopaenia, additional studies assessing the interaction of these conditions need to be conducted to elucidate how the presence of sarcopaenia can exacerbate the progression of HF and vice-versa. Resistance training combined with nutritional protein intake seems to be effective in the treatment of sarcopaenia, although current pharmacotherapies have not been extensively studied with this endpoint in mind. In conclusion, sarcopaenia is interwoven with HF and leads to worse exercise capacity in these patients. The mechanisms associated with this bilateral relationship between sarcopaenia and HF are still to be elucidated, leading to effective treatment, not only for the heart, but also for the skeletal muscle.
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  • Journal Article

    Default mode network alterations after intermittent theta burst stimulation in healthy subjects 

    Singh, Aditya; Erwin-Grabner, Tracy; Sutcliffe, Grant; Paulus, Walter; Dechent, Peter; Antal, Andrea; Goya-Maldonado, Roberto
    Translational Psychiatry 2020; 10(1)
    Understanding the mechanisms by which intermittent theta burst stimulation (iTBS) protocols exert changes in the default-mode network (DMN) is paramount to develop therapeutically more effective approaches in the future. While a full session (3000 pulses) of 10 Hz repetitive transcranial magnetic stimulation (HF-rTMS) reduces the functional connectivity (FC) of the DMN and the subgenual anterior cingulate cortex, the current understanding of the effects of a single session of iTBS on the DMN in healthy subjects is limited. Here, we use a previously validated target selection approach for an unprecedented investigation into the effects of a single session (1800 pulses) of iTBS over the DMN in healthy controls. Twenty-six healthy subjects participated in a double-blind, crossover, sham-controlled study. After iTBS to the personalized left dorsolateral prefrontal cortex (DLPFC) targets, we investigated the time lapse of effects in the DMN and its relationship to the harm avoidance (HA) personality trait measure (Temperament and Character Inventory/TCI). Approximately 25-30 min after stimulation, we observed reduced FC between the DMN and the rostral and dorsal anterior cingulate cortex (dACC). About 45 min after stimulation the FC of rostral and dACC strongly decreased further, as did the FC of right anterior insula (AI) with the DMN. Also, we report a positive correlation between the FC decrease in the rostral ACC and the HA domain of TCI, indicating that the HA scores can potentially predict iTBS response. Overall, our results show the time lapse by which iTBS at left-DLPFC targets reduces the FC between DMN and the dACC and right AI, regions typically described as nodes of the salience network.
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  • Journal Article

    Cerebrospinal fluid lipocalin 2 as a novel biomarker for the differential diagnosis of vascular dementia 

    Llorens, Franc; Hermann, Peter; Villar-Piqué, Anna; Diaz-Lucena, Daniela; Nägga, Katarina; Hansson, Oskar; Santana, Isabel; Schmitz, Matthias; Schmidt, Christian; Varges, Daniela; et al.
    Goebel, StefanDumurgier, JulienZetterberg, HenrikBlennow, KajPaquet, ClaireBaldeiras, InêsFerrer, IsidroZerr, Inga
    Nature Communications 2020; 11(1) p.1-11
    The clinical diagnosis of vascular dementia (VaD) is based on imaging criteria, and specific biochemical markers are not available. Here, we investigated the potential of cerebrospinal fluid (CSF) lipocalin 2 (LCN2), a secreted glycoprotein that has been suggested as mediating neuronal damage in vascular brain injuries. The study included four independent cohorts with a total n = 472 samples. LCN2 was significantly elevated in VaD compared to controls, Alzheimer's disease (AD), other neurodegenerative dementias, and cognitively unimpaired patients with cerebrovascular disease. LCN2 discriminated VaD from AD without coexisting VaD with high accuracy. The main findings were consistent over all cohorts. Neuropathology disclosed a high percentage of macrophages linked to subacute infarcts, reactive astrocytes, and damaged blood vessels in multi-infarct dementia when compared to AD. We conclude that CSF LCN2 is a promising candidate biochemical marker in the differential diagnosis of VaD and neurodegenerative dementias.
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  • Journal Article

    Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder: a multicentre study 

    Postuma, Ronald B.; Iranzo, Alex; Hu, Michele; Högl, Birgit; Boeve, Bradley F.; Manni, Raffaele; Oertel, Wolfgang H.; Arnulf, Isabelle; Ferini-Strambi, Luigi; Puligheddu, Monica; et al.
    Antelmi, ElenaCochen De Cock, ValerieArnaldi, DarioMollenhauer, BritVidenovic, AleksandarSonka, KarelJung, Ki-YoungKunz, DieterDauvilliers, YvesProvini, FedericaLewis, Simon J.Buskova, JitkaPavlova, MilenaHeidbreder, AnnaMontplaisir, Jacques Y.Santamaria, JoanBarber, Thomas R.Stefani, AmbraSt.Louis, Erik K.Terzaghi, MicheleJanzen, AnnetteLeu-Semenescu, SmandraPlazzi, GuiseppeNobili, FlavioSixel-Doering, FriederikeDusek, PetrBes, FrederikCortelli, PietroEhgoetz Martens, KaylenaGagnon, Jean-FrancoisGaig, CarlesZucconi, MarcoTrenkwalder, ClaudiaGan-Or, ZivLo, ChristineRolinski, MichalMahlknecht, PhilipHolzknecht, EviBoeve, Angel R.Teigen, Luke N.Toscano, GianpaoloMayer, GeertMorbelli, SilviaDawson, BenjaminPelletier, Amelie
    Brain 2019; 142(3) p.744-759
    Idiopathic REM sleep behaviour disorder (iRBD) is a powerful early sign of Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. This provides an unprecedented opportunity to directly observe prodromal neurodegenerative states, and potentially intervene with neuroprotective therapy. For future neuroprotective trials, it is essential to accurately estimate phenoconversion rate and identify potential predictors of phenoconversion. This study assessed the neurodegenerative disease risk and predictors of neurodegeneration in a large multicentre cohort of iRBD. We combined prospective follow-up data from 24 centres of the International RBD Study Group. At baseline, patients with polysomnographically-confirmed iRBD without parkinsonism or dementia underwent sleep, motor, cognitive, autonomic and special sensory testing. Patients were then prospectively followed, during which risk of dementia and parkinsonsim were assessed. The risk of dementia and parkinsonism was estimated with Kaplan-Meier analysis. Predictors of phenoconversion were assessed with Cox proportional hazards analysis, adjusting for age, sex, and centre. Sample size estimates for disease-modifying trials were calculated using a time-to-event analysis. Overall, 1280 patients were recruited. The average age was 66.3 ± 8.4 and 82.5% were male. Average follow-up was 4.6 years (range = 1-19 years). The overall conversion rate from iRBD to an overt neurodegenerative syndrome was 6.3% per year, with 73.5% converting after 12-year follow-up. The rate of phenoconversion was significantly increased with abnormal quantitative motor testing [hazard ratio (HR) = 3.16], objective motor examination (HR = 3.03), olfactory deficit (HR = 2.62), mild cognitive impairment (HR = 1.91-2.37), erectile dysfunction (HR = 2.13), motor symptoms (HR = 2.11), an abnormal DAT scan (HR = 1.98), colour vision abnormalities (HR = 1.69), constipation (HR = 1.67), REM atonia loss (HR = 1.54), and age (HR = 1.54). There was no significant predictive value of sex, daytime somnolence, insomnia, restless legs syndrome, sleep apnoea, urinary dysfunction, orthostatic symptoms, depression, anxiety, or hyperechogenicity on substantia nigra ultrasound. Among predictive markers, only cognitive variables were different at baseline between those converting to primary dementia versus parkinsonism. Sample size estimates for definitive neuroprotective trials ranged from 142 to 366 patients per arm. This large multicentre study documents the high phenoconversion rate from iRBD to an overt neurodegenerative syndrome. Our findings provide estimates of the relative predictive value of prodromal markers, which can be used to stratify patients for neuroprotective trials.
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  • Journal Article

    Studying Brugada Syndrome With an SCN1B Variants in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes 

    El-Battrawy, Ibrahim; Müller, Jonas; Zhao, Zhihan; Cyganek, Lukas; Zhong, Rujia; Zhang, Feng; Kleinsorge, Mandy; Lan, Huan; Li, Xin; Xu, Qiang; et al.
    Huang, MengyingLiao, ZhenxingMoscu-Gregor, AlexanderAlbers, SebastianDinkel, HendrikLang, SiegfriedDiecke, SebastianZimmermann, Wolfram-HubertusUtikal, JochenWieland, ThomasBorggrefe, MartinZhou, XiaoboAkin, Ibrahim
    Frontiers in Cell and Developmental Biology 2019; 7: Art. 261
    Background: Among rare channelopathies BrS patients are at high risk of sudden cardiac death (SCD). SCN5A mutations are found in a quarter of patients. Other rare gene mutations including SCN1B have been implicated to BrS. Studying the human cellular phenotype of BrS associated with rare gene mutation remains lacking. Objectives: We sought to study the cellular phenotype of BrS with the SCN1B gene variants using human-induced pluripotent stem cell (hiPSCs)-derived cardiomyocytes (hiPSC-CMs). Methods and Results: A BrS patient suffering from recurrent syncope harboring a two variants (c.629T > C and c.637C > A) in SCN1B, which encodes the function-modifying sodium channel beta1 subunit, and three independent healthy subjects were recruited and their skin biopsies were used to generate hiPSCs, which were differentiated into cardiomyocytes (hiPSC-CMs) for studying the cellular electrophysiology. A significantly reduced peak and late sodium channel current (INa) and a shift of activation curve to more positive potential as well as a shift of inactivation curve to more negative potential were detected in hiPSC-CMs of the BrS patient, indicating that the SCN1B variants impact the function of sodium channels in cardiomyocytes. The reduced INa led to a reduction of amplitude (APA) and upstroke velocity (V max ) of action potentials. Ajmaline, a sodium channel blocker, showed a stronger effect on APA and Vmax in BrS cells as compared to cells from healthy donors. Furthermore, carbachol was able to increase arrhythmia events and the beating frequency in BrS. Conclusion: Our hiPSC-CMs from a BrS-patient with two variants in SCN1B recapitulated some key phenotypic features of BrS and can provide a platform for studies on BrS with SCN1B variants
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  • Journal Article

    Recent advances in cardio‐oncology: a report from the ‘Heart Failure Association 2019 and World Congress on Acute Heart Failure 2019’ 

    Anker, Markus S.; Hadzibegovic, Sara; Lena, Alessia; Belenkov, Yury; Bergler‐Klein, Jutta; Boer, Rudolf A.; Farmakis, Dimitrios; Haehling, Stephan; Iakobishvili, Zaza; Maack, Christoph; et al.
    Pudil, RadekSkouri, HadiCohen‐Solal, AlainTocchetti, Carlo G.Coats, Andrew J.S.Seferović, Petar M.Lyon, Alexander R.
    ESC Heart Failure 2019; 6(6) p.1140-1148
    While anti-cancer therapies, including chemotherapy, immunotherapy, radiotherapy, and targeted therapy, are constantly advancing, cardiovascular toxicity has become a major challenge for cardiologists and oncologists. This has led to an increasing demand of cardio-oncology units in Europe and a growing interest of clinicians and researchers. The Heart Failure 2019 meeting of the Heart Failure Association of the European Society of Cardiology in Athens has therefore created a scientific programme that included four dedicated sessions on the topic along with several additional lectures. The major points that were discussed at the congress included the implementation and delivery of a cardio-oncology service, the collaboration among cardio-oncology experts, and the risk stratification, prevention, and early recognition of cardiotoxicity. Furthermore, sessions addressed the numerous different anti-cancer therapies associated with cardiotoxic effects and provided guidance on how to treat cancer patients who develop cardiovascular disease before, during, and after treatment.
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  • Journal Article

    Changes in topographical relation between the ductus arteriosus and left subclavian artery in human embryos: a study using serial sagittal sections 

    Jin, Z.W.; Yamamoto, M.; Kim, J.H.; Murakami, G.; Wilting, J.; Rodríguez-Vázquez, J. F.
    Folia Morphologica 2019; 78(4) p.720-728
    At birth, the ductus arteriosus (DA) merges with the aortic arch in the slightly caudal side of the origin of the left subclavian artery (SCA). Since the SCA (seventh segmental arteries) were fixed on a level of the seventh cervical-first thoracic vertebral bodies, the confluence of DA should migrate caudally. We aimed to describe timing and sequence of the topographical change using serial sagittal sections of 36 human embryos and fetuses (CRL 8-64 mm; 5-10 weeks) those made easy evaluation of the vertebral levels possible in a few section. The DA or sixth pharyngeal arch artery seemed to slide down in front of the sympathetic nerve trunk along 1.0-1.2 mm from the second cervical vertebral level at 5-6 weeks and, at 6 weeks (CRL14-17 mm), the DA confluence with aorta reached the seventh cervical level. Because of the highly elongated common carotid artery, the sliding of DA confluence seemed to be much shorter than the growing cervical vertebrae growing from 1 mm to 2.4 mm. At the final topographical change at 6-7 weeks, the DA confluence further descended to a site 1-vertebral length below the left SCA origin. From 6 to 9 weeks, a distance from the top of the aortic arch to the left SCA origin was almost stable: 0.3-0.5 mm at 6 weeks and 0.4-0.6 mm at 9 weeks. The heart descent and the caudal extension of the trachea and bronchi, those occurred before the DA sliding, were likely to be a major driving force for the sliding.
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  • Journal Article

    Cost‐effectiveness of a cardiac contractility modulation device in heart failure with normal QRS duration 

    Witte, Klaus; Hasenfuss, Gerd; Kloppe, Axel; Burkhoff, Daniel; Green, Michelle; Moss, Joe; Peel, Alison; Mealing, Stuart; Durand Zaleski, Isabelle; Cowie, Martin R.
    ESC Heart Failure 2019; 6(6) p.1178-1187
    AIMS: The objective of this paper is to assess whether cardiac contractility modulation (via the Optimizer System) plus standard of care (SoC) is a cost-effective treatment for people with heart failure [New York Heart Association (NYHA) III, left ventricular ejection fraction of 25-45%, and narrow QRS] compared against SoC alone from the perspective of the English National Health Service. METHODS AND RESULTS: We developed a regression equation-based cost-effectiveness model, using individual patient data from three randomized control trials (FIX-HF-5 Phases 1 and 2, and FIX-HF-5C) to populate the majority of parameters. A series of regression equations predicted NYHA class over time, mortality, all-cause hospitalization rates, and health-related quality of life. We conducted the analysis in line with the National Institute for Health and Care Excellence reference case, modelling costs from an English National Health Service perspective, and considering outcomes in quality-adjusted life years (QALYs) over a patient lifetime perspective. Our base case analysis produced an incremental cost per additional QALY of GBP22 988 (€25 750) when comparing Optimizer + SoC to SoC alone. This result was not sensitive to parameter uncertainty but was sensitive to the time horizon over which costs and QALYs were captured and the duration over which a survival benefit with Optimizer + SoC can be assumed to apply. CONCLUSIONS: Cardiac contractility modulation is likely to be cost-effective in people with heart failure with reduced ejection fraction, NYHA III, and narrow QRS, provided that the treatment benefit can be maintained beyond the duration of the existing clinical trial follow-up. This analysis supports the current recommendations of the European Society of Cardiology that this therapy may be considered for such patients.
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  • Journal Article

    Methylomic profiling in trisomy 21 identifies cognition- and Alzheimer’s disease-related dysregulation 

    Haertle, Larissa; Müller, Tobias; Lardenoije, Roy; Maierhofer, Anna; Dittrich, Marcus; Riemens, Renzo J. M.; Stora, Samantha; Roche, Mathilde; Leber, Markus; Riedel-Heller, Steffi; et al.
    Wagner, MichaelScherer, MartinRavel, AiméMircher, ClotildeCieuta-Walti, CecileDurand, Sophievan de Hove, Daniel L. A.Hoffmann, PerRamirez, AlfredoHaaf, ThomasEl Hajj, NadyMégarbané, André
    Clinical Epigenetics 2019; 11(1): Art. 195
    BACKGROUND: Trisomy 21 (T21) is associated with intellectual disability that ranges from mild to profound with an average intellectual quotient of around 50. Furthermore, T21 patients have a high risk of developing Alzheimer's disease (AD) early in life, characterized by the presence of senile plaques of amyloid protein and neurofibrillary tangles, leading to neuronal loss and cognitive decline. We postulate that epigenetic factors contribute to the observed variability in intellectual disability, as well as at the level of neurodegeneration seen in T21 individuals. MATERIALS AND METHODS: A genome-wide DNA methylation study was performed using Illumina Infinium® MethylationEPIC BeadChips on whole blood DNA of 3 male T21 patients with low IQ, 8 T21 patients with high IQ (4 males and 4 females), and 21 age- and sex-matched control samples (12 males and 9 females) in order to determine whether DNA methylation alterations could help explain variation in cognitive impairment between individuals with T21. In view of the increased risk of developing AD in T21 individuals, we additionally investigated the T21-associated sites in published blood DNA methylation data from the AgeCoDe cohort (German study on Ageing, Cognition, and Dementia). AgeCoDe represents a prospective longitudinal study including non-demented individuals at baseline of which a part develops AD dementia at follow-up. RESULTS: Two thousand seven hundred sixteen differentially methylated sites and regions discriminating T21 and healthy individuals were identified. In the T21 high and low IQ comparison, a single CpG located in the promoter of PELI1 was differentially methylated after multiple testing adjustment. For the same contrast, 69 differentially methylated regions were identified. Performing a targeted association analysis for the significant T21-associated CpG sites in the AgeCoDe cohort, we found that 9 showed significant methylation differences related to AD dementia, including one in the ADAM10 gene. This gene has previously been shown to play a role in the prevention of amyloid plaque formation in the brain. CONCLUSION: The differentially methylated regions may help understand the interaction between methylation alterations and cognitive function. In addition, ADAM10 might be a valuable blood-based biomarker for at least the early detection of AD.
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  • Journal Article

    General practitioners’ concepts on issuing out-of-pocket prescriptions for hypnotics and sedatives in Germany 

    Schmalstieg-Bahr, Katharina; Müller, Christiane A.; Hummers, Eva
    Family Practice 2019; 36(6) p.785-790
    BACKGROUND: In Germany, almost 50% of prescriptions for benzodiazepines and drugs as Zolpidem and Zopiclone are as out-of-pocket (OOP) prescriptions-requiring patients to buy the drug at their own expense-although almost 90% of the population has statutory health insurance covering medication costs. OBJECTIVE: To understand why general practitioners (GPs) choose this prescribing method since needed medications are insurance covered, and unnecessary drugs should not be prescribed at all. METHODS: In this qualitative study, 17 semi-structured interviews with GPs were conducted, audio recorded and transcribed verbatim. Transcripts were analysed with grounded theory to extract a model explaining the described behaviour. RESULTS: Knowing the significant medical risks and insecurity about regulations makes GPs wish to avoid hypnotics and sedatives. They achieve this by 'Creating a barrier' (central phenomenon) and employing the strategy 'Using an out-of-pocket prescription', which not only generates costs for the patient but also reduces the physicians´ legal and financial accountability. The perceived patient type, expected problem duration and diagnosis influence the decision about the prescription form: patients with an alcohol or drug addiction or those with 'uncomplicated' insomnia are more likely to receive an OOP prescription. Patients with any psychiatric diagnosis will likely receive a statutory health insurance prescription. DISCUSSION: Current regulations do not provide guidance to GPs regarding hypnotics and sedatives. A clear regulatory framework and guidelines could possibly reduce physicians' defensive attitudes about these drugs and their use of OOP prescriptions. The approach to use OOP prescriptions as a barrier to reduce patients' medication use lacks evidence regarding effectiveness.
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  • Journal Article

    Molecular biomarkers in multiple sclerosis 

    Ziemssen, Tjalf; Akgün, Katja; Brück, Wolfgang
    Journal of Neuroinflammation 2019; 16(1): Art. 272
    Multiple sclerosis (MS) is an inflammatory-neurodegenerative disease of the central nervous system presenting with significant inter- and intraindividual heterogeneity. However, the application of clinical and imaging biomarkers is currently not able to allow individual characterization and prediction. Complementary, molecular biomarkers which are easily quantifiable come from the areas of immunology and neurobiology due to the causal pathomechanisms and can excellently complement other disease characteristics. Only a few molecular biomarkers have so far been routinely used in clinical practice as their validation and transfer take a long time. This review describes the characteristics that an ideal MS biomarker should have and the challenges of establishing new biomarkers. In addition, clinically relevant and promising biomarkers from the blood and cerebrospinal fluid are presented which are useful for MS diagnosis and prognosis as well as for the assessment of therapy response and side effects.
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  • 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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