TY - JOUR A1 - Nguemeni, Carine A1 - Homola, György A. A1 - Nakchbandi, Luis A1 - Pham, Mirko A1 - Volkmann, Jens A1 - Zeller, Daniel T1 - A Single Session of Anodal Cerebellar Transcranial Direct Current Stimulation Does Not Induce Facilitation of Locomotor Consolidation in Patients With Multiple Sclerosis JF - Frontiers in Human Neuroscience N2 - Background: Multiple sclerosis (MS) may cause variable functional impairment. The discrepancy between functional impairment and brain imaging findings in patients with MS (PwMS) might be attributed to differential adaptive and consolidation capacities. Modulating those abilities could contribute to a favorable clinical course of the disease. Objectives: We examined the effect of cerebellar transcranial direct current stimulation (c-tDCS) on locomotor adaptation and consolidation in PwMS using a split-belt treadmill (SBT) paradigm. Methods: 40 PwMS and 30 matched healthy controls performed a locomotor adaptation task on a SBT. First, we assessed locomotor adaptation in PwMS. In a second investigation, this training was followed by cerebellar anodal tDCS applied immediately after the task ipsilateral to the fast leg (T0). The SBT paradigm was repeated 24 h (T1) and 78 h (T2) post-stimulation to evaluate consolidation. Results: The gait dynamics and adaptation on the SBT were comparable between PwMS and controls. We found no effects of offline cerebellar anodal tDCS on locomotor adaptation and consolidation. Participants who received the active stimulation showed the same retention index than sham-stimulated subjects at T1 (p = 0.33) and T2 (p = 0.46). Conclusion: Locomotor adaptation is preserved in people with mild-to-moderate MS. However, cerebellar anodal tDCS applied immediately post-training does not further enhance this ability. Future studies should define the neurobiological substrates of maintained plasticity in PwMS and how these substrates can be manipulated to improve compensation. Systematic assessments of methodological variables for cerebellar tDCS are urgently needed to increase the consistency and replicability of the results across experiments in various settings. KW - multiple sclerosis KW - cerebellar tDCS KW - split-belt treadmill KW - locomotor adaptation KW - consolidation Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-215291 SN - 1662-5161 VL - 14 ER - TY - JOUR A1 - Wirsching, Isabelle A1 - Ort, Nora A1 - Üçeyler, Nurcan T1 - ALS or ALS mimic by neuroborreliosis — A case report JF - Clinical Case Reports N2 - Comprehensive investigation in motor neuron disease is vital not to miss a treatable differential diagnosis. Neuroborreliosis should be considered during an ALS work‐up. However, false‐positive CSF results do occur, and thus, results should be interpreted carefully in context of all clinical test results. KW - ALS mimic KW - El Escorial KW - motor neuron disease KW - muscle atrophy KW - neuroborreliosis Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201308 VL - 8 ER - TY - JOUR A1 - Appeltshauser, Luise A1 - Brunder, Anna-Michelle A1 - Heinius, Annika A1 - Körtvélyessy, Peter A1 - Wandinger, Klaus-Peter A1 - Junker, Ralf A1 - Villmann, Carmen A1 - Sommer, Claudia A1 - Leypoldt, Frank A1 - Doppler, Kathrin T1 - Antiparanodal antibodies and IgG subclasses in acute autoimmune neuropathy JF - Neurology: Neuroimmunology & Neuroinflammation N2 - Objective To determine whether IgG subclasses of antiparanodal autoantibodies are related to disease course and treatment response in acute- to subacute-onset neuropathies, we retrospectively screened 161 baseline serum/CSF samples and 66 follow-up serum/CSF samples. Methods We used ELISA and immunofluorescence assays to detect antiparanodal IgG and their subclasses and titers in serum/CSF of patients with Guillain-Barre syndrome (GBS), recurrent GBS (R-GBS), Miller-Fisher syndrome, and acute- to subacute-onset chronic inflammatory demyelinating polyradiculoneuropathy (A-CIDP). We evaluated clinical data retrospectively. Results We detected antiparanodal autoantibodies with a prevalence of 4.3% (7/161), more often in A-CIDP (4/23, 17.4%) compared with GBS (3/114, 2.6%). Longitudinal subclass analysis in the patients with GBS revealed IgG2/3 autoantibodies against Caspr-1 and against anti-contactin-1/Caspr-1, which disappeared at remission. At disease onset, patients with A-CIDP had IgG2/3 anti-Caspr-1 and anti-contactin-1/Caspr-1 or IgG4 anti-contactin-1 antibodies, IgG3 being associated with good response to IV immunoglobulins (IVIg). In the chronic phase of disease, IgG subclass of one patient with A-CIDP switched from IgG3 to IgG4. Conclusion Our data (1) confirm and extend previous observations that antiparanodal IgG2/3 but not IgG4 antibodies can occur in acute-onset neuropathies manifesting as monophasic GBS, (2) suggest association of IgG3 to a favorable response to IVIg, and (3) lend support to the hypothesis that in some patients, an IgG subclass switch from IgG3 to IgG4 may be the correlate of a secondary progressive or relapsing course following a GBS-like onset. KW - Guillain-Barre-Syndrome KW - inflammatory demyelinating polyradiculoneuropathy KW - musk myasthenia gravis KW - periperal nerve KW - neurofascin KW - autoantibodies KW - ontactin 1 KW - biopsies KW - binding KW - switch Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-230079 VL - 7 IS - 5 ER - TY - THES A1 - Buchwald, Sina T1 - Autoimmune Enzephalitiden am Universitätsklinikum Würzburg von 2006-2016 T1 - Cases of autoimmune encephalitis at the Universitätsklinikum Würzburg from 2006-2016 N2 - In den Jahren von 2006 bis 2016 sind am Universitätsklinikum Würzburg insgesamt 26 Patienten mit der Diagnose einer Autoimmunen Enzephalitis behandelt worden. Diese Arbeit zeigt ihre Krankheitsverläufe, Outcome, die gefundenen Antikörper und die Therapien der jeweiligen Patienten. Im zweiten Schritt wurden die Daten mit den in der Literatur bereits beschrieben Fällen verglichen, um Gemeinsamkeiten, aber auch Unterschiede aufzeigen zu können. N2 - In the time from 2006 to 2016, 26 patients with the diagnosis "autoimmune encephalitis” were treated at the Universitätsklinikum in Würzburg. This paper shows their data, antibody findings, treatments and outcomes. In a second step, this data was compared with cases that have already been described in literature to show similarities and differences. KW - Enzephalitis KW - Autoimmun KW - Encephalitis KW - autoimmune Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-207202 ER - TY - JOUR A1 - Isaias, Ioannis U. A1 - Brumberg, Joachim A1 - Pozzi, Nicoló G. A1 - Palmisano, Chiara A1 - Canessa, Andrea A1 - Marotta, Giogio A1 - Volkmann, Jens A1 - Pezzoli, Gianni T1 - Brain metabolic alterations herald falls in patients with Parkinson's disease JF - Annals of Clinical and Translational Neurology N2 - Pathophysiological understanding of gait and balance disorders in Parkinson’s disease is insufficient and late recognition of fall risk limits efficacious followup to prevent or delay falls. We show a distinctive reduction of glucose metabolism in the left posterior parietal cortex, with increased metabolic activity in the cerebellum, in parkinsonian patients 6–8 months before their first fall episode. Falls in Parkinson’s disease may arise from altered cortical processing of body spatial orientation, possibly predicted by abnormal cortical metabolism. KW - Parkionson's disease KW - brain metabolic alterations Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-235982 VL - 7 IS - 4 ER - TY - JOUR A1 - Evdokimov, Dimitar A1 - Dinkel, Philine A1 - Frank, Johanna A1 - Sommer, Claudia A1 - Üçeyler, Nurcan T1 - Characterization of dermal skin innervation in fibromyalgia syndrome JF - PLoS One N2 - Introduction We characterized dermal innervation in patients with fibromyalgia syndrome (FMS) as potential contribution to small fiber pathology. Methods Skin biopsies of the calf were collected (86 FMS patients, 35 healthy controls). Skin was immunoreacted with antibodies against protein gene product 9.5, calcitonine gene-related peptide, substance P, CD31, and neurofilament 200 for small fiber subtypes. We assessed two skin sections per patient; on each skin section, two dermal areas (150 x 700 mu m each) were investigated for dermal nerve fiber length (DNFL). Results In FMS patients we found reduced DNFL of fibers with vessel contact compared to healthy controls (p<0.05). There were no differences for the other nerve fiber subtypes. Discussion We found less dermal nerve fibers in contact with blood vessels in FMS patients than in controls. The pathophysiological relevance of this finding is unclear, but we suggest the possibility of a relationship with impaired thermal tolerance commonly reported by FMS patients. KW - nerve-fibers KW - cutaneous innervation KW - substance-P KW - pain KW - classification KW - reinnervation KW - expression KW - diagnosis KW - epidermis KW - criteria Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229299 VL - 15 IS - 1 ER - TY - JOUR A1 - Üçeyler, Nurcan A1 - Buchholz, Hans-Georg A1 - Kewenig, Susanne A1 - Ament, Stephan-Johann A1 - Birklein, Frank A1 - Schreckenberger, Mathias A1 - Sommer, Claudia T1 - Cortical Binding Potential of Opioid Receptors in Patients With Fibromyalgia Syndrome and Reduced Systemic Interleukin-4 Levels – A Pilot Study JF - Frontiers in Neuroscience N2 - Objective: We investigated cerebral opioid receptor binding potential in patients with fibromyalgia syndrome (FMS) using positron-emission-tomography (PET) and correlated our results with patients’ systemic interleukin-4 (IL-4) gene expression. Methods: In this pilot study, seven FMS patients (1 man, 6 women) agreed to participate in experimental PET scans. All patients underwent neurological examination, were investigated with questionnaires for pain, depression, and FMS symptoms. Additionally, blood for IL-4 gene expression analysis was withdrawn at two time points with a median latency of 1.3 years. Patients were investigated in a PET scanner using the opioid receptor ligand F-18-fluoro-ethyl-diprenorphine ([18F]FEDPN) and results were compared with laboratory normative values. Results: Neurological examination was normal in all FMS patients. Reduced opioid receptor binding was found in mid cingulate cortex compared to healthy controls (p < 0.005). Interestingly, three patients with high systemic IL-4 gene expression had increased opioid receptor binding in the fronto-basal cortex compared to those with low IL-4 gene expression (p < 0.005). Conclusion: Our data give further evidence for a reduction in cortical opioid receptor availability in FMS patients as another potential central nervous system contributor to pain in FMS. KW - fibromyalgia syndrome KW - PET KW - brain KW - opioid KW - IL-4 Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-204457 SN - 1662-453X VL - 14 ER - TY - THES A1 - Kuzkina, Anastasia T1 - Dermal α-synuclein oligomers and aggregates in Parkinson’s disease T1 - Nachweis von Alpha-Synuclein-Oligomeren und -Aggregaten in Hautbiopsien von Parkinson-Patienten N2 - Lewy bodies and Lewy neurites are neuropathological hallmarks of Parkinson’s disease (PD). These depositions in the brain mostly consist of aggregated α-synuclein (α-syn) phosphorylated at Ser129. A number of studies reported detection of phosphorylated α-syn (p-α-syn) in the dermal nerve fibers in Parkinson’s disease. The objective of this study was to investigate whether pathological α-syn accumulations detected in the skin represent aggregated protein. A number of methods aimed at detecting α-syn oligomers and aggregates were first tested and optimized on the brain samples in PD and normal control. These methods included proximity ligation assay (PLA), PET-blot, immunohistochemical (IHC) stains with α-syn aggregate (5G4) or oligomer specific (ASyO5) antibodies and a stain against native α-syn (syn211) after proteinase K (PK) digestion. Subsequently, the most specific methods (stains with 5G4, ASyO5 and syn211 after PK digestion) were studied in two separate patient and control cohorts. Anti-p-α-syn stain was performed in parallel. Single sections from at least 2 biopsy sites from 44 patients and 22 controls (cohort 1) as well as serial sections of 4 biopsy sites from 27 patients and 5 controls (cohort 2) were systematically studied for presence of aggregated and oligomeric α-syn. In total, 5G4 positive deposits were found in 24% (cohort 1) and 37% (cohort 2), ASyO5 positive lesions in 17,7% (cohort 1) and 33% (cohort 2), syn211 positive lesions after PK digestion in 38,7% (cohort 1) and 48% (cohort 2) of cases. There was a major overlap among positivity for a particular staining on the patient level and in most cases, the same nerve fiber was found to be positive for all 4 markers in neighboring sections. Among the skin biopsies which contained p-α-syn accumulation, 59% were also PK resistant, 41% were 5G4 positive and 45% were ASyO5 positive. The samples belonging to normal controls did not show any positive signal in either of the newly established stainings or in the anti-p-α-syn staining. Using 3 distinct IHC methods, α-syn oligomers and aggregates were detectable in the majority of p-α-syn positive skin biopsies. This finding supports the hypothesis that α-syn aggregation occurs in the peripheral (i.e. dermal) nerves and can be specifically detected using skin biopsy. N2 - Die neuropathologischen Kennzeichen des Morbus Parkinson sind Lewy-Körperchen und Lewy-Neuriten. Diese Ablagerungen im Gehirn bestehen hauptsächlich aus aggregiertem α-Synuclein (α-Syn), das am Ser129 phosphoryliert ist. Mehrere Studien konnten zeigen, dass phosphoryliertes α-Syn (p-α-Syn) auch in Nervenfasern der Haut von Parkinsonpatienten nachweisbar ist. Das Ziel dieser Arbeit war, zu untersuchen, ob es sich bei den pathologischen Ablagerungen von p-α-Syn in der Haut wie im Gehirn um Aggregate handelt. Mehrere Methoden, die dem Nachweis von α-Syn-Oligomere und Aggregate dienen, wurden zuerst an Gehirnen von einem Parkinsonpatienten und Normalkontrolle getestet und optimiert, darunter: Proximity Ligation Assay (PLA), PET-Blot, immunhistochemische Färbungen mit α-Syn-Aggregat- (5G4) oder Oligomer-spezifischen Antikörper (ASyO5) und eine Färbung mit einem Antikörper gegen natives α-Syn (syn211) nach Verdau mit Proteinase K (PK). Danach wurden die spezifischsten Methoden (Färbung mit 5G4, ASyO5 und syn211 nach PK-Verdau) an den Hautstanzbiopsien von zwei Patienten- und Normalkontrollkohorten untersucht. Parallel wurde in den Biopsien das p-α-Syn angefärbt. Einzelschnitte von je mind. 2 Biopsiestellen von 44 Patienten und 22 Kontrollen (Kohorte 1) sowie Serienschnitte von je 4 Biopsiestellen von 27 Patienten und 5 Kontrollen (Kohorte 2) wurden systematisch nach Vorliegen von aggregierten und oligomerischen α-Syn untersucht. Zusammenfassend, wurden 5G4-positive Ablagerungen in 24% (Kohorte 1) und 37% (2. Kohorte), ASyO5-positive Läsionen in 17,7% (Kohorte 1) und 33% (Kohorte 2), syn211-positive Läsionen nach PK-Verdau in 38,7% (Kohorte 1) und 48% (Kohorte 2) der Fälle gefunden. Das p-α-Syn wurde entsprechend in 43,6% und 48% der Fälle detektiert. Es zeigte sich die Tendenz, dass Patienten, bei denen p-α-Syn nachweisbar war, auch für mehrere der neuen Marker positiv waren; auch häufig waren für alle 4 Marker positive Nervenfasern in naheliegenden Schnitte zu sehen, was für eine Kolokalisation spricht. Unter den Hautbiopsien, in den p-α-Syn-Ablagerungen zu sehen waren, hatten 59% gleichzeitig PK-resistente, 41% 5G4- und 45% ASyO5-positive Ablagerungen. Bei Kontrollen waren Ablagerungen weder mit den neu eingeführten Methoden noch mit anti-p-α-Syn-Färbung detektierbar. Mit Hilfe von drei unterschiedlichen immunhistochemischen Methoden waren Oligomere und Aggregate vom α-Syn im Großteil der p-α-Syn-positiven Hautbiopsien nachweisbar. Dieser Befund unterstützt die Hypothese, dass die Ablagerung von α-Syn-Aggregaten auch in peripheren (v.a. dermalen) Nerven vorkommt und spezifisch nachgewiesen werden kann. KW - Parkinson-Krankheit KW - Biomarker KW - Haut KW - Biopsie KW - parkinson's disease KW - skin biopsy KW - alpha-synuclein KW - biomarker Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-204369 ER - TY - THES A1 - Kreß, Luisa Sophia T1 - Determination of cytokine and axon guidance molecule profiles in patients with small fiber neuropathy T1 - Bestimmung von Zytokin- und Axon Guidance Molekül-Profilen bei Patienten mit Kleinfaserneuropathie N2 - The pathophysiological mechanisms of pain in small fiber neuropathy (SFN) are unclear. Based on experimental and clinical studies, sensitized nociceptors in the skin are reported to be involved in pain development. These nociceptors may be sensitized by cutaneous and systemic pain mediators e.g. pro- and anti-inflammatory cytokines. The aim of our study was, to measure the systemic and local gene expression of pro- and anti-inflammatory cytokines in white blood cells (WBC) as well as in primary fibroblasts and keratinocytes obtained from human skin of patients with SFN. Furthermore, gene expression levels of axon guidance molecules and their receptors, as potential regulators of the intraepidermal nerve fiber density (IENFD), were investigated. 55 patients and 31 healthy controls were prospectively recruited. Participants underwent extensive clinical phenotyping and blood sampling, 6-mm skin punch biopsies were taken from the right lateral calf and the upper thigh. Systemic relative gene expression levels (ΔG) of the interleukin (IL)-1β, IL-2, IL-6, IL-8, and tumor necrosis factor (TNF) was measured in WBC. Skin punch biopsies were taken to determine the IENFD and to obtain primary fibroblast and keratinocyte cell cultures. Skin cells were then used for investigation of ΔG in axon guidance molecules netrin 1 (NTN1) and ephrin A4 (EPHA4) as well as their receptors Unc5b receptor, and ephrin A4 (EFNA4) as well as cytokines IL-1β, IL-4, IL-6, IL-8, IL-10, TNF, and transforming growth factor (TGF). Systemically, gene expression of IL-2, IL-8, and TNF was higher in SFN patients compared to healthy controls. In keratinocytes, higher expression levels of NTN1 and TGF were found when comparing the SFN patients to the controls. In fibroblasts higher gene expression was shown in NTN1, Unc5b, IL-6, and IL-8 when comparing patients to healthy controls. The systemically and local elevated levels of pro-inflammatory, algesic cytokines in SFN patients compared to healthy controls, confirms a potential pathophysiological role in the development of neuropathic pain. Data also indicate fibroblasts and keratinocytes to influence subepidermal and intraepidermal nerve fiber growth through the expression of NTN1 and Unc5b. Thus, skin cells may contribute to the development of neuropathic pain through local denervation. N2 - Der Pathomechanismus von Schmerz bei Small fiber Neuropathie (SFN) ist unklar. Auf Grundlage tierexperimenteller und klinischer Studien wird die Einwirkung kutaner und systemischer Schmerzmediatoren auf sensibilisierte Nozizeptoren in der Haut als mögliche Ursache diskutiert. In diesem Zusammenhang gab es Hinweise auf die Bedeutung von pro- und anti-inflammatorischen Zytokinen in der Pathophysiologie neuropathischer Schmerzen. Ziel der Studie war es, die systemische und lokale Genexpression pro- und anti-inflammatorischer Zytokine in Leukozyten sowie kutanen Fibroblasten und Keratinozyten von Patienten mit SFN zu messen. Ferner wurde untersucht, inwieweit die Expression repellierender Axon Guidance Moleküle und ihrer Rezeptoren in Hautzellen die intraepidermale Nervenfaserdichte (IENFD) regulieren könnte. Insgesamt konnten 55 SFN PatientInnen und 31 gesunde KontrollprobandInnen prospektiv rekrutiert werden. Nach ausführlicher klinischer Phänotypisierung und Blutentnahme wurden bei allen StudienteilnehmerInnen 6-mm Hautstanzbiopsien am lateralen Unter- und Oberschenkel entnommen. Die Messung der systemisch relativen Genexpression (ΔG) der Zytokine Interleukin (IL)-1β, IL-2, IL-6, IL-8 und des tumor necrose factors (TNF) erfolgte aus Leukozyten. Aus den Hautstanzbiopsien, die u.a. zur Bestimmung der IENFD verwendet wurden, wurden außerdem Primärzellkulturen von Keratinozyten und Fibroblasten angelegt, aus denen die lokale ΔG von Axon Guidance Molekülen Netrin 1 (NTN1) und Ephrin A4 (EPHA4), deren Rezeptoren Unc5b, und Ephrin A4 receptor (EFNA4) sowie der Zytokine IL-1β, IL-4, IL-6, IL-8, IL-10, TNF und des transforming growth factors (TGF) erfolgte. Systemisch zeigte sich eine höhere Genexpression für IL-2, IL-8 und TNF bei SFN Patienten im Vergleich zu gesunden Kontrollen. In Keratinozyten konnten höhere Expressionen von NTN1 und TGF-β1 bei Vergleich der Patientengruppe mit der Kontrollgruppe nachgewiesen werden. In Fibroblasten zeigte sich im Gruppenvergleich eine höhere Genexpression für NTN1, Unc5b sowie für IL-6 und IL-8. Die systemisch und lokal bei SFN Patienten nachgewiesene höhere Expression algetischer, pro-inflammatorischer Zytokine verglichen mit Kontrollen unterstützt eine mögliche pathophysiologische Rolle bei der Entstehung von neuropathischen Schmerzen. Ferner weisen die Daten darauf hin, dass Fibroblasten und Keratinozyten durch die Expression von NTN1 und Unc5b Einfluss auf das subepidermale und intraepidermale Nervenfaserwachstum nehmen und durch lokale Denervierung bei der Entstehung neuropathischer Schmerzen mitwirken könnten. KW - Neuropathischer Schmerz KW - Pathomechanismus KW - Cytokine KW - small fiber neuropathy KW - axon guidance molecules KW - pathophysilogical mechanisms KW - cytokines KW - skin cells Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-209113 ER - TY - THES A1 - Emmerich, Christoph T1 - Die Rolle der clathrin- und dynaminabhängigen Endozytose bei der Internalisation von anti-Amphiphysin-Autoantikörpern im Falle des Stiff-Person-Syndroms, untersucht am Zellkulturmodell hippocampaler Neurone T1 - The role of clathrin- and dynamin dependent endocytosis in internalisation of anti-amphiphysin-autoantibodies in case of Stiff-Person-Syndrom N2 - In dieser Arbeit wurde mit Hilfe von small-molecule Inhibitoren die Rolle von clathrin- und dynaminabhängigen Endozytosemechanismen bei der Aufnahme von anti-Amphiphysin-Autoantikörpern am Zellkulturmodell primärer hippocampaler Neurone untersucht. Hierbei konnte eine Beeinflussung der Autoaantikörperaufnahme durch die Intervention gezeigt werden. Außerdem erfolgte der Versuch der Etablierung eines siRNA knockdowns unter Zuhilfenahme unterschiedlicher Traansfektionsreaaagenzien. N2 - This thesis investigated the role of clathrin and dynamin dependent endocytosis in internalisation of anti-amphiphysin-autoantibodies in primary mouse hippocampal neurons by using small molecule inhibitors. An influence in the uptake due to small molecule treatment can be shown. Furthermore an attempt of siRNA knockdown establishment was performed using different transfection reagents. KW - siRNA KW - small molecule KW - Stiff-Person-Syndrom KW - anti-Amphiphysin Antikörper KW - siRNA KW - small-molecule Inhibitoren KW - Stiff-Person-Syndrom KW - anti-amphiphysin antibodies KW - small-molecule inhibitors Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-209360 ER -