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Cognition in patients with myelin oligodendrocyte glycoprotein antibody-associated disease: a prospective, longitudinal, multicentre study of 113 patients (CogniMOG-Study)
Get PDFBACKGROUND: Data on cognition in patients with myelin oligodendrocyte glycoprotein antibody- associated disease (MOGAD) are limited to studies with small sample sizes. Therefore, we aimed to analyse the extent, characteristics and the longitudinal course of potential cognitive deficits in patients with MOGAD. METHODS: The CogniMOG-Study is a prospective, longitudinal and multicentre observational study of 113 patients with MOGAD. Individual cognitive performance was assessed using the Paced Auditory Serial Addition Task (PASAT), the Symbol Digit Modalities Test (SDMT) and the Multiple Sclerosis Inventory Cognition (MuSIC), which are standardised against normative data from healthy controls. Cognitive performance was assessed at baseline and at 1-year and 2-year follow-up assessments. Multiple linear regression was used to analyse demographic and clinical predictors of cognitive deficits identified in previous correlation analyses. RESULTS: At baseline, the study sample of MOGAD patients showed impaired standardised performance on MuSIC semantic fluency (mean=-0.29, 95% CI (-0.47 to -0.12)) and MuSIC congruent speed (mean=-0.73, 95% CI (-1.23 to -0.23)). Around 1 in 10 patients showed deficits in two or more cognitive measures (11%). No decline in cognition was observed during the 1-year and 2-year follow-up period. Cerebral lesions were found to be negatively predictive for SDMT (B=-8.85, 95% CI (-13.57 to -4.14)) and MuSIC semantic fluency (B=-4.17, 95% CI (-6.10 to -2.25)) test performance. CONCLUSIONS: Based on these data, we conclude that MOGAD patients show reduced visuomotor processing speed and semantic fluency to the extent that the disease burden includes cerebral lesions
A phase I study of MAGE-A1-targeted T1367 T-cell receptor-based cell therapy in patients with advanced multiple myeloma
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New MERS-CoV Vaccine
No full textThe present invention relates to a mutant receptor-binding domain (MERS-mRBD) of MERS-CoV (middle east respiratory syndrome coronavirus) or a fragment thereof and a mutant spike protein (MERS-mSpike) of MERS-CoV or a fragment thereof. Furthermore, the present invention relates to a mutant spike protein (MERS-mSpike) of MERS-CoV or a fragment thereof comprising the MERS-mRBD or the fragment thereof. Furthermore, the present invention relates to a polypeptide or protein comprising the MERS- mRBD or the fragment thereof or MERS-mSpike or the fragment thereof and a nucleic acid comprising a nucleotide sequence encoding for the MERS-mRBD or the fragment thereof or the MERS-mSpike or the fragment thereof. Furthermore, the present invention relates to a vaccine composition comprising one or more MERS-mRBDs or fragments thereof, one or more MERS -mSpikes, one or more polypeptide or proteins and/or one or more nucleic acids according to the present invention. Furthermore, the present invention relates to the one or more MERS-mRBDs or fragments thereof, the one or more MERS-mSpikes, the one or more polypeptides or proteins, the one or more nucleic acids and/or the vaccine composition according to the present invention for use in the prevention and/or treatment of diseases caused by MERS-CoV in a subject
Heart failure and obesity: translational approaches and therapeutic perspectives. A scientific statement of the Heart Failure Association of the ESC
Get PDFObesity and heart failure (HF) represent two growing pandemics. In the general population, obesity affects one in eight adults and is linked with an increased risk for HF. Obesity is even more common in patients with HF, where it complicates the diagnosis of HF and is linked with worse symptoms and impaired exercise capacity. Over the past few years, new evidence on the mechanisms linking obesity with HF has been reported, particularly in relation to HF with preserved ejection fraction. Novel therapies inducing weight loss appear to have favourable effects on health status and cardiovascular risk. Against the backdrop of this rapidly evolving evidence landscape, HF clinicians are increasingly required to tailor their preventive, diagnostic, and therapeutic approaches to HF in the presence of obesity. This scientific statement by the Heart Failure Association of the European Society of Cardiology provides an up-to-date summary on obesity in HF, covering key areas such as epidemiology, translational aspects, diagnostic challenges, therapeutic approaches, and trial design
Multiple Sklerose
No full textZur Behandlung der multiplen Sklerose werden krankheitsmodifizierende Immuntherapeutika und symptomatisch wirkende Arzneistoffe eingesetzt. Die Verordnung von Beta-Interferonen für die Behandlung der schubförmig-remittierenden multiplen Sklerose geht seit Jahren zu Gunsten anderer Arzneistoffe (insbesondere Dimethylfumarat, Glatirameracetat, Teriflunomid, Ocrelizumab und Natalizumab) zurück. Eine rückläufige Tendenz ist aber jetzt auch für Diemthylfumarat, Glatirameracetat und Fingolimod erkennbar. Als Muskelrelaxanzien (Antispastika) stehen Baclofen, Tizanidin und Botulinumtoxin bei der symptomatischen Behandlung der multiplen Sklerose im Vordergrund. Muskelrelaxanzien mit unzureichender Beleglage (z. B. Chininsulfat, Methocarbamol, Pridinol) wie auch schon 2022 im Jahr deutlich häufiger verordnet. Dies ist unter dem Aspekt der evidenzbasierten Medizin nicht nachvollziehbar und sehr kritikwürdig. Möglicherweise liegt dieses wissenschaftlich nicht begründete Verordnungsverhalten daran, dass die DDD-Kosten für diese Muskelrelaxantien sehr viel niedriger sind als für die Immuntherapeutika, die offensichtlich wegen der hohen Kosten jetzt weniger häufig verordnet werden
Spike-in enhanced phosphoproteomics uncovers synergistic signaling responses to MEK inhibition in colon cancer cells
Get PDFTargeted kinase inhibitors are a cornerstone of cancer therapy, but their success is often hindered by the complexity of cellular signaling networks that can lead to resistance. Overcoming this challenge necessitates a deep understanding of cellular signaling responses. While standard global phosphoproteomics offers extensive insights, lengthy processing times, the complexity of data interpretation, and frequent omission of crucial phosphorylation sites limit its utility. Here, we combine data-independent acquisition (DIA) with spike-in of synthetic heavy stable isotope-labeled phosphopeptides to facilitate the targeted detection of particularly informative phosphorylation sites. Our spike-in enhanced detection in DIA (SPIED-DIA) approach integrates the improved sensitivity of spike-in-based targeted detection with the discovery potential of global phosphoproteomics into a simple workflow. We employed this method to investigate synergistic signaling responses in colorectal cancer cell lines following MEK inhibition. Our findings highlight that combining MEK inhibition with growth factor stimulation synergistically activates JNK signaling in HCT116 cells. This synergy emphasizes the therapeutic potential of concurrently targeting MEK and JNK pathways, as evidenced by the significantly impaired growth of HCT116 cells when treated with both inhibitors. Our results demonstrate that SPIED-DIA effectively identifies synergistic signaling responses in colorectal cancer cells, presenting a valuable tool for uncovering new therapeutic targets and strategies in cancer treatment
RNF20 links the DNA damage response and metabolic rewiring in lung cancer through HIF1α
Get PDFDefective DNA repair and metabolic rewiring are highly intertwined in promoting the development and progression of cancer. However, the molecular players at their interface remain poorly understood. Here we show that an RNF20-HIF1α axis links the DNA damage response and metabolic reprogramming in lung cancer. We demonstrate that RNF20, which catalyzes monoubiquitylation of histone H2B (H2Bub1), controls Rbx1 expression and thereby the activity of the VHL ubiquitin ligase complex and HIF1α levels. Ablation of a single Rnf20 allele significantly increases the incidence of lung tumors in mice. Mechanistically, Rnf20 haploinsufficiency results in inadequate tumor suppression via the Rnf20-H2Bub1-p53 axis and induces DNA damage, cell growth, epithelial-mesenchymal transition (EMT), and metabolic rewiring through HIF1α-mediated RNA polymerase II promoter-proximal pause release, which is independent of H2Bub1. Importantly, decreased RNF20 levels correlate with increased expression of HIF1α and its target genes, suggesting HIF1α inhibition as a promising therapeutic approach for lung cancer patients with reduced RNF20 activity
RECLAIM - a retrospective, multicenter observational study aimed at enabling the development of artificial intelligence-driven prognostic models for disease progression in multiple sclerosis
Get PDFMultiple sclerosis (MS) is characterized by a progressive worsening of disability over time. As many regulatory-cleared disease-modifying treatments aiming to slow down this progression are now available, a clear need has arisen for a personalized and data-driven approach to treatment optimization in order to more efficiently slow down disease progression and eventually, progressive disability worsening. This strongly depends on the availability of biomarkers that can detect and differentiate between the different forms of disease worsening, and on predictive models to estimate the disease trajectory for each patient under certain treatment conditions. To this end, we here describe a multicenter, retrospective, observational study, aimed at setting up a harmonized database to allow the development, training, optimization, and validation of such novel biomarkers and AI-based decision models. Additionally, the data will be used to develop the tools required to better monitor this progression and to generate further insights on disease worsening and progression, patient prognosis, treatment decisions and responses, and patient profiles of patients with MS
Inversion efficiency model yields improved accuracy in MP2RAGE-based T(1) mapping in the human brain at 7.0T
Get PDFEstimation of the longitudinal relaxation time T(1) from the MP2RAGE pulse sequence is based on a monoexponential signal evolution model. However, magnetization transfer (MT) caused by the inversion pulse induces a fast relaxation component, which appears as a reduction in the efficiency of the inversion. This may explain the underestimation of T(1) derived from MP2RAGE. To address this systematic bias, an "apparent" inversion efficiency (f(inv)) was introduced, which comprises all mechanisms that affect the inversion in the monoexponential MP2RAGE signal model. The model was then extended by calibrating an empirical linear dependence of f(inv) on R(1) = 1/T(1), resulting in increased accuracy of the estimated T(1). The apparent inversion efficiency f(inv) and the apparent T(1)* (yielding T(1) by auxiliary B(1)(+) mapping) were mapped at 7T in healthy adults using phase-sensitive inversion recovery (IR) with four consecutive RAGE trains (PS-MP4RAGE) in conjunction with adiabatic inversion using time-resampled (TR)-FOCI and hyperbolic secant pulses. Upon validation by conventional IR-EPI, PS-MP4RAGE was used to calibrate the linear f(inv) model for the human brain. These 3D T(1) maps also served as a reference to assess the improvement of the MP2RAGE-based T(1) estimates. The apparent inversion efficiency f(inv) was consistently smaller in white matter (WM) than in gray matter (~0.73 vs. ~0.84). The difference in WM T(1) between MP2RAGE and the reference PS-MP4RAGE technique was reduced by more than 200 ms when using the suggested f(inv) model. MT effects after spin inversion in MP2RAGE can be accounted for by calibrating the apparent inversion efficiency f(inv) without introducing additional parameters. The proposed empirical model retains the B(1)(+) compensation inherent to MP2RAGE and facilitates accurate T(1) quantification in brain tissue