A5024300923- Ion channel regulation and function
- Cardiac electrophysiology and arrhythmias
- Melanoma and MAPK Pathways
- Immunotherapy and Immune Responses
- Cutaneous Melanoma Detection and Management
- Cancer Immunotherapy and Biomarkers
- Cutaneous lymphoproliferative disorders research
- Blind Source Separation Techniques
- Autoimmune Bullous Skin Diseases
- HER2/EGFR in Cancer Research
- Ion Channels and Receptors
- Receptor Mechanisms and Signaling
- CAR-T cell therapy research
- Nonmelanoma Skin Cancer Studies
- Cancer Genomics and Diagnostics
- Neuroscience and Neuropharmacology Research
- Advanced Fluorescence Microscopy Techniques
- Fault Detection and Control Systems
- Nicotinic Acetylcholine Receptors Study
- Protein Tyrosine Phosphatases
- Signaling Pathways in Disease
- Cancer, Hypoxia, and Metabolism
- Cancer Mechanisms and Therapy
- Bioactive Compounds and Antitumor Agents
- Full-Duplex Wireless Communications
Universitätsmedizin Göttingen
2014-2024
University of Göttingen
2024
Charles University
2014-2022
General University Hospital in Prague
2017-2019
Columbia University
2004-2011
University of California San Francisco Medical Center
2011
Czech Academy of Sciences, Institute of Physiology
2003
Slovak Academy of Sciences
1999-2003
Czech Academy of Sciences
2003
To investigate the dynamics and propensity for arrhythmias in intact transgenic hearts comprehensively, optical strategies panoramic fluorescence imaging of action potential (AP) propagation are essential. In particular, mechanism-oriented molecular studies usually depend on mouse only a few millimeters size. Furthermore, temporal scales heart remain challenge with rates ranging from 200 min-1 (e.g. depressed sinus node function) to over 1200 during fast arrhythmias. meet these challenging...
During exercise, defects in calcium (Ca 2+ ) release have been proposed to impair muscle function. Here, we show that during exercise mice and humans, the major Ca channel required for excitation–contraction coupling (ECC) skeletal muscle, ryanodine receptor (RyR1), is progressively PKA-hyperphosphorylated, S -nitrosylated, depleted of phosphodiesterase PDE4D3 RyR1 stabilizing subunit calstabin1 (FKBP12), resulting “leaky” channels cause decreased tolerance mice. Mice with muscle-specific...
Macrophages in advanced atherosclerotic lesions accumulate large amounts of unesterified, or “free,” cholesterol (FC). FC accumulation induces macrophage apoptosis, which likely contributes to plaque destabilization. Apoptosis is triggered by the enrichment endoplasmic reticulum (ER) with FC, resulting depletion ER calcium stores, and induction unfolded protein response. To explain mechanism depletion, we hypothesized that normally cholesterol-poor membrane inhibits pump,...
Increased sarcoplasmic reticulum (SR) Ca2+ leak via the cardiac ryanodine receptor/calcium release channel (RyR2) is thought to play a role in heart failure (HF) progression. Inhibition of this an emerging therapeutic strategy. To explore chronic PKA phosphorylation RyR2 HF pathogenesis and treatment, we generated knockin mouse with aspartic acid replacing serine 2808 (mice are referred herein as RyR2-S2808D+/+ mice). This mutation mimics constitutive hyperphosphorylation RyR2, which causes...
The canonical atrial myocyte (AM) is characterized by sparse transverse tubule (TT) invaginations and slow intracellular Ca2+ propagation but exhibits rapid contractile activation that susceptible to loss of function during hypertrophic remodeling. Here, we have identified a membrane structure Ca2+-signaling complex may enhance the speed contraction independently phospholamban regulation. This axial couplon was observed in human mouse atria composed voluminous tubules (ATs) with extensive...
Rationale: Mutations in the cardiac type 2 ryanodine receptor (RyR2) have been linked to catecholaminergic polymorphic ventricular tachycardia (CPVT). CPVT-associated RyR2 mutations cause fatal arrhythmias young individuals during β-adrenergic stimulation. Objective: This study sought determine effects of a novel RyR2-G230C mutation and whether this RyR2-P2328S alter sensitivity channel luminal calcium (Ca 2+ ). Methods Results: Functional characterizations recombinant human channels were...
Abstract The most common histological subtypes of cutaneous melanoma include superficial spreading and nodular melanoma. However, the spectrum somatic mutations developed in those lesions all potential druggable targets have not yet been fully elucidated. We present results a sequence capture NGS analysis 114 primary melanomas identifying driver using biostatistical, immunohistochemical and/or functional approach. frequency pathogenic or likely variants were identified across 54 evaluated...
Sustained elevation of intracellular calcium by Ca2+ release-activated channels is required for lymphocyte activation. entry requires endoplasmic reticulum (ER) depletion and prolonged activation inositol 1,4,5-trisphosphate receptor (IP(3)R)/Ca2+ release channels. However, a major isoform in ER, IP3R1, inhibited elevated levels cytosolic Ca2+, the mechanism that enables IP(3)R1 unclear. We show binds to scaffolding protein linker activated T cells colocalizes with cell during activation,...
Mg 2+ , an important constituent of the intracellular milieu in cardiac myocytes, is known to inhibit ryanodine receptor (RyR) Ca release channels by competing with at cytosolic activation sites channel. However, significance this competition for local, dynamic -signaling processes thought govern excitation-contraction (EC) coupling remains largely unknown. In present study, stimuli different waveforms (i.e., sustained and brief) were generated photolysis caged compound nitrophenyl...
In the current study, sensitivity and specificity of methods HER2 status detection were studied in 55 patients presenting with gastric/gastroesophageal junction carcinoma (30 intestinal 25 diffuse), small biopsy (endoscopy; n=33) resection specimens (n=22). The primary objective present study was to compare various for assessment status, regards each method, as well their concordance. all cases, determined using immunohistochemistry (IHC), fluorescence situ hybridization (FISH), silver...
Glucose transporter-1 (Glut-1) is a membrane glycoprotein that is, together with other glucose transporters, responsible for the regulation of uptake. An increased expression this protein seems to be general feature several malignant tumors are able reprogram their metabolism and switch from oxidative phosphorylation aerobic glycolysis.We performed comprehensive immunohistochemical analysis Glut-1 in 336 endometrial samples, including tumors, nontumor lesions, normal tissues.Expression was...
Abstract The objective of our study was to compare the five different scoring methods tumor‐infiltrating lymphocytes (TILs) assessment in a group 213 cases superficial spreading and nodular melanoma. include (a) Clark scoring; (b) Melanoma Institute Australia system; (c) system used Saldanha et al.; (d) TCGA modified by Park (e) recently proposed “International Immuno‐Oncology Biomarker Working Group” for TILs all solid tumors. Prediction survival with three main...
Cutaneous collagenous vasculopathy (CCV) is an extremely rare acquired microangiopathy of unknown etiology. The authors describe a case 68-year-old man, carrier heterozygous pathogenic variant the glucocerebrosidase (GBA) gene, who was diagnosed with CCV, revealing uncommon fibrinogen positivity in direct immunofluorescence. patient subsequently multiple myeloma. Treatment myeloma combined chemotherapy including bortezomib, followed by autologous stem cell transplantation, led to significant...
Measurements of ryanodine receptor (RyR) activity during dynamic changes calcium concentration have suggested that RyR has at least four binding sites, and activation transpires as an increase in the within high open probability H-mode. Binding several Ca2+ ions H-mode should manifest itself steady-state by presence multiple closed times. However, previously only two times were detected activity. Here we recorded single cardiac RyRs with temporal resolution compared it to data simulated...
We propose and investigate a hidden Markov model (HMM) for the analysis of dependent, aggregated, superimposed two-state signal recordings. A major motivation this work is that often these signals cannot be observed individually but only their superposition. Among others, such models are in high demand understanding cross-talk between ion channels, where each single channel measured separately. As an essential building block, we introduce parameterized vector norm dependent chain...
Autoři popisují klinický případ pacientky s metastazujícím melanomem, u níž se v samém počátku cílené léčby enkorafenibem a binimetinibem objevila oční toxicita ve formě bilaterálního odloučení zevních vrstev sítnice. Subjektivní obtíže zrakem odezněly do 2 měsíců kontrolní OCT potvrdilo reparaci odloučení. Cílená léčba dabrafenibem trametinibem další linii nevykázala příznaky toxicity. Diskutována je melanomu, její typy, závažnost management. Při každé návštěvě pacienta léčeného cílenou...
Autoři prezentují případ kompletní léčebné odpovědi u pacienta léčeného pro metastazující karcinom z Merkelových buněk kombinací radioterapie a imunoterapie avelumabem. Imunoterapie byla předčasně ukončena relaps myelodysplastického syndromu. I přes předčasné ukončení trvá obraz remise onemocnění. Diskutovány jsou klinické histopatologické vlastnosti karcinomu doporučený terapeutický algoritmus. Pozornost je věnována managementu léčby
Protinádorová imunoterapie je zlatým standardem moderní léčby v rostoucím počtu metastazujících či lokálně pokročilých solidních nádorů.Tato léčba dosahuje signifikantních a trvalých léčebných odpovědí přináší prodloužení doby do progrese celkového přežití za současného zlepšení kvality života.V oblasti maligních kožních nádorů dobře znám léčebný efekt u metastazujícího melanomu, něhož se stala systémové léčby.Efekt imunoterapeutik byl však prokázán i nemelanomových kůže, konkrétně...
Inhibitory mutované BRAF kinázy dohromady s inhibitory MEK jsou jednou z alternativ moderní systémové léčby metastazujícího melanomu.BRAF a též prokázaly efekt v adjuvantním podání.Tyto léky vykazují specifické spektrum nežádoucích účinků, přičemž kožní toxicita patří mezi nejčastější je pro jednotlivé kombinace léků vysoce
Melanom je nejzhoubnějším kožním nádorem, který znám pro svou vysokou mortalitu a opožděné zakládání metastáz.Terapie metastazujícího melanomu v současné době prochází "zlatou érou", jelikož se na trhu objevují nová léčiva ze skupin imunoterapeutik cílených léků.Tyto léky signifikantně zvyšují četnost navozených remisí prodlužují celkové přežití.Princip založen blokování inhibičních kontrolních bodů imunity, s cílem zvýšit efektivitu vlastního imunitního systému vůči nádorovým buňkám.Na trh...