BACKGROUND: Renal cell carcinoma (RCC) is a disease typified by anomalies in cell metabolism. The function of mitochondria, including subunits of mitochondrial respiratory complex II (CII), in particular SDHB, are often affected. Here we investigated the state and function of CII in RCC patients. METHODS: We evaluated tumour tissue as well as the adjacent healthy kidney tissue of 78 patients with RCC of different histotypes, focusing on their mitochondrial function. As clear cell RCC (ccRCC) is by far the most frequent histotype of RCC, we focused on these patients, which were grouped based on the pathological WHO/ISUP grading system to low- and high-grade patients, indicative of prognosis. We also evaluated mitochondrial function in organoids derived from tumour tissue of 7 patients. RESULTS: ccRCC tumours were characterized by mutated von Hippel-Lindau gene and high expression of carbonic anhydrase IX. We found low levels of mitochondrial DNA, protein and function, together with CII function in ccRCC tumour tissue, but not in other RCC types and non-tumour tissues. Mitochondrial content increased in high-grade tumours, while the function of CII remained low. Tumour organoids from ccRCC patients recapitulated molecular characteristics of RCC tissue. CONCLUSIONS: Our findings suggest that the state of CII, epitomized by its assembly and SDHB levels, deteriorates with the progressive severity of ccRCC. These observations hold the potential for stratification of patients with worse prognosis and may guide the exploration of targeted therapeutic interventions.
- MeSH
- antigeny nádorové MeSH
- dospělí MeSH
- karboanhydrasa IX metabolismus genetika MeSH
- karcinom z renálních buněk * patologie metabolismus genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- mitochondriální DNA genetika metabolismus MeSH
- mitochondrie * metabolismus patologie genetika MeSH
- mutace MeSH
- nádorový supresorový protein VHL genetika metabolismus MeSH
- nádory ledvin * patologie metabolismus genetika MeSH
- respirační komplex II * metabolismus genetika MeSH
- senioři MeSH
- sukcinátdehydrogenasa genetika metabolismus MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Cystathionine β-synthase (CBS) deficiency (classical homocystinuria) has a wide range of severity. Mildly affected patients typically present as adults with thromboembolism and respond to treatment with pyridoxine. Severely affected patients usually present during childhood with learning difficulties, ectopia lentis and skeletal abnormalities; they are pyridoxine non-responders (NR) or partial responders (PR) and require treatment with a low-methionine diet and/or betaine. The European network and registry for Homocystinurias and methylation Defects (E-HOD) has published management guidelines for CBS deficiency and recommended keeping plasma total homocysteine (tHcy) concentrations below 100 μmol/L. We have now analysed data from 311 patients in the registry to see how closely treatment follows the guidelines. Pyridoxine-responsive patients generally achieved tHcy concentrations below 50 μmol/L, but many NRs and PRs had a mean tHcy considerably above 100 μmol/L. Most NRs were managed with betaine and a special diet. This usually involved severe protein restriction and a methionine-free amino acid mixture, but some patients had a natural protein intake substantially above the WHO safe minimum. Work is needed on the methionine content of dietary protein as estimates vary widely. Contrary to the guidelines, most NRs were on pyridoxine, sometimes at dangerously high doses. tHcy concentrations were similar in groups prescribed high or low betaine doses and natural protein intakes. High tHcy levels were probably often due to poor compliance. Comparing time-to-event graphs for NR patients detected by newborn screening and those ascertained clinically showed that treatment could prevent thromboembolism (risk ratio 0.073) and lens dislocation (risk ratio 0.069).
- MeSH
- betain * terapeutické užití MeSH
- cystathionin-beta-synthasa nedostatek MeSH
- dítě MeSH
- dospělí MeSH
- homocystein * krev metabolismus MeSH
- homocystinurie * farmakoterapie MeSH
- kojenec MeSH
- lidé MeSH
- methionin * nedostatek MeSH
- mladiství MeSH
- mladý dospělý MeSH
- novorozenec MeSH
- předškolní dítě MeSH
- pyridoxin * terapeutické užití MeSH
- registrace * MeSH
- výsledek terapie MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- novorozenec MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Renální karcinom je histologicky diverzní onemocnění s variabilním a často nepředvídatelným chováním. Profilování genové exprese se jeví jako slibná technika k upřesnění diagnózy a stagingu renálního karcinomu a též k přesnějšímu zacílení léčby (1).
Renal cell carcinoma (RCC) is a histologically diverse disease, with variable and often unpredictable clinical behavior. Gene expression profiling is a promising technique for refining the diagnosis and staging of RCC, as well as for highlighting potential therapeutic targets (1).
- MeSH
- faktor 1 indukovatelný hypoxií analýza MeSH
- genetické testování * metody MeSH
- hepatocytární růstový faktor analýza MeSH
- imunoterapie metody MeSH
- inhibitory kontrolních bodů terapeutické užití MeSH
- karboanhydrasa IX analýza MeSH
- lidé MeSH
- nádory ledvin * farmakoterapie genetika imunologie MeSH
- prediktivní hodnota testů MeSH
- tkáňový inhibitor metaloproteinasy 1 analýza MeSH
- Check Tag
- lidé MeSH
Spontaneous tumor regression is a recognized phenomenon across various cancer types. Recent research emphasizes the alterations in autoantibodies against carbonic anhydrase I (CA I) (anti-CA I) levels as potential prognostic markers for various malignancies. Particularly, autoantibodies targeting CA I and II appear to induce cellular damage by inhibiting their respective protein's catalytic functions. Our study illuminates the profound impact of anti-CA I autoantibodies from patient serum on the esterase activity of human CA I, exhibiting inhibitory effects akin to the acetazolamide inhibitor. Concurrently, our newly synthesized mouse monoclonal IgG antibody, mAb 2B8, against human CA I showcased a potent inhibitory action. An in-depth exploration into mAb 2B8's binding dynamics with its target enzyme was undertaken. Leveraging epitope extraction and phage display library techniques, we identified the amino acid sequence DFWTYP (positions 191-196 of CA I) as crucial for mAb 2B8's interaction. In 3-D structural analysis, this sequence is spatially adjacent to a previously identified epitope (DFWTYP) that interacts with patient-derived autoantibodies. Critically, mAb 2B8 demonstrated an ability to infiltrate eukaryotic cells, engaging specifically with its intracytoplasmic target. This positions mAb 2B8 as a promising model for future studies aimed at tumor cell eradication.
- MeSH
- autoprotilátky * imunologie metabolismus MeSH
- epitopy imunologie chemie MeSH
- karboanhydrasa I * metabolismus antagonisté a inhibitory MeSH
- lidé MeSH
- monoklonální protilátky * imunologie MeSH
- myši MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Succinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC) is a rare subtype of renal neoplasm predominantly affecting younger individuals. It is characterized by germline mutations in SDHx genes, particularly type B. Histologically, SDH-deficient RCC features eosinophilic cytoplasmic cells forming solid nests or microcysts, sometimes entrapping normal tubules. We present three SDH-deficient RCC cases with overlapping morphological features with fumarate hydratase-deficient RCC and TFEB-rearranged RCC, an appearance that has not been previously described. All tumors lacked SDHB expression and harbored pathogenic SDHB mutations, with the germline nature confirmed in two cases. Metastasis developed in two patients. Our case set highlights the diagnostic challenges of molecularly defined renal tumors and expands the morphological spectrum of SDH-deficient RCC with unusual histological features. Clinically, these tumors appear to be aggressive.
- MeSH
- dediferenciace buněk MeSH
- dospělí MeSH
- fumarasa nedostatek genetika MeSH
- karcinom z renálních buněk * genetika patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádorové biomarkery genetika analýza MeSH
- nádory ledvin * patologie genetika MeSH
- sukcinátdehydrogenasa * nedostatek genetika MeSH
- transkripční faktory BHLH-Zip genetika MeSH
- zárodečné mutace MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
Hyponatremie je stanovena jako koncentrace sodíku nižší než 135 mmol/l. Jedná se o celosvětově nejčastější poruchu elektrolytů. Nejčastějšími projevy hyponatremie jsou gastrointestinální a neurologické obtíže. Příležitostně může vést hyponatremie k poruchám srdečního rytmu. V námi prezentované kazuistice vedla těžká hyponatremie k sinusové bradykardii s alternujícím stupněm atrioventrikulární blokády a srdeční zástavě. Obnovení sinusového rytmu bylo dosaženo až po úpravě koncentrace sodíku. Těžká hyponatremie a protrahovaná zástava oběhu však u pacienta vedly k malignímu otoku mozku. Tento jedinečný případ zdůrazňuje kritickou roli sodíku v srdeční elektrofyziologii a ukazuje důležitost monitorace koncentrace sodíku u pacientů se zástavou oběhu.
Hyponatremia, characterized by sodium levels below 135 mmol/l, is the most prevalent electrolyte disorder worldwide. It presents with a wide range of clinical symptoms, particularly in the neurological and gastrointestinal domains, occasionally leading to cardiac arrhythmias. In our specific case, severe hyponatremia resulting from potomania resulted in sinus bradycardia with alternating atrioventricular block and subsequent cardiac arrest. Restoration of sinus rhythm was achieved following correction of the sodium levels. However severe hyponatremia and long-lasting CPR resulted in brain oedema, which ultimately led to brain death. Per national regulations, the patient was enrolled in an organ donor program, resulting in successful organ transplants. This unique case underscores the critical role of sodium levels in cardiac electrophysiology and highlights the necessity of monitoring electrolyte levels in patients experiencing cardiac arrest.
- MeSH
- edém mozku etiologie MeSH
- elektrokardiografie MeSH
- fosfopyruváthydratasa analýza MeSH
- hypertrofie pravé komory srdeční komplikace MeSH
- hyponatremie * komplikace MeSH
- kardiopulmonální resuscitace MeSH
- lidé středního věku MeSH
- lidé MeSH
- mozková smrt MeSH
- pití alkoholu škodlivé účinky MeSH
- pitva MeSH
- recidiva MeSH
- srdeční zástava * etiologie komplikace patologie terapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
The cerebral biomarkers, neurofilament light chain (NfL), amyloid-β, tau, and neuron specific enolase (NSE) reflect a wide spectrum of neurological damage in the brain and spinal cord. With this study, we aimed to assess whether these biomarkers hold any potential diagnostic value for the three most common canine neurological diseases. Canines suffering from meningoencephalitis of unknown origin (MUO), brain tumors, and selected non-infectious myelopathies were included. For each diagnosis, we analyzed these biomarkers in the cerebrospinal fluid collected via cranial puncture from the cisterna magna. Elevated levels of CSF tau, NfL, and NSE were observed in MUO, with all three biomarkers being intercorrelated. Tau and NSE were increased while amyloid-β was decreased in dogs suffering from tumors. In contrast, no biomarker changes were observed in dogs with myelopathies. Covariates such as age, sex, or castration had minimal impact. CSF biomarkers may reflect molecular changes related to MUO and tumors, but not to non-infectious myelopathies. The combination of NfL, tau, and NSE may represent useful biomarkers for MUO as they reflect the same pathology and are not influenced by age.
- MeSH
- amyloidní beta-protein mozkomíšní mok MeSH
- biologické markery * mozkomíšní mok MeSH
- fosfopyruváthydratasa mozkomíšní mok MeSH
- meningoencefalitida mozkomíšní mok veterinární diagnóza MeSH
- nádory mozku mozkomíšní mok veterinární MeSH
- nemoci nervového systému mozkomíšní mok veterinární diagnóza MeSH
- nemoci psů * mozkomíšní mok diagnóza MeSH
- neurofilamentové proteiny * mozkomíšní mok MeSH
- proteiny tau * mozkomíšní mok MeSH
- psi MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- psi MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
This review summarises progress in the research of homocystinuria (HCU) in the past three decades. HCU due to cystathionine β-synthase (CBS) was discovered in 1962, and Prof. Jan Peter Kraus summarised developments in the field in the first-ever Komrower lecture in 1993. In the past three decades, significant advancements have been achieved in the biology of CBS, including gene organisation, tissue expression, 3D structures, and regulatory mechanisms. Renewed interest in CBS arose in the late 1990s when this enzyme was implicated in biogenesis of H2S. Advancements in genetic and biochemical techniques enabled the identification of several hundreds of pathogenic CBS variants and the misfolding of missense mutations as a common mechanism. Several cellular, invertebrate and murine HCU models allowed us to gain insights into functional and metabolic pathophysiology of the disease. Establishing the E-HOD consortium and patient networks, HCU Network Australia and HCU Network America, offered new possibilities for acquiring clinical data in registries and data on patients' quality of life. A recent analysis of data from the E-HOD registry showed that the clinical variability of HCU is broad, extending from severe childhood disease to milder (late) adulthood forms, which typically respond to pyridoxine. Pyridoxine responsiveness appears to be the key factor determining the clinical course of HCU. Increased awareness about HCU played a role in developing novel therapies, such as gene therapy, correction of misfolding by chaperones, removal of methionine from the gut and enzyme therapies that decrease homocysteine or methionine in the circulation.
BACKGROUND: Cystathionine β-synthase (CBS)-deficient homocystinuria (HCU) is an inherited disorder of sulfur amino acid metabolism with varying severity and organ complications, and a limited knowledge about underlying pathophysiological processes. Here we aimed at getting an in-depth insight into disease mechanisms using a transgenic mouse model of HCU (I278T). METHODS: We assessed metabolic, proteomic and sphingolipidomic changes, and mitochondrial function in tissues and body fluids of I278T mice and WT controls. Furthermore, we evaluated the efficacy of methionine-restricted diet (MRD) in I278T mice. RESULTS: In WT mice, we observed a distinct tissue/body fluid compartmentalization of metabolites with up to six-orders of magnitude differences in concentrations among various organs. The I278T mice exhibited the anticipated metabolic imbalance with signs of an increased production of hydrogen sulfide and disturbed persulfidation of free aminothiols. HCU resulted in a significant dysregulation of liver proteome affecting biological oxidations, conjugation of compounds, and metabolism of amino acids, vitamins, cofactors and lipids. Liver sphingolipidomics indicated upregulation of the pro-proliferative sphingosine-1-phosphate signaling pathway. Liver mitochondrial function of HCU mice did not seem to be impaired compared to controls. MRD in I278T mice improved metabolic balance in all tissues and substantially reduced dysregulation of liver proteome. CONCLUSION: The study highlights distinct tissue compartmentalization of sulfur-related metabolites in normal mice, extensive metabolome, proteome and sphingolipidome disruptions in I278T mice, and the efficacy of MRD to alleviate some of the HCU-related biochemical abnormalities.
- MeSH
- cystathionin-beta-synthasa * metabolismus nedostatek genetika MeSH
- homocystinurie * metabolismus genetika MeSH
- játra * metabolismus MeSH
- lipidomika metody MeSH
- metabolomika * metody MeSH
- mitochondrie metabolismus MeSH
- modely nemocí na zvířatech * MeSH
- myši transgenní * MeSH
- myši MeSH
- proteom metabolismus MeSH
- proteomika * metody MeSH
- sfingolipidy * metabolismus MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Limited evidence exists for prognostic performance of biomarkers in patients resuscitated from out-of-hospital cardiac arrest (OHCA) with extracorporeal CPR (ECPR). We hypothesized that (1) the time course and (2) prognostic performance of biomarkers might differ between CPR and ECPR in a sub-analysis of Prague-OHCA study. METHODS: Patients received either CPR (n = 164) or ECPR (n = 92). The primary outcome was favorable neurologic survival at 180 days [cerebral performance category (CPC) 1-2]. Secondary outcomes included biomarkers of neurologic injury, inflammation and hemocoagulation. RESULTS: Favorable neurologic outcome was not different between groups: CPR 29.3% vs. ECPR 21.7%; p = 0.191. Biomarkers exhibited similar trajectories in both groups, with better values in patients with CPC 1-2. Procalcitonin (PCT) was higher in ECPR group at 24-72 h (all p < 0.01). Neuron-specific enolase (NSE), C-reactive protein and neutrophil-to-lymphocyte ratio did not differ between groups. Platelets, D-dimers and fibrinogen were lower in ECPR vs. CPR groups at 24-72 h (all p < 0.001). ROC analysis (24-48-72 h) showed the best performance of NSE in both CPR and ECPR groups (AUC 0.89 vs. 0.78; 0.9 vs. 0.9; 0.91 vs. 0.9). PCT showed good performance specifically in ECPR (0.72 vs. 0.84; 0.73 vs. 0.87; 0.73 vs. 0.86). Optimal cutoff points of NSE and PCT were higher in ECPR vs. CPR. CONCLUSIONS: Biomarkers exhibited similar trajectories although absolute values tended to be higher in ECPR. NSE had superior performance in both groups. PCT showed a good performance specifically in ECPR. Additional biomarkers may have modest incremental value. Prognostication algorithms should reflect the resuscitation method.
- MeSH
- biologické markery * krev MeSH
- fosfopyruváthydratasa krev MeSH
- kardiopulmonální resuscitace * metody MeSH
- lidé středního věku MeSH
- lidé MeSH
- mimotělní membránová oxygenace * metody MeSH
- prognóza MeSH
- prokalcitonin krev MeSH
- senioři MeSH
- zástava srdce mimo nemocnici * terapie krev mortalita MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
