- MeSH
- biologické markery MeSH
- humanizované monoklonální protilátky terapeutické užití MeSH
- intermediární filamenta MeSH
- klíšťová encefalitida * genetika prevence a kontrola terapie MeSH
- lidé MeSH
- Parkinsonova nemoc postencefalitická MeSH
- polymorfismus genetický MeSH
- rizikové faktory MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- novinové články MeSH
- rozhovory MeSH
Lamins, the nuclear intermediate filaments, are important regulators of nuclear structural integrity as well as nuclear functional processes such as DNA transcription, replication and repair, and epigenetic regulations. A portion of phosphorylated lamin A/C localizes to the nuclear interior in interphase, forming a lamin A/C pool with specific properties and distinct functions. Nucleoplasmic lamin A/C molecular functions are mainly dependent on its binding partners; therefore, revealing new interactions could give us new clues on the lamin A/C mechanism of action. In the present study, we show that lamin A/C interacts with nuclear phosphoinositides (PIPs), and with nuclear myosin I (NM1). Both NM1 and nuclear PIPs have been previously reported as important regulators of gene expression and DNA damage/repair. Furthermore, phosphorylated lamin A/C forms a complex with NM1 in a phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2)-dependent manner in the nuclear interior. Taken together, our study reveals a previously unidentified interaction between phosphorylated lamin A/C, NM1, and PI(4,5)P2 and suggests new possible ways of nucleoplasmic lamin A/C regulation, function, and importance for the formation of functional nuclear microdomains.
- MeSH
- buněčné jádro * metabolismus MeSH
- interfáze MeSH
- intermediární filamenta metabolismus MeSH
- lamin typ A * metabolismus MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Neurofilament light (NfL) levels reflect inflammatory disease activity in multiple sclerosis (MS), but it is less clear if NfL also can serve as a biomarker for MS progression in treated patients without relapses and focal lesion accrual. In addition, it has not been well established if clinically effective treatment re-establishes an age and sex pattern for cerebrospinal fluid NfL (cNfL) as seen in controls, and to what degree levels are affected by disability level and magnetic resonance imaging (MRI) atrophy metrics. METHODS: We included subjects for whom cNfL levels had been determined as per clinical routine or in clinical research, classified as healthy controls (HCs, n = 89), MS-free disease controls (DCs, n = 251), untreated MS patients (uMS; n = 296), relapse-free treated MS patients (tMS; n = 78), and ProTEct-MS clinical trial participants (pMS; n = 41). RESULTS: Using linear regression, we found a positive association between cNfL and age, as well as lower concentrations among women, in all groups, except for uMS patients. In contrast, disability level in the entire MS cohort, or T1 and T2 lesion volumes, brain parenchymal fraction, thalamic fraction, and cortical thickness in the pMS trial cohort, did not correlate with cNfL concentrations. Furthermore, the cNfL levels in tMS and pMS groups did not differ. CONCLUSIONS: In participants with MS lacking signs of inflammatory disease activity, disease modulatory therapy reinstates an age and sex cNfL pattern similar to that of control subjects. No significant association was found between cNfL levels and clinical worsening, disability level, or MRI metrics.
- MeSH
- biologické markery mozkomíšní mok MeSH
- demografie MeSH
- intermediární filamenta patologie MeSH
- lidé MeSH
- magnetická rezonanční tomografie MeSH
- relabující-remitující roztroušená skleróza * MeSH
- roztroušená skleróza * diagnostické zobrazování MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Misdiagnosis is frequent in early motor neuron disease (MND), typically compressive radiculopathy, or in patients with restricted MND phenotype. In this retrospective, single tertiary centre study, we measured levels of neurofilament light (NfL) and phosphorylated neurofilament heavy (p-NfH) chain in cerebrospinal fluid (CSF) and of p-NfH in serum with commercially available ELISA kits and assessed their respective diagnostic performance as a marker of MND. The entire study population (n = 164) comprised 71 MND patients, 30 patients with compressive myelo- or radiculopathy, and 63 disease controls (DC). Among MND patients, we specified subgroups with only lower motoneuron involvement (MND-LMN, n = 15) and with confounding nerve roots or spinal cord compression (MND-C, n = 18), representing clinical diagnostic pitfalls. MND-LMN displayed significantly lower CSF NfL (p = 0.003) and p-NFH (p = 0.017), but not serum p-NfH (p = 0.347) levels compared to other MND patients (n = 56). The discriminative ability (area under the curve-AUC) of both CSF Nfs towards all MND patients was comparable to each other but significantly higher than that of p-NfH in serum (ps < 0.001). AUC of both CSF Nfs between MND-LMN and DC and also between MND-C and myelo-/radiculopathies were reduced, as compared to AUC between other MND and DC or myelo-/radiculopathies, respectively. Our results suggest that both Nfs in CSF represent a reliable diagnostic marker in a general MND population, fulfilling Awaji criteria. As for diagnostic pitfalls, and also for p-NfH in serum, their discriminative ability and, therefore, clinical utility appears to be limited.
- MeSH
- biologické markery krev MeSH
- intermediární filamenta * MeSH
- lidé MeSH
- roztroušená skleróza * krev prevence a kontrola MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- směrnice pro lékařskou praxi MeSH
- Geografické názvy
- Slovenská republika MeSH
Intermediate filaments (IFs) are essential constituents of the metazoan cytoskeleton. A vast family of cytoplasmic IF proteins are capable of self-assembly from soluble tetrameric species into typical 10-12 nm wide filaments. The primary structure of these proteins includes the signature central 'rod' domain of ~ 300 residues which forms a dimeric α-helical coiled coil composed of three segments (coil1A, coil1B and coil2) interconnected by non-helical, flexible linkers (L1 and L12). The rod is flanked by flexible terminal head and tail domains. At present, the molecular architecture of mature IFs is only poorly known, limiting our capacity to rationalize the effect of numerous disease-related mutations found in IF proteins. Here we addressed the molecular structure of soluble vimentin tetramers which are formed by two antiparallel, staggered dimers with coil1B domains aligned (A11 tetramers). By examining a series of progressive truncations, we show that the presence of the coil1A domain is essential for the tetramer formation. In addition, we employed a novel chemical cross-linking pipeline including isotope labelling to identify intra- and interdimeric cross-links within the tetramer. We conclude that the tetramer is synergistically stabilized by the interactions of the aligned coil1B domains, the interactions between coil1A and the N-terminal portion of coil2, and the electrostatic attraction between the oppositely charged head and rod domains. Our cross-linking data indicate that, starting with a straight A11 tetramer, flexibility of linkers L1 and L12 enables 'backfolding' of both the coil1A and coil2 domains onto the tetrameric core formed by the coil1B domains. Through additional small-angle X-ray scattering experiments we show that the elongated A11 tetramers dominate in low ionic strength solutions, while there is also a significant structural flexibility especially in the terminal domains.
OBJECTIVE: To investigate relationships between serum neurofilament light chain (sNfL), ubiquitin C-terminal hydrolase L1 (sUCHL1), tau (sTau) and glial fibrillary acidic protein (sGFAP) levels and disease activity/disability in neuromyelitis optica spectrum disorder (NMOSD), and the effects of inebilizumab on these biomarkers in N-MOmentum. METHODS: N-MOmentum randomised participants to receive inebilizumab or placebo with a randomised controlled period (RCP) of 28 weeks and an open-label follow-up period of ≥2 years. The sNfL, sUCHL1, sTau and sGFAP were measured using single-molecule arrays in 1260 scheduled and attack-related samples from N-MOmentum participants (immunoglobulin G (IgG) autoantibodies to aquaporin-4-positive, myelin oligodendrocyte glycoprotein-IgG-positive or double autoantibody-negative) and two control groups (healthy donors and patients with relapsing-remitting multiple sclerosis). RESULTS: The concentration of all four biomarkers increased during NMOSD attacks. At attack, sNfL had the strongest correlation with disability worsening during attacks (Spearman R2=0.40; p=0.01) and prediction of disability worsening after attacks (sNfL cut-off 32 pg/mL; area under the curve 0.71 (95% CI 0.51 to 0.89); p=0.02), but only sGFAP predicted upcoming attacks. At RCP end, fewer inebilizumab-treated than placebo-treated participants had sNfL>16 pg/mL (22% vs 45%; OR 0.36 (95% CI 0.17 to 0.76); p=0.004). CONCLUSIONS: Compared with sGFAP, sTau and sUCHL1, sNfL at attack was the strongest predictor of disability worsening at attack and follow-up, suggesting a role for identifying participants with NMOSD at risk of limited post-relapse recovery. Treatment with inebilizumab was associated with lower levels of sGFAP and sNfL than placebo. TRIAL REGISTRATION NUMBER: NCT02200770.
AIM: The aim of this study was to identify whether NfL and CXCL13 cerebrospinal fluid (CSF) concentrations at diagnostic lumbar puncture can predict the course of multiple sclerosis (MS) in terms of relapses, higher expanded disability status scale (EDSS) and magnetic resonance imaging (MRI) activity. METHODS: We conducted a single-centre prospective observational cohort study at the MS center, University Hospital Ostrava, Czech Republic. CSF NfL (cNfL) and CXCL13 concentrations were examined (ELISA method) in patients with clinically isolated syndrome (CIS) and relapsing-remitting MS (RRMS) at the time of diagnostic lumbar puncture. RESULTS: A total of 44 patients with CIS or early RRMS were enrolled, 31 (70.5%) of whom were women. The median age at the time of CSF sampling was 31.21 years (IQR 25.43-39.32), and the follow-up period was 54.6 months (IQR 44.03-59.48). In the simple and multiple logistic regression models, CXCL13 levels did not predict relapses, MRI activity or EDSS > 2.5. Similarly, cNfL concentrations did not predict relapses or MRI activity in either model. In the multiple regression, higher cNfL levels were associated with reaching EDSS > 2.5 (odds ratio [OR] 1.002, 95% confidence interval [CI] 1.000 to 1.003). CONCLUSIONS: Our data did not confirm cNfL and/or CXCL13 CSF levels were predictive factors for disease activity such as relapses and MRI activity at the time of diagnostic lumbar puncture in patients with RRMS. While cNfL CSF levels predicted higher disability only after adjustment for other known risk factors, elevated CSF CXCL13 did not predict higher disability at all.
- MeSH
- biologické markery mozkomíšní mok MeSH
- chemokin CXCL13 MeSH
- dospělí MeSH
- intermediární filamenta MeSH
- lidé MeSH
- progrese nemoci MeSH
- prospektivní studie MeSH
- recidiva MeSH
- relabující-remitující roztroušená skleróza * diagnostické zobrazování mozkomíšní mok MeSH
- roztroušená skleróza * diagnóza mozkomíšní mok MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- pozorovací studie MeSH
BACKGROUND: Serum neurofilaments (sNfs), especially the most investigated serum neurofilament light chain (sNfL), are promising biomarkers in multiple sclerosis (MS). However, their clinical utility is still limited, given the availability and costs of accessible analytical methods. The gold standard for the detection of sNfs is represented by the single molecule arrays (SIMOA). Recently, a high sensitivity enzyme-linked immunosorbent assay (hsELISA) has also been introduced. The objective of the study was to compare both assays for the determination of sNfL and neurofilament heavy chain (sNfH) concentrations in a defined MS cohort. The second objective was to identify contributing factors to sNfs concentrations determined by hsELISA. METHODS: Serum samples were collected from MS patients attending the MS Centre, University Hospital Ostrava, Czech Republic. The levels of sNfs were detected using SIMOA and hsELISA assays. RESULTS: The Spearman's rank correlation coefficient between the sNfL SIMOA and sNfL hsELISA and between the sNfH SIMOA and sNfH hsELISA was moderate rs= 0.543 (p = 0.001) and rs= 0.583 (p = 0.001), respectively. The Passing-Bablok regression analysis demonstrated bias between both methods. Equally significant bias between the methods was confirmed by the Bland-Altman plots. Furthermore, confounding factors affecting the sNfL levels were glomerular filtration rate (eGFR; 95% CI -2.34 to -0.04) and sex (95% CI -2.38 to -0.10). The sNfH levels were affected by age (95% CI 0.01 to 0.07), eGFR (95% CI -2.45 to -0.02), body mass index (BMI; 95% CI -0.31 to -0.05), and blood volume (95% CI 0.69 to 3.35). CONCLUSION: This analytical study showed significant differences between hsELISA and SIMOA methods, especially for the sNfH concentrations. We identified confounding factors for sNfs levels determined by hsELISA. The sNfs levels were influenced by renal function and sex, whilst sNfH levels were affected by age, BMI, and total blood volume.
- MeSH
- biologické markery MeSH
- ELISA MeSH
- intermediární filamenta * MeSH
- lidé MeSH
- roztroušená skleróza * diagnóza MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
Extensive axonal and neuronal loss is the main cause of severe manifestations and poor outcomes in tick-borne encephalitis (TBE). Phosphorylated neurofilament heavy subunit (pNF-H) is an essential component of axons, and its detection in cerebrospinal fluid (CSF) or serum can indicate the degree of neuroaxonal damage. We examined the use of pNF-H as a biomarker of neuroaxonal injury in TBE. In 89 patients with acute TBE, we measured CSF levels of pNF-H and 3 other markers of brain injury (glial fibrillary acidic protein, S100B and ubiquitin C-terminal hydrolase L1) and compared the results to those for patients with meningitis of other aetiology and controls. Serum pNF-H levels were measured in 80 patients and compared with findings for 90 healthy blood donors. TBE patients had significantly (P<0.001) higher CSF pNF-H levels than controls as early as hospital admission. Serum pNF-H concentrations were significantly higher in samples from TBE patients collected at hospital discharge (P<0.0001) than in controls. TBE patients with the highest peak values of serum pNF-H, exceeding 10 000 pg ml-1, had a very severe disease course, with coma or tetraplegia. Patients requiring intensive care had significantly higher serum pNF-H levels than other TBE patients (P<0.01). Elevated serum pNF-H values were also observed in patients with incomplete recovery (P<0.05). Peak serum pNF-H levels correlated positively with the duration of hospitalization (P=0.005). Measurement of pNF-H levels in TBE patients might be useful for assessing disease severity and determining prognosis.
- MeSH
- biologické markery MeSH
- intermediární filamenta MeSH
- klíšťová encefalitida * diagnóza MeSH
- lidé MeSH
- prognóza MeSH
- progrese nemoci MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
