Precursor
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- MeSH
- dikumarol terapeutické užití MeSH
- hemokoagulace účinky léků MeSH
- heparin MeSH
- lidé MeSH
- protrombin krev MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- srovnávací studie MeSH
Tau, as a microtubule (MT)-associated protein, participates in key neuronal functions such as the regulation of MT dynamics, axonal transport, and neurite outgrowth. Alternative splicing of exon 10 in the tau primary transcript gives rise to protein isoforms with three (3R) or four (4R) MT binding repeats. Although tau isoforms are balanced in the normal adult human brain, imbalances in 3R:4R ratio have been tightly associated with the pathogenesis of several neurodegenerative disorders, yet the underlying molecular mechanisms remain elusive. Several studies exploiting tau overexpression and/or mutations suggested that perturbations in tau metabolism impair axonal transport. Nevertheless, no physiological model has yet demonstrated the consequences of altering the endogenous relative content of tau isoforms over axonal transport regulation. Here, we addressed this issue using a trans-splicing strategy that allows modulating tau exon 10 inclusion/exclusion in differentiated human-derived neurons. Upon changes in 3R:4R tau relative content, neurons showed no morphological changes, but live imaging studies revealed that the dynamics of the amyloid precursor protein (APP) were significantly impaired. Single trajectory analyses of the moving vesicles showed that predominance of 3R tau favored the anterograde movement of APP vesicles, increasing anterograde run lengths and reducing retrograde runs and segmental velocities. Conversely, the imbalance toward the 4R isoform promoted a retrograde bias by a significant reduction of anterograde velocities. These findings suggest that changes in 3R:4R tau ratio has an impact on the regulation of axonal transport and specifically in APP dynamics, which might link tau isoform imbalances with APP abnormal metabolism in neurodegenerative processes. SIGNIFICANCE STATEMENT: The tau protein has a relevant role in the transport of cargos throughout neurons. Dysfunction in tau metabolism underlies several neurological disorders leading to dementia. In the adult human brain, two tau isoforms are found in equal amounts, whereas changes in such equilibrium have been associated with neurodegenerative diseases. We investigated the role of tau in human neurons in culture and found that perturbations in the endogenous balance of tau isoforms were sufficient to impair the transport of the Alzheimer's disease-related amyloid precursor protein (APP), although neuronal morphology was normal. Our results provide evidence of a direct relationship between tau isoform imbalance and defects in axonal transport, which induce an abnormal APP metabolism with important implications in neurodegeneration.
- MeSH
- amyloidový prekurzorový protein beta metabolismus MeSH
- axonální transport fyziologie MeSH
- kultivované buňky MeSH
- lidé MeSH
- myši MeSH
- neurony metabolismus ultrastruktura MeSH
- protein - isoformy MeSH
- proteiny tau metabolismus MeSH
- tauopatie metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
B-cell precursors (BCP) arise from hematopoietic stem cells in bone marrow (BM). Identification and characterization of the different BCP subsets has contributed to the understanding of normal B-cell development. BCP first rearrange their immunoglobulin (Ig) heavy chain (IGH) genes to form the pre-B-cell receptor (pre-BCR) complex together with surrogate light chains. Appropriate signaling via this pre-BCR complex is followed by rearrangement of the Ig light chain genes, resulting in the formation, and selection of functional BCR molecules. Consecutive production, expression, and functional selection of the pre-BCR and BCR complexes guide the BCP differentiation process that coincides with corresponding immunophenotypic changes. We studied BCP differentiation in human BM samples from healthy controls and patients with a known genetic defect in V(D)J recombination or pre-BCR signaling to unravel normal immunophenotypic changes and to determine the effect of differentiation blocks caused by the specific genetic defects. Accordingly, we designed a 10-color antibody panel to study human BCP development in BM by flow cytometry, which allows identification of classical preB-I, preB-II, and mature B-cells as defined via BCR-related markers with further characterization by additional markers. We observed heterogeneous phenotypes associated with more than one B-cell maturation pathway, particularly for the preB-I and preB-II stages in which V(D)J recombination takes place, with asynchronous marker expression patterns. Next Generation Sequencing of complete IGH gene rearrangements in sorted BCP subsets unraveled their rearrangement status, indicating that BCP differentiation does not follow a single linear pathway. In conclusion, B-cell development in human BM is not a linear process, but a rather complex network of parallel pathways dictated by V(D)J-recombination-driven checkpoints and pre-BCR/BCR mediated-signaling occurring during B-cell production and selection. It can also be described as asynchronous, because precursor B-cells do not differentiate as full population between the different stages, but rather transit as a continuum, which seems influenced (in part) by V-D-J recombination-driven checkpoints.
- MeSH
- buněčná diferenciace genetika imunologie MeSH
- dítě MeSH
- lidé MeSH
- prekurzorové B-lymfoidní buňky imunologie MeSH
- průtoková cytometrie metody MeSH
- receptory antigenů B-buněk genetika imunologie MeSH
- syndromy imunologické nedostatečnosti genetika imunologie MeSH
- těžké řetězce imunoglobulinů genetika MeSH
- V(D)J rekombinace genetika imunologie MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: Acute promyelocytic leukemia (APL) is a relatively rare subtype of acute myeloid leukemia. It has become the best curable subtype of acute leukemias in adults due to the inclusion of all-trans-retinoic acid (ATRA) in the treatment. Despite the efficacy of ATRA, chemotherapy must be added in APL patients in order to maintain durable complete remission. However, chemotherapy administration is inevitably related to many complications, including the risk of secondary malignancies. T-lymphoblastic lymphoma (T-LBL) is an infrequent disease that belongs to the group of highly aggressive lymphomas. CASE REPORT: The authors describe the case of a 25-year-old woman who was treated for APL in 2002 and developed precursor T-LBL 5 years later. CONCLUSION: Several cases of secondary acute lymphoblastic leukemias in 'cured' APL patients have been described, but probably no patient with secondary precursor T-LBL. Secondary malignancy has become one of the topics discussed (not only) in APL patients. It is apparently related to the excellent treatment outcomes and long-term survival. Better tailored treatment based on relevant prognostic factors allowing chemotherapy reduction or omission in some patients is needed.
The aberrantly expressed microRNAs (miRNAs) including miR-29c-3p have been reported in the brains of Alzheimer's disease (AD) patients in recent researches. Nevertheless, the functional role and underlying molecular mechanism of miR-29c-3p in AD pathogenesis are still not well elucidated. The purpose of this study was to examine whether miR-29c-3p regulated beta-Ameyloid (Abeta)-induced neurotoxicity by targeting beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1). The expressions of miR 29c 3p and BACE1 mRNA and protein levels in Abeta-treated PC12 cellular AD model were examined by qRT-PCR and western blot analyses. Luciferase reporter assay verified the potential target of miR 29c 3p. Cell viability, apoptosis, and caspase-3 activity in PC12 cells were detected by the MTT assay, flow cytometry, and caspase-3 activity assay, respectively. Our results indicated that miR-29c-3p downregulation and BACE1 upregulation existed in the cellular AD model of PC12 cells. Moreover, miR-29c-3p directly inhibited BACE1 expression. miR-29c-3p overexpression and BACE1 knockdown strengthened Abeta-induced cell apoptosis, and caspase-3 activity in PC12 cells, which was partially eliminated by over-expression of BACE1. Conversely, BACE1 knockdown reversed the miR-29c-3p inhibition- mediated inhibitory effect on Abeta-induced cell toxicity, apoptosis, and caspase-3 activity in PC12 cells. Considering, miR-29c-3p attenuated Abeta-induced neurotoxicity through targeting BACE1 in an cellular AD model of PC12, providing a potential therapeutic target for AD treatment.
- MeSH
- Alzheimerova nemoc * metabolismus MeSH
- amyloidní beta-protein toxicita genetika metabolismus MeSH
- amyloidový prekurzorový protein beta genetika metabolismus MeSH
- aspartátové endopeptidasy genetika metabolismus MeSH
- kaspasa 3 metabolismus MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- mikro RNA * genetika metabolismus MeSH
- nádorové buněčné linie MeSH
- sekretasy genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Východisko. Přestože byly již popsány bodové mutace v genu pro prekurzor amyloidního proteinu u nemocných s Alzheimerovou demencí, stále existuje část nemocných, u nichž nebyla tato mutace nalezena a nebyla rovněž nalezena vazba k dalším uvažovaným genetickým lokusům na chromozomech 14 a 19. Proto byla skupina osob s Alzheimerovou demencí podrobena testování na přítomnost mutace v APP genu (v pozici 717). Metody a výsledky. U vybrané skupiny osob s Alzheimerovou demencí (AD) jsou nacházeny mutace v genu pro prekurzor amyloidního proteinu v pozici 717 jeho transmembránové domény. Analyzovali jsme genomovou DNA mozkové tkáně osob české národnosti pro přítomnost této mutace pomocí polymerázové řetězové reakce s následným ověřením sekvenační analýzou. U každé osoby byla prováděna genetická analýza z mozkových oblastí lobus frontalis, lobus temporalis, lobus parietalis a hippocampus. Použité metody byly polymerázová řetězová reakce (PCR), sekvenace. Z celkového počtu 18 osob s prokázanou Alzheimerovou demencí a 6 nepříbuzných osob bez histopatologických znaků Alzheimerovy demence po 90. roce života, byly nalezeny 3 sekvenační změny v pozici 717 exonu 17 transmembránové domény prekurzoru beta-4 amyloidního glykoproteinu. V prvním případě se jednalo o záměnu thyminu za adenin v kodonu 717, ve druhém případě se jednalo o záměnu cytosinu za thymin, ve třetím případě byla nalezena sporadická mutace guaninu za thymin v kodonu 717. Závěry. Ukazuje se, že kodon 717 by mohl být tzv. hot-spot místem preferovaným pro přednostní vznik mutací v kodonu 717 genu pro amyloidní proteinový prekurzor (APP).
Background. Although locus mutations in the gene for the amyloid precursor protein were already described in patients with Alzheimer's disease, there still are some patients where this mutation was not found and no link was found with other possible genetic loci on chromosomes 14 and 19. Therefore a group of subjects with Alzheimer's disease was subjected to tests for the presence of a mutation in the APP gene (in position 717). Methods and Results. In a selected group of subjects with Alzheimer's disease (AD) in the gene for amyloid precursor protein in position 717 mutations of its transmembraneous region are found. The authors analyzed the genome DNA of cerebral tissue of Czech subjects for the presence of this mutation by means of the polymerase chain reaction with subsequent verification by sequencing analysis. In every subject genetic analyses from cerebral areas of the frontal lobe, temporal lobe, parietal lobe and hippocampus were performed. The methods used were the polymerase chain reaction (PCR) and sequencing. From the total number of 18 subjects with confirmed Alzheimer's disease and six non-related subjects without histopathological signs of Alzheimer's disease after the age of 90 years, three sequencing changes were found in position 717 of exon 17 of the transmembranous region of the precursor of beta-4 amyloid glycoprotein. In the first case it was substitution of thymin for adenine in codon 717, in the second case substitution of cytosine for thymine, in the third case a sporadic mutation of guanine for thymine in codon 717 was found. Conclusions. It was revealed that codon 717 could be a so-called hot spot site preferred for the preferential development of mutations in codon 717 in the gene for the amyloid precursor protein (APP).
BACKGROUND AND OBJECTIVE: Inotuzumab ozogamicin is an antibody-drug conjugate approved for treating relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in adults. Pediatric pharmacokinetic data of inotuzumab ozogamicin are lacking. This study is the first to examine the population pharmacokinetics of inotuzumab ozogamicin in pediatric patients with relapsed/refractory BCP-ALL. METHODS: From 531 adult patients with B-cell non-Hodgkin's lymphoma, 234 adult patients with BCP-ALL, and 53 pediatric patients with BCP-ALL, 8924 inotuzumab ozogamicin serum concentrations were analyzed using non-linear mixed-effects modeling. A published adult inotuzumab ozogamicin population-pharmacokinetic model, a two-compartment model with linear and time-dependent clearance, was adapted to describe the pediatric data. RESULTS: Modifications in this analysis, compared to the published adult model, included: (i) re-estimating pharmacokinetic parameters and covariate effects; (ii) modifying covariate representation; and (iii) introducing relevant pediatric covariate effects (age on the decay coefficient of time-dependent clearance and ALL effect (disease type and/or different bioanalytical analysis methods) on initial values of time-dependent clearance). For patients with relapsed/refractory BCP-ALL, increasing age was associated with a decreasing decay coefficient of time-dependent clearance, reflecting that the target-mediated drug clearance declines more rapidly in children. In pediatric BCP-ALL, the median [interquartile range] cumulative area under the concentration-time curve was significantly higher among responders (n = 42) versus non-responders (n = 10) at the end of the first cycle (26.1 [18.9-35.0] vs 10.1 [9.19-16.1], × 103 ng*h/mL, p < 0.001). From simulations performed at the recommended pediatric phase II dose, inotuzumab ozogamicin exposure reached a similar level as observed in responding pediatric trial participants. CONCLUSIONS: The pharmacokinetic profile of inotuzumab ozogamicin in pediatric patients with relapsed/refractory BCP-ALL was well described in this study. No dose adjustment is required clinically for pediatric patients with BCP-ALL based on the simulated inotuzumab ozogamicin exposure at the recommended pediatric phase II dose, promising efficacy and acceptable tolerability.
- MeSH
- biologické modely MeSH
- dítě MeSH
- dospělí MeSH
- inotuzumab ozogamicin * farmakokinetika aplikace a dávkování MeSH
- kojenec MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- pre-B-buněčná leukemie * farmakoterapie krev MeSH
- předškolní dítě MeSH
- protinádorové látky imunologicky aktivní * farmakokinetika aplikace a dávkování terapeutické užití MeSH
- recidiva MeSH
- senioři MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- kojenec MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
