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Full recovery from spinal cord injury requires axon regeneration to re-establish motor and sensory pathways. In mammals, the failure of sensory and motor axon regeneration has many causes intrinsic and extrinsic to neurons, amongst which is the lack of adhesion molecules needed to interact with the damaged spinal cord. This study addressed this limitation by expressing the integrin adhesion molecule α9, along with its activator kindlin-1, in sensory neurons via adeno-associated viral (AAV) vectors. This enabled sensory axons to regenerate through spinal cord injuries and extend to the brainstem, restoring sensory pathways, touch sensation and sensory behaviours. One of the integrin ligands in the injured spinal cord is tenascin-C, which serves as a substrate for α9β1 integrin, a key receptor in developmental axon guidance. However, the adult PNS and CNS neurons lack this receptor. Sensory neurons were transduced with α9 integrin (which pairs with endogenous β1 to form a α9β1 tenascin receptor) together with the integrin activator kindlin-1. Regeneration from sensory neurons transduced with α9integrin and kindlin-1 was examined after C4 and after T10 dorsal column lesions with C6,7 and L4,5 sensory ganglia injected with AAV1 vectors. In animals treated with α9 integrin and kindlin-1, sensory axons regenerated through tenascin-C-expressing connective tissue strands and bridges across the lesions and then re-entered the CNS tissue. Many axons regenerated rostrally to the level of the medulla. Axons grew through the dorsal grey matter rather than their normal pathway the dorsal columns. Growth was slow, axons taking 12 weeks to grow from T10 to the medulla, a distance of 4-5 cm. Functional recovery was confirmed through cFos activation in neurons rostral to the injury after nerve stimulation and VGLUT1/2 staining indicating new synapse formation above the lesion. Behavioural recovery was seen in both heat and mechanical sensation, as well as tape removal tests. This approach demonstrates the potential of integrin-based therapies for long distance sensory axon regeneration and functional recovery following thoracic and partial recovery after cervical spinal cord injury.
- MeSH
- axony MeSH
- Dependovirus genetika MeSH
- genetické vektory MeSH
- krysa rodu rattus MeSH
- modely nemocí na zvířatech MeSH
- myši MeSH
- nervové receptory * metabolismus fyziologie patologie MeSH
- obnova funkce fyziologie MeSH
- poranění míchy * patologie patofyziologie metabolismus MeSH
- potkani Sprague-Dawley MeSH
- proteiny nervové tkáně metabolismus genetika MeSH
- regenerace nervu * fyziologie MeSH
- tenascin metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
The distribution and morphology of neuronal degeneration were observed and analyzed in each sector of the zona incerta in a lithium‐pilocarpine (LiCl) Wistar rat model of status epilepticus in 12, 15, 18, 21, and 25‐day‐old rats and survival intervals of 4, 8, 12, 24, and 48 hours. Status epilepticus was induced via intraperitoneal (IP) injection of LiCl (3 mmol/kg) 24 hours before an injection of pilocarpine (40 mg/kg, IP). Motor seizures were suppressed by paraldehyde (0.3‐0.6 ml/kg, IP) two hours after status epilepticus onset. Animals were anesthetized using urethane and perfused with phosphate‐buffered saline followed by 4% paraformaldehyde. Brains were sectioned and Nissl stained for map guidance, with fluoro‐Jade B fluorescence used to detect degenerated neurons. Fluoro‐jade B‐positive neurons were plotted to a standard stereotaxic atlas, their distribution was quantified, and their long‐axis diameter was measured. Fluoro‐jade B‐positive neurons were found in pups aged 15 days and older 24 hours after status epilepticus, in which their numbers increased, and their perikaryon size decreased with advancing age. Thus, neuronal damage severity was dependent on age and survival interval. Neuronal damage was only found in the rostral sector of the zona incerta, a region that exhibits a small number of inhibitory neurons and is reciprocally connected to the limbic cortex. This system of hyperactivity, coupled with inhibitory neurons, may be the underlying cause of the neuronal degeneration and explain why it was confined to the rostral sector of the zona incerta.
- MeSH
- chlorid lithný toxicita MeSH
- degenerace nervu * patologie etiologie MeSH
- fluoresceiny MeSH
- krysa rodu rattus MeSH
- modely nemocí na zvířatech MeSH
- neurony * patologie MeSH
- novorozená zvířata MeSH
- pilokarpin toxicita MeSH
- potkani Wistar MeSH
- status epilepticus * patologie chemicky indukované komplikace MeSH
- věkové faktory MeSH
- zona incerta * patologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Úvod: Zduření v oblasti hlavy a krku je častým nálezem v otorinolaryngologii. Jeho přesná a časná diagnostika je předpokladem úspěšné léčby, především v případě zhoubných nádorů. Běžně je tenkojehlová aspirační biopsie (FNAB – fine-needle aspiration biopsy) zatížena vysokým počtem nediagnostických vzorků, zatímco otevřená biopsie představuje výkon s vyšším rizikem komplikací a nezřídka nutností hospitalizace. Biopsie tlustou jehlou (CNB – core-needle biopsy) představuje nejméně invazivní metodu k získání tkáně k histologickému vyšetření. Materiál a metodika: V retrospektivní studii bylo hodnoceno celkem 70 CNB u 62 pacientů v období 6/2020–12/2022 s cílem stanovit senzitivitu a specificitu CNB při diagnostice neoplazií v oblasti hlavy a krku. Všechny CNB v souboru byly provedeny otorinolaryngologem. Výsledky: V celém souboru jsme dosáhli senzitivity a specificity ve stanovení neoplazie 69,5 % a 90,9 %. Pro maligní nádor tyto hodnoty činily 53,9 %, resp. 100 %. V případě spinocelulárního karcinomu byla senzitivita 83,3 % a specificita 100 % Pro diagnózu lymfomu jsme dosáhli hodnot 33,3 % pro senzitivitu a 100 % pro specificitu. V oblasti slinných žláz byla neoplazie pomocí CNB diagnostikována se senzitivitou 74,3 % a specificitou 87,5 %. Zaznamenali jsme jedinou komplikaci v podobě krátkodobé dysfunkce lícního nervu. Závěr: Námi dosažené výsledky ukazují na potenciál CNB v diagnostice nádorů v oblasti hlavy a krku. V případě stanovení diagnózy spinocelulárního karcinomu dosahuje vysoké specificity, zatímco u lymfomů ji limituje nízká senzitivita. Ultrazvuková navigace je výhodou především u malých a špatně hmatných lézí.
Introduction: A neck lump is a common finding in ENT practice. Its early and precise diagnostics are the corner stone for successful treatment, especially in cases of malignant tumours. Commonly used fine-needle aspiration biopsy has a high rate of non-diagnostic results, while open surgical biopsy poses a procedure with a higher incidence of complications and the necessity of hospital admission. Core-needle biopsy (CNB) represents the least invasive method of obtaining a tissue sample sufficient for histological examination. Methods: In our retrospective study, we investigated 70 CNBs taken from 62 patients between 6/2020 to 12/2022. The outcome measures were the sensitivity and specificity of CNB in diagnosing neoplasia of the head and neck. All CNBs were performed by an otorhinolaryngologist. Results: In the entire cohort, the sensitivity and specificity for neoplasia were 69.5% and 90.9%, respectively. For malignancy, the sensitivity was 53.9% and the specificity was 100%. In cases of squamous cell carcinoma, we reached 83.3% for sensitivity and 100% for specificity. For lymphoma, the sensitivity and specificity were 33.3% and 100%, respectively. CNB sensitivity and specificity for salivary neoplasia were 74. % and 87.5%, respectively. We encoutered a single complication, i.e. temporary paresis of the facial nerve, which resolved spontaneously soon afterwards. Conclusion: Our results underline the potential of CNB in diagnosing head and neck neoplasias. It is highly specific for squamous cell carcinoma, while it lacks sufficient sensitivity for lymphomas. Ultrasound guidance is recommended especially for small and impalpable lessions.
- Klíčová slova
- biopsie tlustou jehlou,
- MeSH
- biopsie metody MeSH
- lidé MeSH
- nádory hlavy a krku * diagnóza MeSH
- retrospektivní studie MeSH
- Check Tag
- lidé MeSH
AIM: In 2005-2006, a chikungunya epidemic of unprecedented magnitude hit Reunion Island, which raised a public health concern through the substantial proportions of long-lasting manifestations. To understand the pathophysiology underlying chronic chikungunya (CC), we designed the CHIKGene cohort study and collected blood samples from 133 subjects diagnosed with CC and from 86 control individuals that had recovered within 3 months, 12-to-15 years after exposure. METHODS: We conducted bulk RNAseq analysis on peripheral blood mononuclear cells to find differentially expressed genes (DEGs), gene set enrichment analysis (GSEA) and gene ontologies to uncover top-level enriched terms associated with DEGs, and weighted gene correlation network analysis (WGCNA) to elucidate underlying cellular processes. RESULTS: Among 1549 DEGs, gene expression analysis identified 10 top genes including NR4A2 and TRIM58 (upregulated in CC), IGHG3 and IGHV3-49 (downregulated in CC) linked to immune regulation, OSBP2 (upregulated in CC) and SEMA6B (downregulated in CC) linked to neuronal homeostasis and axon guidance, respectively. GSEA and WGCNA unveiled cellular processes such as "Metabolism of RNA" and "Cell Cycle". CONCLUSIONS: This study uncovers a shift in gene expression of CC subjects. IGHG3 and IGHV3-49 gene shut-offs spotlight the importance of neutralizing antibodies against chikungunya virus in the progression to chronic disease. Human diseases associations highlight connections to rheumatoid arthritis, nervous and cardiac systems. GSEA and WGCNA bounce the hypotheses of a persistent viral reservoir or an increased susceptibility to RNA viral pathogens with new onset infections. Together, our findings might offer potential targets for therapeutic options aimed at alleviating chronic chikungunya.
- MeSH
- chronická nemoc MeSH
- dospělí MeSH
- horečka chikungunya * genetika epidemiologie virologie MeSH
- kohortové studie MeSH
- leukocyty mononukleární MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
- stanovení celkové genové exprese MeSH
- transkriptom * MeSH
- virus chikungunya MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Réunion MeSH
During hypoxia, tissues are subjected to an inadequate oxygen supply, disrupting the balance needed to maintain normal function. This deficiency can occur due to reduced oxygen delivery caused by impaired blood flow or a decline in the blood's ability to carry oxygen. In tumors, hypoxia and vascularization play crucial roles, shaping their microenvironments and influencing cancer progression, response to treatment and metastatic potential. This chapter provides guidance on the use of non-invasive imaging methods including Positron Emission Tomography and Magnetic Resonance Imaging to study tumor oxygenation in pre-clinical settings. These imaging techniques offer valuable insights into tumor vascularity and oxygen levels, aiding in understanding tumor behavior and treatment effects. For example, PET imaging uses tracers such as [18F]-fluoromisonidazole (FMISO) to visualize hypoxic areas within tumors, while MRI complements this with anatomical and functional images. Although directly assessing tumor hypoxia with MRI remains challenging, techniques like Blood Oxygen Level Dependent (BOLD) and Dynamic Contrast-Enhanced MRI (DCE-MRI) provide valuable information. BOLD can track changes in oxygen levels during oxygen challenges, while DCE-MRI offers real-time access to perfusion and vessel permeability data. Integrating data from these imaging modalities can help assess oxygen supply, refine treatment strategies, enhance therapeutic effectiveness, and ultimately improve patient outcomes.
- MeSH
- hypoxie diagnostické zobrazování MeSH
- kyslík metabolismus MeSH
- lidé MeSH
- magnetická rezonanční tomografie * metody MeSH
- misonidazol analogy a deriváty MeSH
- myši MeSH
- nádorová hypoxie MeSH
- nádory diagnostické zobrazování krevní zásobení patologie MeSH
- patologická angiogeneze diagnostické zobrazování patologie MeSH
- pozitronová emisní tomografie * metody MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
MICAL proteins play a crucial role in cellular dynamics by binding and disassembling actin filaments, impacting processes like axon guidance, cytokinesis, and cell morphology. Their cellular activity is tightly controlled, as dysregulation can lead to detrimental effects on cellular morphology. Although previous studies have suggested that MICALs are autoinhibited, and require Rab proteins to become active, the detailed molecular mechanisms remained unclear. Here, we report the cryo-EM structure of human MICAL1 at a nominal resolution of 3.1 Å. Structural analyses, alongside biochemical and functional studies, show that MICAL1 autoinhibition is mediated by an intramolecular interaction between its N-terminal catalytic and C-terminal coiled-coil domains, blocking F-actin interaction. Moreover, we demonstrate that allosteric changes in the coiled-coil domain and the binding of the tripartite assembly of CH-L2α1-LIM domains to the coiled-coil domain are crucial for MICAL activation and autoinhibition. These mechanisms appear to be evolutionarily conserved, suggesting a potential universality across the MICAL family.
- MeSH
- aktiny metabolismus chemie MeSH
- alosterická regulace MeSH
- calponiny MeSH
- elektronová kryomikroskopie * MeSH
- lidé MeSH
- mikrofilamenta metabolismus ultrastruktura MeSH
- mikrofilamentové proteiny metabolismus chemie ultrastruktura MeSH
- molekulární modely MeSH
- oxygenasy se smíšenou funkcí MeSH
- proteinové domény MeSH
- proteiny s doménou LIM metabolismus chemie genetika MeSH
- vazba proteinů * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Structural neuroplasticity such as neurite extension and dendritic spine dynamics is enhanced by brain-derived neurotrophic factor (BDNF) and impaired by types of inhibitory molecules that induce growth cone collapse and actin depolymerization, for example, myelin-associated inhibitors, chondroitin sulfate proteoglycans, and negative guidance molecules. These inhibitory molecules can activate RhoA/rho-associated coiled-coil containing protein kinase (ROCK) signaling (known to restrict structural plasticity). Intermittent hypoxia (IH) and high-intensity interval training (HIIT) are known to upregulate BDNF that is associated with improvements in learning and memory and greater functional recovery following neural insults. We investigated whether the RhoA/ROCK signaling pathway is also modulated by IH and HIIT in the hippocampus, cortex, and lumbar spinal cord of male Wistar rats. The gene expression of 25 RhoA/ROCK signaling pathway components was determined following IH, HIIT, or IH combined with HIIT (30 min/day, 5 days/wk, 6 wk). IH included 10 3-min bouts that alternated between hypoxia (15% O2) and normoxia. HIIT included 10 3-min bouts alternating between treadmill speeds of 50 cm·s-1 and 15 cm·s-1. In the hippocampus, IH and HIIT significantly downregulated Acan and NgR2 mRNA that are involved in the inhibition of neuroplasticity. However, IH and IH + HIIT significantly upregulated Lingo-1 and NgR3 in the cortex. This is the first time IH and HIIT have been linked to the modulation of plasticity-inhibiting pathways. These results provide a fundamental step toward elucidating the interplay between the neurotrophic and inhibitory mechanisms involved in experience-driven neural plasticity that will aid in optimizing physiological interventions for the treatment of cognitive decline or neurorehabilitation.NEW & NOTEWORTHY Intermittent hypoxia (IH) and high-intensity interval training (HIIT) enhance neuroplasticity and upregulate neurotrophic factors in the central nervous system (CNS). We provide evidence that IH and IH + HIIT also have the capacity to regulate genes involved in the RhoA/ROCK signaling pathway that is known to restrict structural plasticity in the CNS. This provides a new mechanistic insight into how these interventions may enhance hippocampal-related plasticity and facilitate learning, memory, and neuroregeneration.
- MeSH
- hipokampus * metabolismus MeSH
- hypoxie metabolismus patofyziologie MeSH
- kinázy asociované s rho * metabolismus genetika MeSH
- krysa rodu rattus MeSH
- mícha metabolismus fyziologie MeSH
- mozková kůra metabolismus fyziologie MeSH
- neuroplasticita fyziologie MeSH
- potkani Wistar * MeSH
- rho proteiny vázající GTP MeSH
- rhoA protein vázající GTP metabolismus MeSH
- signální transdukce * fyziologie MeSH
- vysoce intenzivní intervalový trénink * MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Chimeric antigen receptor (CAR) T-cell therapy has shown promise in patients with late-line refractory multiple myeloma, with response rates ranging from 73 to 98%. To date, three products have been approved: Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), which are approved by the US Food and Drug Administration, the European Medicines Agency, Health Canada (ide-cel only), and Brazil ANVISA (cilta-cel only); and equecabtagene autoleucel (eque-cel), which was approved by the Chinese National Medical Products Administration. CAR T-cell therapy is different from previous anti-myeloma therapeutics with unique toxic effects that require distinct mitigation strategies. Thus, a panel of experts from the International Myeloma Working Group was assembled to provide guidance for clinical use of CAR T-cell therapy in myeloma. This consensus opinion is from experts in the field of haematopoietic cell transplantation, cell therapy, and multiple myeloma therapeutics.
- MeSH
- chimerické antigenní receptory * imunologie terapeutické užití MeSH
- imunoterapie adoptivní * škodlivé účinky MeSH
- konsensus * MeSH
- lidé MeSH
- mnohočetný myelom * terapie imunologie MeSH
- receptory antigenů T-buněk terapeutické užití imunologie MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- směrnice pro lékařskou praxi MeSH
Experts from the European Leukemia Net (ELN) working group for adult acute lymphoblastic leukemia have identified an unmet need for guidance regarding management of adult acute lymphoblastic leukemia (ALL) from diagnosis to aftercare. The group has previously summarized their recommendations regarding diagnostic approaches, prognostic factors, and assessment of ALL. The current recommendation summarizes clinical management. It covers treatment approaches, including the use of new immunotherapies, application of minimal residual disease for treatment decisions, management of specific subgroups, and challenging treatment situations as well as late effects and supportive care. The recommendation provides guidance for physicians caring for adult patients with ALL which has to be complemented by regional expertise preferably provided by national academic study groups.
- MeSH
- akutní lymfatická leukemie * terapie diagnóza MeSH
- dospělí MeSH
- lidé MeSH
- management nemoci MeSH
- prognóza MeSH
- reziduální nádor diagnóza terapie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- směrnice pro lékařskou praxi MeSH
- Geografické názvy
- Evropa MeSH
Working groups of the European LeukemiaNet have published several important consensus guidelines. Acute lymphoblastic leukemia (ALL) has many different clinical and biological subgroups and the knowledge on disease biology and therapeutic options is increasing exponentially. The European Working Group for Adult ALL has therefore summarized the current state of the art and provided comprehensive consensus recommendations for diagnostic approaches, biologic and clinical characterization, prognostic factors, and risk stratification as well as definitions of endpoints and outcomes. Aspects of treatment, management of subgroups and specific situations, aftercare, and supportive care are covered in a separate publication. The present recommendation intends to provide guidance for the initial management of adult patients with ALL and to define principles as a basis for future collaborative research.
