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INTRODUCTION: Anti-amyloid antibodies for the treatment of Alzheimer ́s disease (AD) are currently being evaluated for approval and reimbursement in Europe. An approval brings opportunities, but also challenges to health care systems across Europe. The objective of this position paper is to provide guidance from experts in the field in terms of navigating implementation. METHODS: Members of the European Alzheimer's Disease Consortium and a representative of Alzheimer Europe convened to formulate recommendations covering key areas related to the possible implementation of anti-amyloid antibodies in AD through online discussions and 2 rounds of online voting with an 80% threshold for a position to be accepted. RESULTS: In total, 24 recommendations were developed covering the research landscape and priorities within research in AD following a possible approval, potential impact on health care systems and diagnostic pathways, and communication to patients about anti-amyloid antibodies. Anti-amyloid antibodies are regarded as a substantial innovation with an important clinical impact. In addition, however, new compounds with other mechanisms of action and/or route of administration are also needed. Approval of new treatments will require changes to existing patient pathways and real-world data needs to be generated. CONCLUSION: Comprehensive guidance is provided on the potential implementation of anti-amyloid antibody therapies in Europe following possible approval. Emphasis is placed on the necessity of regularly updating recommendations as new evidence emerges in the coming years.
- MeSH
- Alzheimerova nemoc * farmakoterapie terapie MeSH
- amyloidní beta-protein * imunologie MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Geografické názvy
- Evropa MeSH
Influenza is a significant global health problem, causing disease and hospitalisations in elderly individuals and infants. While updated vaccines are available every year, their effectiveness is moderate at best. FLUniversal is a European Union funded consortium, aiming to develop a universal influenza vaccine by bringing together partners with expertise in different areas of vaccine development. An intranasal live attenuated vaccine, DeltaFLU, will be produced using an innovative platform; preclinical assessment in animal models and clinical studies using a controlled human infection model (CHIM) will be conducted for assessment of safety, immunogenicity and protective efficacy; and finally, comprehensive immunological analysis of blood and nasal mucosa will elucidate vaccine responses and potential new correlates of protection (CoPs). In addition to a universal influenza vaccine, listed as a top priority by the EU, FLUniversal seeks to deliver an enhanced vaccine manufacturing technology that is superior in terms of efficiency, production costs and production speed - especially critical in the face of a potential new pandemic. Moreover, an influenza CHIM with a focus on harmonisation of clinical procedures and assays will be established to generate translatable and reproducible data. Newly generated knowledge on mechanisms of protection, CoPs and new molecular analysis tools may significantly contribute to our knowledge on influenza infection and influenza vaccines. In conclusion, FLUniversal is an innovative and ambitious public-private partnership, aiming to present a new development pathway for influenza vaccines, and maximising impact by bringing together leading partners from academy and industry with a shared purpose of collaboration and innovation.
- MeSH
- aplikace intranazální MeSH
- atenuované vakcíny imunologie aplikace a dávkování MeSH
- chřipka lidská * prevence a kontrola imunologie MeSH
- Evropská unie MeSH
- lidé MeSH
- partnerství veřejného a soukromého sektoru * MeSH
- vakcíny proti chřipce * imunologie aplikace a dávkování MeSH
- vývoj vakcíny * MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Alzheimer disease (AD) is a life-limiting neurodegenerative disorder that disproportionately affects women. Indeed, sex and gender are emerging as crucial modifiers of diagnostic and therapeutic pathways in AD. This Review provides an overview of the interactions of sex and gender with important developments in AD and offers insights into priorities for future research to facilitate the development and implementation of personalized approaches in the shifting paradigm of AD care. In particular, this Review focuses on the influence of sex and gender on important advances in the treatment and diagnosis of AD, including disease-modifying therapies, fluid-based biomarkers, cognitive assessment tools and multidomain lifestyle interventional studies.
- MeSH
- Alzheimerova nemoc * terapie diagnóza epidemiologie MeSH
- biologické markery MeSH
- lidé MeSH
- pohlavní dimorfismus * MeSH
- sexuální faktory MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
BACKGROUND: The progression and recurrence are the fatal prognostic factors in glioma patients. However, the therapeutic role and potential mechanism of TRAF7 in glioma patients remain largely unknown. METHODS: TRAF7 RNA-seq was analysed with the TCGA and CGGA databases between glioma tissues and normal brain tissues. The expression of TRAF7, cellular senescence and cell cycle arrest pathways in glioma tissues and cell lines was detected by real-time quantitative PCR (RT-qPCR), western blotting and immunohistochemistry. The interaction between TRAF7 and KLF4 was determined by Co-immunoprecipitation (Co-IP) assays. The functions of TRAF7 combined with lomustine in glioma were assessed by both in vitro, in vivo and patient-derived primary and recurrent glioma stem cell (GSC) assays. RESULTS: High TRAF7 expression is closely associated with a higher recurrence rate and poorer overall survival (OS). In vitro, TRAF7 knockdown significantly inhibits glioma cell proliferation, invasion, and migration. RNA-seq analysis revealed that TRAF7 inhibition activates pathways related to cellular senescence and cell cycle arrest. In both in vitro and patient-derived GSC assays, the combination of sh-TRAF7 and lomustine enhanced therapeutic efficacy by inducing senescence and G0/G1 cell cycle arrest, surpassing the effects of lomustine or TRAF7 inhibition alone. Mechanistically, TRAF7 interacts with KLF4, and a rescue assay demonstrated that KLF4 overexpression could reverse the effects of TRAF7 depletion on proliferation and cellular senescence. In vivo, TRAF7 knockdown combined with lomustine treatment effectively suppressed glioma growth. CONCLUSION: TRAF7 could be used as a predictive biomarker and the potential therapeutic target among National Comprehensive Cancer Network (NCCN) treatment guidelines in the progression and recurrence of glioma. Lomustine, regulating cellular senescence and cell cycle could be the priority choice in glioma patients with high-level TRAF7 expression.
- MeSH
- genový knockdown MeSH
- gliom * patologie genetika farmakoterapie metabolismus MeSH
- Krüppel-like faktor 4 MeSH
- lidé MeSH
- lokální recidiva nádoru * genetika patologie MeSH
- lomustin * farmakologie terapeutické užití MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádory mozku * patologie genetika farmakoterapie metabolismus MeSH
- peptidy a proteiny asociované s receptory TNF * genetika metabolismus MeSH
- prognóza MeSH
- progrese nemoci MeSH
- proliferace buněk MeSH
- regulace genové exprese u nádorů MeSH
- stárnutí buněk * účinky léků MeSH
- xenogenní modely - testy protinádorové aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Tunnels in enzymes with buried active sites are key structural features allowing the entry of substrates and the release of products, thus contributing to the catalytic efficiency. Targeting the bottlenecks of protein tunnels is also a powerful protein engineering strategy. However, the identification of functional tunnels in multiple protein structures is a non-trivial task that can only be addressed computationally. We present a pipeline integrating automated structural analysis with an in-house machine-learning predictor for the annotation of protein pockets, followed by the calculation of the energetics of ligand transport via biochemically relevant tunnels. A thorough validation using eight distinct molecular systems revealed that CaverDock analysis of ligand un/binding is on par with time-consuming molecular dynamics simulations, but much faster. The optimized and validated pipeline was applied to annotate more than 17,000 cognate enzyme-ligand complexes. Analysis of ligand un/binding energetics indicates that the top priority tunnel has the most favourable energies in 75% of cases. Moreover, energy profiles of cognate ligands revealed that a simple geometry analysis can correctly identify tunnel bottlenecks only in 50% of cases. Our study provides essential information for the interpretation of results from tunnel calculation and energy profiling in mechanistic enzymology and protein engineering. We formulated several simple rules allowing identification of biochemically relevant tunnels based on the binding pockets, tunnel geometry, and ligand transport energy profiles.Scientific contributionsThe pipeline introduced in this work allows for the detailed analysis of a large set of protein-ligand complexes, focusing on transport pathways. We are introducing a novel predictor for determining the relevance of binding pockets for tunnel calculation. For the first time in the field, we present a high-throughput energetic analysis of ligand binding and unbinding, showing that approximate methods for these simulations can identify additional mutagenesis hotspots in enzymes compared to purely geometrical methods. The predictor is included in the supplementary material and can also be accessed at https://github.com/Faranehhad/Large-Scale-Pocket-Tunnel-Annotation.git . The tunnel data calculated in this study has been made publicly available as part of the ChannelsDB 2.0 database, accessible at https://channelsdb2.biodata.ceitec.cz/ .
- Publikační typ
- časopisecké články MeSH
Revmatoidní artritida (RA) je nejčastější zánětlivé revmatické onemocnění postihující až 1 % populace, které prokazatelně zhoršuje kvalitu života. Bolest je obvykle označována za hlavní limitující symptom pacientů, může být přítomna neustále a úleva od ní je hodnocena jako nejvyšší priorita při zlepšování pocitu zdraví a kvality života. Bolest u RA má komplexní charakter, je způsobena více mechanismy a může být jak nociceptivního, tak neuropatického charakteru. Nociceptivní bolest, která u RA převažuje, vzniká na principu periferní senzitizace (zvýšení citlivosti periferních nervů) působením na periferní nervová zakončení, která jsou drážděna lokálními působky (zánětlivými cytokiny a dalšími mediátory) produkovanými imunitními buňkami a buňkami poškozené tkáně v místě zánětu. Mezi tyto působky řadíme prostaglandiny (zejména prostaglandin E2), interleukin-1, interleukin-6 a cyklooxygenázu typu 1 i 2. Přímý vliv na volná nervová zakončení mají dále kalium, bradykinin a serotonin. Zmíněné působky vedou k podráždění nociceptorů, které uvolňují substanci P a jiné neuropeptidy, jež způsobují degranulaci mastocytů a uvolnění histaminu. Substance P má dále vliv na vazodilataci okolních kapilár, vznik otoku a uvolnění dalších molekul bradykininu. V důsledku zmíněného mechanismu dochází k aktivaci intracelulárních signálních drah a fosforylačních kaskád. Vyjma periferní senzitizace se u RA uplatňuje i senzitizace centrální, tedy zvýšená citlivost nociceptivních neuronů centrálního nervového systému na normální či podprahové podněty. Výsledkem je perzistující bolest a zvýšení citlivosti na bolest i v oblastech mimo postižený kloub, distálních či vzdálených. Tento mechanismus se podílí též na vzniku fibromyalgie, která se vyskytuje až u 20 % pacientů s RA. Přehledné sdělení se zabývá klinickými aspekty bolesti u RA a současnými léčebnými možnostmi.
Rheumatoid arthritis (RA) is the most common inflammatory rheumatic disease, affecting up to 1% of the population, and has been shown to impair quality of life. Pain is usually identified as the main limiting symptom for patients, it can be present all the time, and relief from it is rated as the highest priority in improving health and quality of life. Pain in RA is complex, caused by multiple mechanisms, and can be both nociceptive and neuropathic in nature. Nociceptive pain, which is predominant in RA, is caused by peripheral sensitization (increased sensitivity of peripheral nerves) acting on peripheral nerve endings that are irritated by local agents (inflammatory cytokines and other mediators) produced by immune cells and cells of the damaged tissue at the site of inflammation. These agents include prostaglandins (especially prostaglandin E2), interleukin-1, interleukin-6, and both type 1 and type 2 cyclooxygenase. Potassium, bradykinin, and serotonin also have a direct effect on free nerve endings. These effects lead to irritation of nociceptors, which release substance P and other neuropeptides that cause mast cell degranulation and histamine release. Substance P also affects vasodilation of the surrounding capillaries, the development of edema, and the release of other bradykinin molecules. As a result of this mechanism, intracellular signaling pathways and phosphorylation cascades are activated. Apart from peripheral sensitization, RA also involves central sensitization, i.e. increased sensitivity of nociceptive neurons of the central nervous system to normal or subliminal stimuli. The result is persistent pain and increased sensitivity to pain even in areas outside the affected joint, distal or remote. This mechanism is also involved in the development of fibromyalgia, which occurs in up to 20% of RA patients. This review discusses the clinical aspects of pain in RA and current treatment options.
- MeSH
- analgetika farmakologie klasifikace terapeutické užití MeSH
- chronická bolest * diagnóza etiologie farmakoterapie patofyziologie MeSH
- kanabinoidy farmakologie klasifikace terapeutické užití MeSH
- kvalita života MeSH
- lidé MeSH
- management bolesti metody MeSH
- měření bolesti metody MeSH
- revmatoidní artritida * diagnóza farmakoterapie komplikace patofyziologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Cíle: Hodnocení dlouhodobého vlivu léčby rheoferézou na suchou formu věkem podmíněné makuární degenerace. Materiál a metody: Do hodnocení jsme zařadili 65 pacientů a do kontrolní skupiny 55 pacientů s minimální dobou sledování 60 měsíců. Základní léčba se skládala z 8 procedur rheoferézy, přídatná léčba (booster therapy) ze 2 rheoferéz za 1,5-2 roky po základní léčbě. Hodnotili jsme změny nejlépe korigované zrakové ostrosti, anatomických poměrů a elektrické aktivity sítnice, hematologické, biochemické a imunologické parametry. Výsledky: Léčba rheoferézou významně přispěla: 1) Ke stabilizaci nejlépe korigované zrakové ostrosti léčených pacientů, která se nejprve nevýznamně zvyšovala do 2 let sledování a následně jen mírně klesala. Naproti tomu v kontrolní skupině se zraková ostrost snižovala, do 4 let nevýznamně, poté již statisticky významně. 2) Ke zlepšení morfologického nálezu u 62,4 % léčených pacientů v porovnání se 7,5 % kontrol, naproti tomu k progresi onemocnění do 3. stadia (vlhká forma onemocnění nebo geografická atrofie) s významným poklesem zrakových funkcí došlo jen u 7,1 % léčených pacientů oproti 37,0 % kontrol. 3) K regresi, dokonce i k přiložení drúzového odchlípení retinálního pigmentového epitelu (DPED). Ke zmenšení plochy DPED u 80,4 % léčených pacientů, naproti tomu ke zvětšení plochy DPED u 47,1 % kontrol a rozvoji nového DPED jen u 2 očí léčených pacientů oproti 16 očím kontrol. 4) K udržení integrity vrstvy elipsoidů ve fovee u 68,2 % léčených pacientů, naproti tomu defektní elipsoidní vrstvu ve fovee jsme zaznamenali u 66,6 % kontrol. 5) Ke stabilizaci aktivity gangliových buněk, čípkového systému a aktivity centrální oblasti sítnice s excentricitou mezi 1,8° a 30° u léčených pacientů v porovnání s její alterací v kontrolní skupině projevující se zejména od 3,5 let sledování. 6) K statisticky významnému zlepšení rheologických ukazatelů, a tím ke zvýšení průtoku v mikrocirkulaci a pozitivnímu ovlivnění metabolizmu v sítnici. K pozitivnímu vlivu na klasickou, alternativní i lektinovou cestu aktivace komplementu, snížení hladiny PCSK9 (proprotein konvertáza subticilin kexin 9), a tím i hladiny LDL-cholesterolu a 7) Přídatná léčba 2 procedurami RHF (tzv. „booster therapy“) se zdá být bezpečnou a vhodnou metodou prodloužení fáze stabilizace, či dokonce zlepšení zrakové ostrosti, anatomického a funkčního nálezu. Závěr: Prokázali jsme pozitivní změny anatomických, funkčních i humorálních ukazatelů při léčbě VPMD rheoferézou. Jejich korelace skýtá reálnou možnost ohrožené nemocné vytipovat a řídit individualizovanou intenzitu rheoterapie. Metodika je účinná a bezpečná s nízkým procentem nezávažných vedlejších účinků.
Purpose: Evaluation of the long-term effect of rheopheresis treatment of dry form of age-related macular degeneration (AMD). Materials and Methods: The treatment group consisted of 65 patients and 55 patients in the control group, with a minimum follow-up period of 60 months. The basic treatment consisted of 8 rheopheresis procedures, and the additional treatment (booster therapy) of 2 rheopheresis procedures 1.5–2 years after the basic treatment. We evaluated changes in best corrected visual acuity, anatomical effect, electrical activity of the retina, haematological, biochemical and immunological parameters. Results: Rheopheresis treatment contributed significantly: 1) to stabilisation of best corrected visual acuity of the treated patients, which initially showed an insignificant increased during the 2-years follow-up period, and then slightly decreased. By contrast, visual acuity decreased in the control group, to an insignificant degree up to 4 years, then statistically significantly. 2) to an improvement of the morphological findings in 62.4% of treated patients compared to 7.5% in the control group, while disease progression to stage 3 (neovascular form of the disease or geographic atrophy) with a significant decrease of visual acuity occurred in only 7.1% of treated patients, versus 37.0% in the control group. 3) to regression, even to the attachment of drusenoid pigment epithelial detachment (DPED). To a reduction of the area of DPED in 80.4% of treated patients, in contrast with an steaincrease in the area of DPED in 47.1% of patients in the control group, and the development of new DPED in only 2 eyes of treated patients compared with 16 eyes of patients in the control group. 4) to a preservation of the integrity of the ellipsoid layer in the fovea in 68.2% of the treated patients, while by contrast we found a damaged ellipsoid layer in the fovea in 66.6% of the control patients. 5) to a stabilisation of the activity of ganglion cells, the pineal system and the activity of the central area of the retina, with eccentricity between 1.8° and 30° in the treated patients, compared to alteration in the control group manifested mainly after 3.5 years of the follow-up period. 6) to a statistically significant improvement in rheological parameters, thereby increasing flow in microcirculation and positively influencing the metabolism in the retina. Also to a positive effect on the classical, alternative and lectin pathway of complement activation, a reduction in the level of proprotein convertase subtilisin kexin 9 (PCSK9), and thus also the level of LDLcholesterol, and 7) Additional treatment with 2 RHF procedures (so-called "booster therapy") seems to be a safe and suitable method of prolonging the stabilisation phase, or even improving visual acuity, anatomical and functional findings. Conclusion: We demonstrated positive changes in anatomical, functional and humoral parameters upon rheopheresis treatment of AMD. Their correlation provides a real possibility to identify patients at risk and to manage an individualised regime of rheopheresis therapy. This method of treatment is effective and safe, with a low percentage of non-serious adverse effects.
- MeSH
- geografická atrofie patologie terapie MeSH
- lidé MeSH
- makulární degenerace patologie terapie MeSH
- plazmaferéza * metody škodlivé účinky MeSH
- proproteinkonvertasa subtilisin/kexin typu 9 terapeutické užití MeSH
- retina patologie MeSH
- separace krevních složek metody škodlivé účinky MeSH
- výzkum MeSH
- Check Tag
- lidé MeSH
Aspergillus fumigatus has been designated by the World Health Organization as a critical priority fungal pathogen. Some commercially available diagnostics for many forms of aspergillosis rely on fungal metabolites. These encompass intracellular molecules, cell wall components, and extracellular secretomes. This review summarizes the shortcomings of antibody tests compared to tests of fungal products in body fluids and highlights the application of β-d-glucan, galactomannan, and pentraxin 3 in bronchoalveolar lavage fluids. We also discuss the detection of nucleic acids and next-generation sequencing, along with newer studies on Aspergillus metallophores.
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Východiska: Nejnovější poznatky ohledně podílu mikroRNA na nádorové angiogenezi a onkogenních účincích mikroRNA ukazují na jejich případnou roli v angiogenezi karcinomu prsu. Exozomy získané z nádoru jsou považovány za bohatý zdroj mikroRNA, které dokáží regulovat ostatní buňky v nádorovém mikroprostředí, vč. vaskulárních endoteliálních buněk. Tato studie analyzuje účinek chemoterapie tamoxifenem na expresi klíčové microRNA, miR-329, a upozorňuje na spojitost mezi touto mikroRNA a genem KDM1A, který se účastní dráhy vaskulárního endoteliálního růstového faktoru (VEGF). Materiál a metody: Byly zakoupeny buňky karcinomu prsu MCF-7 a kultivovány v kompletním živném médiu. K těmto buňkám byl přidán tamoxifen a pak byly z média extrahovány jejich exozomy. Z nich byly izolovány RNA a pomocí metody polymerázové řetězové reakce (polymerase chain reaction – PCR) v reálném čase byla zkoumána exprese genů miR-329, VEGF a KDM1A v exozomech. Výsledky: Výsledky této studie ukázaly, že při léčbě tamoxifenem se v exozomech získaných z buněk karcinomu prsu MCF-7 zvýšila exprese genů miR-329. Exprese genů KDM1A a VEGF v exozomech buněk ošetřených léčivem byla downregulovaná. Závěr: Výsledky tohoto experimentu ukázaly, že po přidání tamoxifenu k buňkám karcinomu prsu dochází vlivem zvýšení miR-329 ke snížení exprese VEGF a KDM1A. Tím se snižuje angiogeneze a uplatňují se tak protinádorové účinky tohoto léku.
Background: Recent developments regarding the contribution of microRNAs to tumor angiogenesis and the oncogenic effects of microRNAs point to their potential role in breast cancer angiogenesis. Tumor-derived exosomes are considered a rich source of microRNAs that can regulate the function of other cells in the tumor microenvironment, including vascular endothelial cells. This study analyzes the effect of tamoxifen chemotherapy on the expression of a key microRNA, miR-329, and introduces a regulatory link between this microRNA and the KDM1A gene associated with the vascular endothelial growth factor (VEGF) messaging pathway. Materials and methods: MCF-7 breast cancer cells were purchased and cultured in a complete culture medium. These cells were treated with tamoxifen and then their exosomes were extracted from the culture medium. The RNAs of the exosomes were isolated and the expression of miR-329, VEGF, and KDM1A genes in the exosomes was investigated using the real-time polymerase chain reaction (PCR) method. Results: The results of this study showed that tamoxifen treatment increased the expression of miR-329 in exosomes derived from MCF-7 cancer cells. The expression of KDM1A and VEGF genes in drug-treated cell exosomes is downregulated. Conclusion: The results of this experiment demonstrated that the treatment of breast cancer cells with tamoxifen reduces the expression of VEGF and KDM1A by increasing miR-329. The treatment therefore reduces angiogenesis, and thus its anti-tumor effects are applied.
- Klíčová slova
- KDM1A,
- MeSH
- exozom účinky léků MeSH
- lidé MeSH
- mikro RNA analýza genetika MeSH
- nádorové biomarkery analýza MeSH
- nádorové buněčné linie patologie MeSH
- nádory prsu * genetika MeSH
- patologická angiogeneze * etiologie patologie MeSH
- tamoxifen terapeutické užití MeSH
- vaskulární endoteliální růstový faktor A analýza genetika MeSH
- výzkum MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- klinická studie MeSH
Mycotoxins are natural metabolites produced by fungi that contaminate food and feed worldwide. They can pose a threat to human and animal health, mainly causing chronic effects, e.g., immunotoxic and carcinogenic. Due to climate change, an increase in European population exposure to mycotoxins is expected to occur, raising public health concerns. This urges us to assess the current human exposure to mycotoxins in Europe to allow monitoring exposure and prevent future health impacts. The mycotoxins deoxynivalenol (DON) and fumonisin B1 (FB1) were considered as priority substances to be studied within the European Human Biomonitoring Initiative (HBM4EU) to generate knowledge on internal exposure and their potential health impacts. Several policy questions were addressed concerning hazard characterization, exposure and risk assessment. The present article presents the current advances attained under the HBM4EU, research needs and gaps. Overall, the knowledge on the European population risk from exposure to DON was improved by using new harmonised data and a newly derived reference value. In addition, mechanistic information on FB1 was, for the first time, organized into an adverse outcome pathway for a congenital anomaly. It is expected that this knowledge will support policy making and contribute to driving new Human Biomonitoring (HBM) studies on mycotoxin exposure in Europe.