PRMT1 and PRMT8 regulate retinoic acid-dependent neuronal differentiation with implications to neuropathology.

Retinoids are morphogens and have been implicated in cell fate commitment of embryonic stem cells (ESCs) to neurons. Their effects are mediated by RAR and RXR nuclear receptors. However, transcriptional cofactors required for cell and gene-specific retinoid signaling are not known. Here we show that protein arginine methyl transferase (PRMT) 1 and 8 have key roles in determining retinoid regulated gene expression and cellular specification in a multistage neuronal differentiation model of murine ESCs. PRMT1 acts as a selective modulator, providing the cells with a mechanism to reduce the potency of retinoid signals on regulatory "hotspots." PRMT8 is a retinoid receptor target gene itself and acts as a cell type specific transcriptional coactivator of retinoid signaling at later stages of differentiation. Lack of either of them leads to reduced nuclear arginine methylation, dysregulated neuronal gene expression, and altered neuronal activity. Importantly, depletion of PRMT8 results in altered expression of a distinct set of genes, including markers of gliomagenesis. PRMT8 is almost entirely absent in human glioblastoma tissues. We propose that PRMT1 and PRMT8 serve as a rheostat of retinoid signaling to determine neuronal cell specification in a context-dependent manner and might also be relevant in the development of human brain malignancy

Prognostic role of the expression of invasion-related molecules in glioblastoma.

Background Glioblastoma multiforme (GBM) is the most common malignant disease of the central nervous system. Its prognosis is unfavorable, and the median overall survival of patients is 16 to 24 months. The main cause of the poor survival data are the extensive invasion of cancer cells to the neighboring parenchyma, thus leading to inevitable local recurrence. The extracellular matrix (ECM) is a known factor in tumor invasion, and differences in the ECM of nontumor brain and glioblastoma has been proven. Methods In this research, 20 invasion-related expressions of ECM components were determined in 26 GBM flash-frozen samples using quantitative reverse transcription-polymerase chain reaction and proteomic measurements. Expression data were then set against the survival data of the patients. Results Significant alterations between groups with different survival rates could not be established in the individual evaluation of the expression level of the selected molecules. However, statistical analysis of the expression pattern of invasion-related molecules revealed a correlation with prognosis. The positive predictive values of the messenger RNA (mRNA) and the proteomic expression studies were 0.85 and 0.89, respectively. The receiver operation characteristic value was 0.775 for the mRNA expression data and 0.875 for the protein expression data. Furthermore, a group of molecules, including brevican, cadherin-12, integrin β1, integrin α3, laminin α4, and laminin β1, that play a prominent role in invasion were identified. Conclusions Joint assessment of the expression of invasion-related molecules provides a specific invasion spectrum of the tumor that correlates with the survival of glioblastoma patients. Using statistical classifiers enables the adoption of an invasion spectrum as a considerably accurate prognostic factor while gaining predictive information on potential molecular oncotherapeutic targets at the same time

Novel Concepts of Glioblastoma Therapy Concerning Its Heterogeneity

Although treatment outcomes of glioblastoma, the most malignant central nervous system (CNS) tumor, has improved in the past decades, it is still incurable, and survival has only slightly improved. Advances in molecular biology and genetics have completely transformed our understanding of glioblastoma. Multiple classifications and different diagnostic methods were made according to novel molecular markers. Discovering tumor heterogeneity only partially explains the ineffectiveness of current anti-proliferative therapies. Dynamic heterogeneity secures resistance to combined oncotherapy. As tumor growth proceeds, new therapy-resistant sub clones emerge. Liquid biopsy is a new and promising diagnostic tool that can step up with the dynamic genetic change. Getting a ’real-time’ picture of a specific tumor, anti-invasion and multi-target treatment can be designed. During invasion to the peri-tumoral brain tissue, glioma cells interact with the extracellular matrix components. The expressional levels of these matrix molecules give a characteristic pattern, the invasion spectrum, which possess vast diagnostical, predictive and prognostic information. It is a huge leap forward combating tumor heterogeneity and searching for novel therapies. Using the invasion spectrum of a tumor sample is a novel tool to distinguish between histological subtypes, specifying the tumor grades or different prognostic groups. Moreover, new therapeutic methods and their combinations are under trial. These are crucial steps towards personalized oncotherapy

A szájüregi baktériumok szerepe az aspirációs pneumónia patogenezisében. The role of the oral flora in the pathogenesis of aspiration pneumonia.

A bakteriális pneumónia a fekvőbeteg-intézetek halálos kimenetelű szövődményes megbetegedései között előfordulási gyakoriságban az elsők között szerepel. Az intenzív, valamint krónikus ápolási osztályokon és az idős betegeket kezelő intézetekben fekvők esetében különösen magas morbiditási és mortalitási jellemzői közismertnek tekinthetők. A betegség egyik leggyakoribb típusa az aspirációs pneumónia, melynek etiológiájában a parodontológiai kórképek elsődleges szerepűek. A szerzők cikkükben rámutatnak az aspiráció útján kialakuló bakteriális tüdőgyulladás kiemelkedően nagy betegpopulációt érintő jelentőségére, és részletesen tárgyalják a szájhigiéné és a szájüregi flóra szerepét a kórkép patogenezisében. Ismertetik azokat a jelentősebb bakteriális, enzimatikus és molekuláris mechanizmusokat, melyek a kutatások mai állása szerint az aspirációs pneumónia kialakulásához vezetnek. Mindezek mellett meghatározzák a kórkép legmagasabb incidenciáját mutató veszélyeztetett betegcsoportok és a fekvőbeteg-ellátás részét képező kiemelkedő jelentőségű prevenciós fogászati beavatkozásokat. The bacterial pneumonia is one of the most frequent complications leading to death among hospitalized patients. The morbidity and mortality of pneumonia is extremely high in the intensive care units and in chronic nursing stations, especially in institutes dealing with old patients. The most common form of lung infection is the aspiration pneumonia. Periodontal diseases play an evident role in the etiology of aspiration pneumonia due to their effect to alter the oral bacterial flora. Authors review the significance of pathogen microorganisms originating from the oral cavity in the development of bacterial pneumonia. The extent of the affected population is discussed and the importance of their oral hygiene and bacterial flora is also specified. The bacterial, enzymatic and molecular pathomechanisms leading to aspiration pneumonia are described, and high risk populations and treatment types are determined. The possibilities of prevention methods for aspiration pneumonia are fully explained and recent directions of actual researches and proposals to minimize the incidence of this disease are summarized

Különböző invazivitású agydaganatok extracelluláris mátrixának expressziója. Extracellular matrix of cerebral tumors with different invasiveness

Célkitûzés – A glioblastomák sikertelen kezelésének egyik fô oka az ép agyállomány tumoros infiltrációja miatt kivitelezhetetlen radikális tumoreltávolítás. Ugyanakkor a hasonlóan anaplasztikus carcinomák agyi áttétei jól körülírt intracerebralis daganat képében jelentkeznek, amelyek teljes reszekciója többnyire rutinmûtétnek számít. A tumoros környezeti invázióban az extracelluláris mátrix (ECM) molekulái játszanak döntô szerepet. Két különbözô eredetû és egymástól jelentôsen eltérô agyállományi infiltrációs aktivitással rendelkezô daganat ECM-molekuláinak mRNSszintû expresszióját hasonlítottuk össze. Kérdésfelvetés – Az extracelluláris mátrix mely molekulái lehetnek felelôsek a különbözô eredetû anaplasztikus daganatok eltérô infiltrációs képességéért? Módszer – 23 ECM-alkotó molekula mRNS-expresszióját határoztuk meg kvantitatív reverz transzkriptáz polimeráz láncreakció alkalmazásával négy-négy idegsebészeti mûtétbôl származó glioblastomából és bronchogen adenocarcinoma agyi áttétébôl származó szövetmintában. Öt molekula esetében immunhisztokémiai vizsgálatokat is végeztünk. Eredmények – Kilenc ECM-molekula [brevikán, neurokán, neuroglikán-C, tenaszcin-C, verzikán, mátrixmetalloproteináz (MMP) -2, szindekán-1, -2 és -4] mRNS-expressziójában találtunk egyértelmû különbséget a két daganattípus között. Az immunhisztokémiai vizsgálatok során öt molekulából (neurocan, szindekán, versican, MMP-2 és -9) az MMP-9 kivételével minden esetben az mRNS-expressziós eredményeket alátámasztó különbségeket detektáltunk. Következtetések – A fenti molekulák szerepet játszhatnak a daganatsejtek igen eltérô környezeti agyállomány-inváziójában, és így a malignus gliomák esetében az antiinvazív rákellenes terápia célmolekuláiként is szolgálhatnak. Objectives – Ineffective surgical and radiotherapy of glioblastoma is mainly due to its intensive infiltrating behavior. Contrarily, brain metastases of anaplastic carcinomas are well-circumscribed intracerebral lesions that can be easily exstirpated in most cases. The molecules of the extracellular matrix (ECM) play a pivotal role in the peritumoral infiltration. In this study the mRNA expression of the ECM components was investigated in two types of intracerebral malignoma with different invasion activity. Our aim was to identify the ECM molecules that are responsible for the different intensity of peritumoral infiltration of tumors from different origin. Methods – The mRNA expression of twenty-three ECM molecules was determined by quantitative reverse transcriptase polymerase chain reaction. Four pieces of glioblastoma and four pieces of intracerebral lung adenocarcinoma metastasis from neurosurgical operation were investigated. Immunohistochemical investigations were performed in case of five molecules. Results – The mRNA expression of nine molecules (brevican, neurocan, neuroglycan-C, syndecan-1,2,4, tenascin-C, versican and matrix-metalloproteinase-[MMP]2) differed significantly by comparison of the two tumor types. By immunohistochemistry, neurocan, syndecan, versican and MMP-2 showed alteration in staining intensity according to the mRNA expression, while MMP-9 showed higher staining intensity in the metastatic tumor. Conclusions – The identified molecules can play an important role in the different infiltration activity of tumors from different origin. Thus these ECM-components could serve as targets for anti-invasion therapy in the future

Efficacy and Safety of Gadopiclenol for Contrast-Enhanced MRI of the Central Nervous System: The PICTURE Randomized Clinical Trial

Objectives: Developing new high relaxivity gadolinium-based contrast agents (GBCAs) for magnetic resonance imaging (MRI) allowing dose reduction while maintaining similar diagnostic efficacy is needed, especially in the context of gadolinium retention in tissues. This study aimed to demonstrate that contrast-enhanced MRI of the central nervous system (CNS) with gadopiclenol at 0.05 mmol/kg is not inferior to gadobutrol at 0.1 mmol/kg, and superior to unenhanced MRI. Materials and methods: PICTURE is an international, randomized, double-blinded, controlled, cross-over, phase III study, conducted between June 2019 and September 2020. Adult patients with CNS lesions were randomized to undergo 2 MRIs (interval, 2-14 days) with gadopiclenol (0.05 mmol/kg) then gadobutrol (0.1 mmol/kg) or vice versa. The primary criterion was lesion visualization based on 3 parameters (border delineation, internal morphology, and contrast enhancement), assessed by 3 off-site blinded readers. Key secondary outcomes included lesion-to-background ratio, enhancement percentage, contrast-to-noise ratio, overall diagnostic preference, and adverse events. Results: Of the 256 randomized patients, 250 received at least 1 GBCA administration (mean [SD] age, 57.2 [13.8] years; 53.6% women). The statistical noninferiority of gadopiclenol (0.05 mmol/kg) to gadobutrol (0.1 mmol/kg) was achieved for all parameters and all readers (n = 236, lower limit 95% confidence interval of the difference ≥-0.06, above the noninferiority margin [-0.35], P < 0.0001), as well as its statistical superiority over unenhanced images (n = 239, lower limit 95% confidence interval of the difference ≥1.29, P < 0.0001).Enhancement percentage and lesion-to-background ratio were higher with gadopiclenol for all readers ( P < 0.0001), and contrast-to-noise ratio was higher for 2 readers ( P = 0.02 and P < 0.0001). Three blinded readers preferred images with gadopiclenol for 44.8%, 54.4%, and 57.3% of evaluations, reported no preference for 40.7%, 21.6%, and 23.2%, and preferred images with gadobutrol for 14.5%, 24.1%, and 19.5% ( P < 0.001).Adverse events reported after MRI were similar for gadopiclenol (14.6% of patients) and gadobutrol (17.6%). Adverse events considered related to gadopiclenol (4.9%) and gadobutrol (6.9%) were mainly injection site reactions, and none was serious. Conclusions: Gadopiclenol at 0.05 mmol/kg is not inferior to gadobutrol at 0.1 mmol/kg for MRI of the CNS, confirming that gadopiclenol can be used at half the gadolinium dose used for other GBCAs to achieve similar clinical efficacy