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BACKGROUND AND PURPOSE: Wall enhancement of untreated intracranial aneurysms on MR imaging is thought to predict aneurysm instability. Wall enhancement or enhancement of the aneurysm cavity in coiled intracranial aneurysms is discussed controversially in the literature regarding potential healing mechanisms or adverse inflammatory reactions. Our aim was to compare the occurrence of aneurysm wall enhancement and cavity enhancement between completely occluded intracranial aneurysms and recanalized aneurysms after initially complete coil embolization. MATERIALS AND METHODS: In this single-center cross-sectional study, we evaluated intracranial aneurysms after successful coil embolization for aneurysm recanalization, wall enhancement, and cavity enhancement with 3T MR imaging. We then compared the incidence of wall enhancement and cavity enhancement of completely occluded aneurysms with aneurysms with recanalization using the χ2 test and performed a multivariate linear regression analysis with recanalization size as an independent variable. RESULTS: We evaluated 59 patients (mean age, 54.7 [SD, 12.4] years; 48 women) with 60 intracranial aneurysms and found a significantly higher incidence of wall enhancement in coiled aneurysms with recanalization (n=38) compared with completely occluded aneurysms (n = 22, P = .036). In addition, there was a significantly higher incidence of wall enhancement in aneurysms with recanalization of >3 mm (P = .003). In a multivariate linear regression analysis, wall enhancement (P = .010) and an increase of overall aneurysm size after embolization (P < .001) were significant predictors of recanalization size (corrected R 2= 0.430, CI 95%). CONCLUSIONS: The incidence of aneurysm wall enhancement is increased in coiled intracranial aneurysms with recanalization and is associated with recanalization size.
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Embolisation thérapeutique , Anévrysme intracrânien , Humains , Anévrysme intracrânien/imagerie diagnostique , Anévrysme intracrânien/thérapie , Femelle , Mâle , Adulte d'âge moyen , Études transversales , Embolisation thérapeutique/méthodes , Adulte , Sujet âgé , Résultat thérapeutique , Imagerie par résonance magnétique/méthodesRÉSUMÉ
INTRODUCTION: Covert brain infarcts (CBI) are frequent incidental findings on MRI and associated with future stroke risk in patients without a history of clinically evident cerebrovascular events. However, the prognostic value of CBI in first-ever ischemic stroke patients is unclear and previous studies did not report on different etiological stroke subtypes. We aimed to test CBI phenotypes and their association with stroke recurrence in first-ever ischemic stroke patients according to stroke etiology. PATIENTS AND METHODS: This study is a pooled data analysis of two prospectively collected cohorts of consecutive first-ever ischemic stroke patients admitted to the comprehensive stroke centers of Bern (Switzerland) and Graz (Austria). CBI phenotypes were identified on brain MRI within 72 h after admission. All patients underwent a routine follow-up (median: 12 months) to identify stroke recurrence. RESULTS: Of 1577 consecutive ischemic stroke patients (median age: 71 years), 691 patients showed CBI on brain MRI (44%) and 88 patients had a recurrent ischemic stroke (6%). Baseline CBI were associated with stroke recurrence in multivariable analysis (HR 1.9, 95% CI 1.1-3.3). CBI phenotypes with the highest risk for stroke recurrence were cavitatory CBI in small vessel disease (SVD)-related stroke (HR 7.1, 95% CI 1.6-12.6) and cortical CBI in patients with atrial fibrillation (HR 3.0, 95% CI 1.1-8.1). DISCUSSION AND CONCLUSION: This study reports a ≈ 2-fold increased risk for stroke recurrence in first-ever ischemic stroke patients with CBI. The risk of recurrent stroke was highest in patients with cavitatory CBI in SVD-related stroke and cortical CBI in patients with atrial fibrillation.Subject terms: Covert brain infarcts, stroke.
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Infarctus encéphalique , Accident vasculaire cérébral ischémique , Imagerie par résonance magnétique , Phénotype , Récidive , Humains , Femelle , Mâle , Sujet âgé , Accident vasculaire cérébral ischémique/imagerie diagnostique , Accident vasculaire cérébral ischémique/anatomopathologie , Accident vasculaire cérébral ischémique/étiologie , Adulte d'âge moyen , Infarctus encéphalique/anatomopathologie , Infarctus encéphalique/imagerie diagnostique , Infarctus encéphalique/épidémiologie , Infarctus encéphalique/complications , Sujet âgé de 80 ans ou plus , Facteurs de risque , Études prospectives , Encéphalopathie ischémique/anatomopathologie , Encéphalopathie ischémique/imagerie diagnostique , Encéphalopathie ischémique/étiologie , Encéphalopathie ischémique/épidémiologie , Accident vasculaire cérébral/anatomopathologie , Accident vasculaire cérébral/imagerie diagnostique , Accident vasculaire cérébral/étiologie , Accident vasculaire cérébral/épidémiologie , Encéphale/anatomopathologie , Encéphale/imagerie diagnostiqueRÉSUMÉ
OBJECTIVES: Telomeres are DNA-protein complexes at the ends of linear chromosomes that protect against DNA degradation. Telomeres shorten during normal cell divisions and therefore, telomere length is an indicator of mitotic-cell age. In humans, telomere shortening is a potential biomarker for disease risk, progression and premature death. Physical activity has been associated with longer leukocyte telomere length (LTL) in some studies. In the current study the relationship between LTL, thigh muscle mass and adipose tissue distribution was explored. METHODS: We performed anthropometric measurements and magnetic resonance imaging (MRI) measurements of the thigh in 149 healthy subjects (77 male, 72 female). LTL was measured using qPCR. Additionally, the subjects answered a questionnaire concerning their training behaviour. RESULTS: In male subjects, LTL was significantly associated with thigh muscle mass, independent of age and body mass index (p=0.006). In addition, a slight association of LTL with weekly endurance units in the male group was found. These relations could not be observed in females. CONCLUSIONS: In conclusion, we observed a sex-specific association of LTL and thigh muscle mass in healthy males. The reason of this sex-specific association is currently unclear, but could be related to different training effects and/or hormonal pathways in men and women.
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Télomère , Cuisse , Humains , Mâle , Femelle , Télomère/génétique , Leucocytes , Muscles , ADN/métabolismeRÉSUMÉ
PURPOSE: Since glioma therapy is currently still limited until today, new treatment options for this heterogeneous group of tumours are of great interest. Eukaryotic initiation factors (eIFs) are altered in various cancer entities, including gliomas. The purpose of our study was to evaluate the potential of eIFs as novel targets in glioma treatment. METHODS: We evaluated eIF protein expression and regulation in 22 glioblastoma patient-derived xenografts (GBM PDX) after treatment with established cytostatics and with regards to mutation profile analyses of GBM PDX. RESULTS: We observed decreased expression of several eIFs upon temozolomide (TMZ) treatment independent from the phosphatidylinositol 3-kinase (PI3K)/ AKT/ mammalian target of the rapamycin (mTOR) signalling pathway. These effects of TMZ treatment were not present in TMZ-resistant PDX. Combination therapy of regorafenib and TMZ re- established the eIF/AKT/mTOR axis. CONCLUSION: Our study provides novel insights into chemotherapeutic effects on eIF regulation in gliomas and suggests that eIFs are interesting candidates for future research to improve glioma therapy.
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Tumeurs du cerveau , Glioblastome , Gliome , Humains , Témozolomide/usage thérapeutique , Témozolomide/pharmacologie , Protéines proto-oncogènes c-akt/métabolisme , Phosphatidylinositol 3-kinases/métabolisme , Dacarbazine/usage thérapeutique , Dacarbazine/pharmacologie , Tumeurs du cerveau/génétique , Lignée cellulaire tumorale , Gliome/traitement médicamenteux , Gliome/anatomopathologie , Glioblastome/traitement médicamenteux , Glioblastome/anatomopathologie , Sérine-thréonine kinases TOR/métabolismeRÉSUMÉ
Background: The prognostic roles of clinical and laboratory markers have been exploited to model risk in patients with primary CNS lymphoma, but these approaches do not fully explain the observed variation in outcome. To date, neuroimaging or molecular information is not used. The aim of this study was to determine the utility of radiomic features to capture clinically relevant phenotypes, and to link those to molecular profiles for enhanced risk stratification. Methods: In this retrospective study, we investigated 133 patients across 9 sites in Austria (2005-2018) and an external validation site in South Korea (44 patients, 2013-2016). We used T1-weighted contrast-enhanced MRI and an L1-norm regularized Cox proportional hazard model to derive a radiomic risk score. We integrated radiomic features with DNA methylation profiles using machine learning-based prediction, and validated the most relevant biological associations in tissues and cell lines. Results: The radiomic risk score, consisting of 20 mostly textural features, was a strong and independent predictor of survival (multivariate hazard ratioâ =â 6.56 [3.64-11.81]) that remained valid in the external validation cohort. Radiomic features captured gene regulatory differences such as in BCL6 binding activity, which was put forth as testable treatment target for a subset of patients. Conclusions: The radiomic risk score was a robust and complementary predictor of survival and reflected characteristics in underlying DNA methylation patterns. Leveraging imaging phenotypes to assess risk and inform epigenetic treatment targets provides a concept on which to advance prognostic modeling and precision therapy for this aggressive cancer.
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The brain's extracellular matrix (ECM) is assumed to undergo rearrangements in Alzheimer's disease (AD). Here, we investigated changes of key components of the hyaluronan-based ECM in independent samples of post-mortem brains (N = 19), cerebrospinal fluids (CSF; N = 70), and RNAseq data (N = 107; from The Aging, Dementia and TBI Study) of AD patients and non-demented controls. Group comparisons and correlation analyses of major ECM components in soluble and synaptosomal fractions from frontal, temporal cortex, and hippocampus of control, low-grade, and high-grade AD brains revealed a reduction in brevican in temporal cortex soluble and frontal cortex synaptosomal fractions in AD. In contrast, neurocan, aggrecan and the link protein HAPLN1 were up-regulated in soluble cortical fractions. In comparison, RNAseq data showed no correlation between aggrecan and brevican expression levels and Braak or CERAD stages, but for hippocampal expression of HAPLN1, neurocan and the brevican-interaction partner tenascin-R negative correlations with Braak stages were detected. CSF levels of brevican and neurocan in patients positively correlated with age, total tau, p-Tau, neurofilament-L and Aß1-40. Negative correlations were detected with the Aß ratio and the IgG index. Altogether, our study reveals spatially segregated molecular rearrangements of the ECM in AD brains at RNA or protein levels, which may contribute to the pathogenic process.
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Maladie d'Alzheimer , Protéoglycane-3 à chondroïtine sulfate , Humains , Brévicane/métabolisme , Agrécanes/métabolisme , Protéoglycane-3 à chondroïtine sulfate/liquide cérébrospinal , Maladie d'Alzheimer/métabolisme , Matrice extracellulaire/métabolisme , Encéphale/métabolisme , Protéines tau/métabolisme , Peptides bêta-amyloïdes/métabolisme , Marqueurs biologiques/métabolismeRÉSUMÉ
We present the case of a middle-aged patient who had four recurrent acute basilar artery occlusions over a period of 3 months, each time successfully treated with mechanical thrombectomy. Extensive stroke work-up showed no obvious stroke etiology aside from a dysplastic right vertebral artery with multifocal stenoses. Treatment with different antiplatelet and anticoagulant regimes did not prevent basilar artery occlusion recurrence. Therefore, transarterial coil occlusion of the V4-segment of the right vertebral artery was performed as ultima ratio without complications. At final discharge, the patient had no persistent neurological deficits. No further cerebrovascular events occurred over a 12-month follow-up period.
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The transcription factor nuclear factor-kappa B (NF-κB) is critically involved in inflammation and cancer development. Activation of NF-κB induces the expression and release of several pro-inflammatory proteins, which include the cytokine interleukin-6 (IL-6). Perturbation of the actin cytoskeleton has been previously shown to activate NF-κB signaling. In this study, we analyze the influence of different compounds that modulate the actin cytoskeleton on NF-κB activation, IL-6 signaling and the proteolytic generation of the soluble IL-6 receptor (sIL-6R) in human hepatoma cells. We show that perturbation of the actin cytoskeleton is not sufficient to induce NF-κB activation and IL-6 secretion. However, perturbation of the actin cytoskeleton reduces IL-6-induced activation of the transcription factor STAT3 in Hep3B cells. In contrast, IL-6R proteolysis by the metalloprotease ADAM10 did not depend upon the integrity of the actin cytoskeleton. In summary, we uncover a previously unknown function of the actin cytoskeleton in IL-6-mediated signal transduction in Hep3B cells.
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Cytosquelette d'actine/métabolisme , Interleukine-6/métabolisme , Facteur de transcription NF-kappa B/métabolisme , Récepteurs à l'interleukine-6/métabolisme , Protéine ADAM10/métabolisme , Amyloid precursor protein secretases/métabolisme , Cellules HepG2 , Humains , Protéines membranaires/métabolisme , Facteur de transcription STAT-3/métabolismeRÉSUMÉ
Glioblastoma (GBM) is an utterly devastating cerebral neoplasm and current therapies only marginally improve patients' overall survival (OS). The PI3K/AKT/mTOR pathway participates in gliomagenesis through regulation of cell growth and proliferation. Since it is an upstream regulator of the rate-limiting translation initiation step of protein synthesis, controlled by eukaryotic initiation factors (eIFs), we aimed for a profound basic characterization of 17 eIFs to identify potential novel therapeutic targets for gliomas. Therefore, we retrospectively analyzed expressions of mTOR-related proteins and eIFs in human astrocytoma samples (WHO grades I-IV) and compared them to non-neoplastic cortical control brain tissue (CCBT) using immunoblot analyses and immunohistochemistry. We examined mRNA expression using qRT-PCR and additionally performed in silico analyses to observe the influence of eIFs on patients' survival. Protein and mRNA expressions of eIF3B, eIF3I, eIF4A1, eIF4H, eIF5 and eIF6 were significantly increased in high grade gliomas compared to CCBT and partially in low grade gliomas. However, short OS was only associated with high eIF3I gene expression in low grade gliomas, but not in GBM. In GBM, high eIF4H gene expression significantly correlated with shorter patient survival. In conclusion, we identified eIF3I and eIF4H as the most promising targets for future therapy for glioma patients.
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In this study, we assessed the prognostic relevance of temporal muscle thickness (TMT), likely reflecting patient's frailty, in patients with primary central nervous system lymphoma (PCNSL). In 128 newly diagnosed PCNSL patients TMT was analyzed on cranial magnetic resonance images. Predefined sex-specific TMT cutoff values were used to categorize the patient cohort. Survival analyses, using a log-rank test as well as Cox models adjusted for further prognostic parameters, were performed. The risk of death was significantly increased for PCNSL patients with reduced muscle thickness (hazard ratio of 3.189, 95% CI: 2-097-4.848, p < 0.001). Importantly, the results confirmed that TMT could be used as an independent prognostic marker upon multivariate Cox modeling (hazard ratio of 2.504, 95% CI: 1.608-3.911, p < 0.001) adjusting for sex, age at time of diagnosis, deep brain involvement of the PCNSL lesions, Eastern Cooperative Oncology Group (ECOG) performance status, and methotrexate-based chemotherapy. A TMT value below the sex-related cutoff value at the time of diagnosis is an independent adverse marker in patients with PCNSL. Thus, our results suggest the systematic inclusion of TMT in further translational and clinical studies designed to help validate its role as a prognostic biomarker.
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Sex-specific differences have been increasingly recognized in many human diseases including brain cancer, namely glioblastoma. Primary CNS lymphoma (PCNSL) is an exceedingly rare type of brain cancer that tends to have a higher incidence and worse outcomes in male patients. Yet, relatively little is known about the reasons that contribute to these observed sex-specific differences. Using a population-representative cohort of patients with PCNSL with dense magnetic resonance (MR) imaging and digital pathology annotation (n = 74), we performed sex-specific cluster and survival analyses to explore possible associations. We found three prognostically relevant clusters for females and two for males, characterized by differences in (i) patient demographics, (ii) tumor-associated immune response, and (iii) MR imaging phenotypes. Upon a multivariable analysis, an enhanced FoxP3+ lymphocyte-driven immune response was associated with a shorter overall survival particularly in female patients (HR 1.65, p = 0.035), while an increased extent of contrast enhancement emerged as an adverse predictor of outcomes in male patients (HR 1.05, p < 0.01). In conclusion, we found divergent prognostic constellations between female and male patients with PCNSL that suggest differential roles of tumor-associated immune response and MR imaging phenotypes. Our results further underline the importance of continued sex-specific analyses in the field of brain cancer.
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Keratin proteins form intermediate filaments, which provide structural support for many tissues. Multiple keratin family members are reported to be associated with the progression of liver disease of multiple etiologies. For example, keratin 23 (KRT23) was reported as a stress-inducible protein, whose expression levels correlate with the severity of liver disease. Hepatitis C virus (HCV) is a human pathogen that causes chronic liver diseases including fibrosis, cirrhosis, and hepatocellular carcinoma. However, a link between KRT23 and hepatitis C virus (HCV) infection has not been reported previously. In this study, we investigated KRT23 mRNA levels in datasets from liver biopsies of chronic hepatitis C (CHC) patients and in primary human hepatocytes experimentally infected with HCV, in addition to hepatoma cells. Interestingly, in each of these specimens, we observed an HCV-dependent increase of mRNA levels. Importantly, the KRT23 protein levels in patient plasma decreased upon viral clearance. Ectopic expression of KRT23 enhanced HCV infection; however, CRIPSPR/Cas9-mediated knockout did not show altered replication efficiency. Taken together, our study identifies KRT23 as a novel, virus-induced host-factor for hepatitis C virus.
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Hépatite C/métabolisme , Facteurs cellulaires de l'hôte/métabolisme , Kératines de type I/métabolisme , Carcinome hépatocellulaire/génétique , Lignée cellulaire , Cellules HEK293 , Hepacivirus/génétique , Hepacivirus/métabolisme , Hépatite C/génétique , Hépatite C/physiopathologie , Hépatite C chronique/métabolisme , Hépatocytes/métabolisme , Interactions hôte-pathogène , Humains , Kératines/métabolisme , Kératines de type I/génétique , Foie/métabolisme , Foie/anatomopathologie , Cirrhose du foie/métabolisme , Tumeurs du foie/génétique , ARN messager/métabolisme , Transcriptome/génétique , Réplication viraleRÉSUMÉ
We describe an adult female patient diagnosed with spinal melanotic ependymoma. She underwent surgery with the aim of gross total resection, but only subtotal resection was possible. Therefore, the patient was re-evaluated 6 weeks following surgery. Radiotherapy was considered as further treatment. The diagnosis, clinical course, etiology and pathology are discussed on the basis of the current literature.
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Épendymome/anatomopathologie , Tumeurs du rachis/anatomopathologie , Vertèbres thoraciques/anatomopathologie , Sujet âgé , Épendymome/chirurgie , Femelle , Humains , Imagerie par résonance magnétique , Tumeurs du rachis/chirurgie , Vertèbres thoraciques/chirurgieRÉSUMÉ
In recent years, there was growing interest in postsynaptic density proteins in the central nervous system. Of the most important candidates of this specialized region are proteins belonging to the Homer protein family. This family of scaffolding proteins is suspected to participate in the pathogenesis of a variety of diseases. The present study aims to compare Homer1a expression in the hippocampus and cingulate gyrus of patients with major psychiatric disorders including schizophrenia, bipolar disorder and major depression. Immunohistochemistry was used to analyze changes of Homer1a protein expression in the hippocampal formation and the cingulate gyrus from the respective disease groups. Glial cells of the cingulate gyrus gray matter showed decreased Homer1a levels in bipolar disorder when compared to controls. The same results were seen when comparing cingulate gyrus gray matter glial cells in bipolar disorder with major depression. Stratum oriens glial cells of the hippocampus showed decreased Homer1a levels in bipolar disorder when compared to controls and major depression. Stratum lacunosum glial cells showed decreased Homer1a levels in bipolar disorder when compared to major depression. In stratum oriens interneurons Homer1a levels were increased in all disease groups when compared to controls. Stratum lucidum axons showed decreased Homer1a levels in bipolar disorder when compared to controls. Our data demonstrate altered Homer1a levels in specific brain regions and cell types of patients suffering from schizophrenia, bipolar disorder and major depression. These findings support the role of Homer proteins as interesting candidates in neuropsychiatric pathophysiology and treatment.