Rauchen und Sexualhormone als Einflussfaktoren der Endokrinen Orbitopathie bei Morbus Basedow

M. Basedow-Patientinnen, die rauchen, haben ein 3,4-fach höheres Risiko, eine EO auszubilden und eine 3-fach höhere Wahrscheinlichkeit für eine schwere EO als Nichtraucher. Jedoch erreichte die EO-Manifestationsrate von prämenopausalen Rauchern unter Einnahme hormoneller Kontrazeptiva einen Wert, der dem von Nichtrauchern entspricht. Postmenopausale Patientinnen haben ein 8-fach höheres Risiko zur Ausbildung einer EO als prämenopausale. Unter Hormonsubstitution jedoch fällt die EO-Manifestationsrate der Nichtraucher auf 50% und der Anteil der Nichtraucher mit einer schweren EO von 80% auf 0%. Offensichtlich ist der postmenopausale Östradiolmangel ein zusätzlicher sich auf die EO negativ auswirkender Einflussfaktor, der durch eine Hormonsubstitution aufgehoben wird. Eine Hormonsubstitution zeigt bei Rauchern keine Wirkung. Rauchen wirkt in der Menopause aggressiver, was möglicherweise auf einen Einfluss des Hormonmangels auf die Assoziation zwischen Rauchen und EO zurückzuführen ist

Baseline radiomics features and MYC rearrangement status predict progression in aggressive B-cell lymphoma

We investigated whether the outcome prediction of patients with aggressive B-cell lymphoma can be improved by combining clinical, molecular genotype, and radiomics features. MYC, BCL2, and BCL6 rearrangements were assessed using fluorescence in situ hybridization. Seventeen radiomics features were extracted from the baseline positron emission tomography–computed tomography of 323 patients, which included maximum standardized uptake value (SUV(max)), SUV(peak), SUV(mean), metabolic tumor volume (MTV), total lesion glycolysis, and 12 dissemination features pertaining to distance, differences in uptake and volume between lesions, respectively. Logistic regression with backward feature selection was used to predict progression after 2 years. The predictive value of (1) International Prognostic Index (IPI); (2) IPI plus MYC; (3) IPI, MYC, and MTV; (4) radiomics; and (5) MYC plus radiomics models were tested using the cross-validated area under the curve (CV-AUC) and positive predictive values (PPVs). IPI yielded a CV-AUC of 0.65 ± 0.07 with a PPV of 29.6%. The IPI plus MYC model yielded a CV-AUC of 0.68 ± 0.08. IPI, MYC, and MTV yielded a CV-AUC of 0.74 ± 0.08. The highest model performance of the radiomics model was observed for MTV combined with the maximum distance between the largest lesion and another lesion, the maximum difference in SUV(peak) between 2 lesions, and the sum of distances between all lesions, yielding an improved CV-AUC of 0.77 ± 0.07. The same radiomics features were retained when adding MYC (CV-AUC, 0.77 ± 0.07). PPV was highest for the MYC plus radiomics model (50.0%) and increased by 20% compared with the IPI (29.6%). Adding radiomics features improved model performance and PPV and can, therefore, aid in identifying poor prognosis patients

An artificial intelligence method using FDG PET to predict treatment outcome in diffuse large B cell lymphoma patients

Convolutional neural networks (CNNs) may improve response prediction in diffuse large B-cell lymphoma (DLBCL). The aim of this study was to investigate the feasibility of a CNN using maximum intensity projection (MIP) images from 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) baseline scans to predict the probability of time-to-progression (TTP) within 2 years and compare it with the International Prognostic Index (IPI), i.e. a clinically used score. 296 DLBCL 18F-FDG PET/CT baseline scans collected from a prospective clinical trial (HOVON-84) were analysed. Cross-validation was performed using coronal and sagittal MIPs. An external dataset (340 DLBCL patients) was used to validate the model. Association between the probabilities, metabolic tumour volume and Dmaxbulk was assessed. Probabilities for PET scans with synthetically removed tumors were also assessed. The CNN provided a 2-year TTP prediction with an area under the curve (AUC) of 0.74, outperforming the IPI-based model (AUC = 0.68). Furthermore, high probabilities (> 0.6) of the original MIPs were considerably decreased after removing the tumours (< 0.4, generally). These findings suggest that MIP-based CNNs are able to predict treatment outcome in DLBCL

Epigenetic Silencing of the Circadian Clock Gene CRY1 is Associated with an Indolent Clinical Course in Chronic Lymphocytic Leukemia

Disruption of circadian rhythm is believed to play a critical role in cancer development. Cryptochrome 1 (CRY1) is a core component of the mammalian circadian clock and we have previously shown its deregulated expression in a subgroup of patients with chronic lymphocytic leukemia (CLL). Using real-time RT-PCR in a cohort of 76 CLL patients and 35 normal blood donors we now demonstrate that differential CRY1 mRNA expression in high-risk (HR) CD38+/immunoglobulin variable heavy chain gene (IgVH) unmutated patients as compared to low-risk (LR) CD38−/IgVH mutated patients can be attributed to down-modulation of CRY1 in LR CLL cases. Analysis of the DNA methylation profile of the CRY1 promoter in a subgroup of 57 patients revealed that CRY1 expression in LR CLL cells is silenced by aberrant promoter CpG island hypermethylation. The methylation pattern of the CRY1 promoter proved to have high prognostic impact in CLL where aberrant promoter methylation predicted a favourable outcome. CRY1 mRNA transcript levels did not change over time in the majority of patients where sequential samples were available for analysis. We also compared the CRY1 expression in CLL with other lymphoid malignancies and observed epigenetic silencing of CRY1 in a patient with B cell acute lymphoblastic leukemia (B-ALL)

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Human Mesenchymal Stem Cells Self-Renew and Differentiate According to a Deterministic Hierarchy

BACKGROUND:Mesenchymal progenitor cells (MPCs) have been isolated from a variety of connective tissues, and are commonly called "mesenchymal stem cells" (MSCs). A stem cell is defined as having robust clonal self-renewal and multilineage differentiation potential. Accordingly, the term "MSC" has been criticised, as there is little data demonstrating self-renewal of definitive single-cell-derived (SCD) clonal populations from a mesenchymal cell source. METHODOLOGY/PRINCIPAL FINDINGS:Here we show that a tractable MPC population, human umbilical cord perivascular cells (HUCPVCs), was capable of multilineage differentiation in vitro and, more importantly, contributed to rapid connective tissue healing in vivo by producing bone, cartilage and fibrous stroma. Furthermore, HUCPVCs exhibit a high clonogenic frequency, allowing us to isolate definitive SCD parent and daughter clones from mixed gender suspensions as determined by Y-chromosome fluorescent in situ hybridization. CONCLUSIONS/SIGNIFICANCE:Analysis of the multilineage differentiation capacity of SCD parent clones and daughter clones enabled us to formulate a new hierarchical schema for MSC self-renewal and differentiation in which a self-renewing multipotent MSC gives rise to more restricted self-renewing progenitors that gradually lose differentiation potential until a state of complete restriction to the fibroblast is reached

Sympathoadrenergic modulation of hematopoiesis: a review of available evidence and of therapeutic perspectives

Innervation of the bone marrow (BM) has been described more than one century ago, however the first in vivo evidence that sympathoadrenergic fibers have a role in hematopoiesis dates back to less than 25 years ago. Evidence has since increased showing that adrenergic nerves in the BM release noradrenaline and possibly also dopamine, which act on adrenoceptors and dopaminergic receptors expressed on hematopoietic cells and affect cell survival, proliferation, migration and engraftment ability. Remarkably, dysregulation of adrenergic fibers to the BM is associated with hematopoietic disturbances and myeloproliferative disease. Several adrenergic and dopaminergic agents are already in clinical use for non-hematological indications and with a usually favourable risk-benefit profile, and are therefore potential candidates for non-conventional modulation of hematopoiesis

Parkin Deficiency Delays Motor Decline and Disease Manifestation in a Mouse Model of Synucleinopathy

In synucleinopathies, including Parkinson's disease, partially ubiquitylated α-synuclein species phosphorylated on serine 129 (PS129-α-synuclein) accumulate abnormally. Parkin, an ubiquitin-protein ligase that is dysfunctional in autosomal recessive parkinsonism, protects against α-synuclein-mediated toxicity in various models

Mesenchymal inflammation drives genotoxic stress in hematopoietic stem cells and predicts disease evolution in human pre-leukemia

Mesenchymal niche cells may drive tissue failure and malignant transformation in the hematopoietic system but the molecular mechanisms and their relevance to human disease remain poorly defined. Here, we show that perturbation of mesenchymal cells in a mouse model of the preleukemic disorder Shwachman-Diamond syndrome induces mitochondrial dysfunction, oxidative stress and activation of DNA damage responses in hematopoietic stem and progenitor cells. Massive parallel RNA sequencing of highly purified mesenchymal cells in the mouse model and a range of human preleukemic syndromes identified p53-S100A8/9-TLR inflammatory signaling as a common driving mechanism of genotoxic stress. Transcriptional activation of this signaling axis in the mesenchymal niche predicted leukemic evolution and progression-free survival in myelodysplastic syndrome, the principal leukemia predisposition syndrome. Collectively, our findings reveal a concept of mesenchymal niche-induced genotoxic stress in heterotypic stem and progenitor cells through inflammatory signaling as an actionable determinant of disease outcome in human preleukemia