Epithelial ovarian cancer is a highly heterogeneous disease and remains the most lethal gynaecological malignancy in the Western world. Therapeutic approaches need to account for inter-patient and ...intra-tumoural heterogeneity and detailed characterization of in vitro models representing the different histological and molecular ovarian cancer subtypes is critical to enable reliable preclinical testing. There are approximately 100 publicly available ovarian cancer cell lines but their cellular and molecular characteristics are largely undescribed. We have characterized 39 ovarian cancer cell lines under uniform conditions for growth characteristics, mRNA/microRNA expression, exon sequencing, drug response for clinically-relevant therapeutics and collated all available information on the original clinical features and site of origin. We tested for statistical associations between the cellular and molecular features of the lines and clinical features. Of the 39 ovarian cancer cell lines, 14 were assigned as high-grade serous, four serous-type, one low-grade serous and 20 non-serous type. Three morphological subtypes: Epithelial (n = 21), Round (n = 7) and Spindle (n = 12) were identified that showed distinct biological and molecular characteristics, including overexpression of cell movement and migration-associated genes in the Spindle subtype. Comparison with the original clinical data showed association of the spindle-like tumours with metastasis, advanced stage, suboptimal debulking and poor prognosis. In addition, the expression profiles of Spindle, Round and Epithelial morphologies clustered with the previously described C1-stromal, C5-mesenchymal and C4 ovarian subtype expression profiles respectively. Comprehensive profiling of 39 ovarian cancer cell lines under controlled, uniform conditions demonstrates clinically relevant cellular and genomic characteristics. This data provides a rational basis for selecting models to develop specific treatment approaches for histological and molecular subtypes of ovarian cancer.
Metal halide perovskite photodiodes (PPDs) offer high responsivity and broad spectral sensitivity, making them attractive for low-cost visible and near-infrared sensing. A significant challenge in ...achieving high detectivity in PPDs is lowering the dark current density (J
) and noise current (i
). This is commonly accomplished using charge-blocking layers to reduce charge injection. By analyzing the temperature dependence of J
for lead-tin based PPDs with different bandgaps and electron-blocking layers (EBL), we demonstrate that while EBLs eliminate electron injection, they facilitate undesired thermal charge generation at the EBL-perovskite interface. The interfacial energy offset between the EBL and the perovskite determines the magnitude and activation energy of J
. By increasing this offset we realized a PPD with ultralow J
and i
of 5 × 10
mA cm
and 2 × 10
A Hz
, respectively, and wavelength sensitivity up to 1050 nm, establishing a new design principle to maximize detectivity in perovskite photodiodes.
Abstract
Aims
The dilated cardiomyopathy (DCM) phenotype is the result of combined genetic and acquired triggers. Until now, clinical decision-making in DCM has mainly been based on ejection fraction ...(EF) and NYHA classification, not considering the DCM heterogenicity. The present study aimed to identify patient subgroups by phenotypic clustering integrating aetiologies, comorbidities, and cardiac function along cardiac transcript levels, to unveil pathophysiological differences between DCM subgroups.
Methods and results
We included 795 consecutive DCM patients from the Maastricht Cardiomyopathy Registry who underwent in-depth phenotyping, comprising extensive clinical data on aetiology and comorbodities, imaging and endomyocardial biopsies. Four mutually exclusive and clinically distinct phenogroups (PG) were identified based upon unsupervised hierarchical clustering of principal components: PG1 mild systolic dysfunction, PG2 auto-immune, PG3 genetic and arrhythmias, and PG4 severe systolic dysfunction. RNA-sequencing of cardiac samples (n = 91) revealed a distinct underlying molecular profile per PG: pro-inflammatory (PG2, auto-immune), pro-fibrotic (PG3; arrhythmia), and metabolic (PG4, low EF) gene expression. Furthermore, event-free survival differed among the four phenogroups, also when corrected for well-known clinical predictors. Decision tree modelling identified four clinical parameters (auto-immune disease, EF, atrial fibrillation, and kidney function) by which every DCM patient from two independent DCM cohorts could be placed in one of the four phenogroups with corresponding outcome (n = 789; Spain, n = 352 and Italy, n = 437), showing a feasible applicability of the phenogrouping.
Conclusion
The present study identified four different DCM phenogroups associated with significant differences in clinical presentation, underlying molecular profiles and outcome, paving the way for a more personalized treatment approach.
Graphical Abstract
No validated molecular biomarkers exist to help guide prognosis of renal cell carcinoma (RCC) patients. We seek to evaluate the quality of published prognostic circulating RCC biomarker manuscripts ...using the Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK) guidelines.
The phrase "(renal cell carcinoma OR renal cancer OR kidney cancer OR kidney carcinoma) AND circulating AND (biomarkers OR cell free DNA OR tumor DNA OR methylated cell free DNA OR methylated tumor DNA)" was searched in Embase, Medline and PubMed March 2018. Relevant manuscripts were scored using 48 REMARK sub-criteria for a maximal score of 20 points.
The search identified 535 publications: 33 were manuscripts of primary research and were analyzed. The mean REMARK score was 10.6 (range 6.42-14.2). All manuscripts stated their biomarker, study objectives and method of case selection. The lowest scoring criteria: time lapse between storage of blood/serum and marker assay (n = 2) and lack of flow diagram (n = 2). REMARK scores were significantly higher in publications stating adherence to REMARK guidelines (p = 0.0307) and reporting statistically significant results (p = 0.0318).
Most RCC prognostic biomarker manuscripts poorly adhere to the REMARK guidelines. Better designed studies and appropriate reporting are required to address this urgent unmet need.
To develop evidence-based recommendations for the use of imaging modalities in primary large vessel vasculitis (LVV) including giant cell arteritis (GCA) and Takayasu arteritis (TAK). European League ...Against Rheumatism (EULAR) standardised operating procedures were followed. A systematic literature review was conducted to retrieve data on the role of imaging modalities including ultrasound, MRI, CT and
F-fluorodeoxyglucose positron emission tomography (PET) in LVV. Based on evidence and expert opinion, the task force consisting of 20 physicians, healthcare professionals and patients from 10 EULAR countries developed recommendations, with consensus obtained through voting. The final level of agreement was voted anonymously. A total of 12 recommendations have been formulated. The task force recommends an early imaging test in patients with suspected LVV, with ultrasound and MRI being the first choices in GCA and TAK, respectively. CT or PET may be used alternatively. In case the diagnosis is still in question after clinical examination and imaging, additional investigations including temporal artery biopsy and/or additional imaging are required. In patients with a suspected flare, imaging might help to better assess disease activity. The frequency and choice of imaging modalities for long-term monitoring of structural damage remains an individual decision; close monitoring for aortic aneurysms should be conducted in patients at risk for this complication. All imaging should be performed by a trained specialist using appropriate operational procedures and settings. These are the first EULAR recommendations providing up-to-date guidance for the role of imaging in the diagnosis and monitoring of patients with (suspected) LVV.
Large vessel vasculitis (LVV) is defined as a disease mainly affecting the large arteries, with two major variants, Takayasu arteritis (TA) and giant cell arteritis (GCA). GCA often coexists with ...polymyalgia rheumatica (PMR) in the same patient, since both belong to the same disease spectrum. FDG-PET/CT is a functional imaging technique which is an established tool in oncology, and has also demonstrated a role in the field of inflammatory diseases. Functional FDG-PET combined with anatomical CT angiography, FDG-PET/CT(A), may be of synergistic value for optimal diagnosis, monitoring of disease activity, and evaluating damage progression in LVV. There are currently no guidelines regarding PET imaging acquisition for LVV and PMR, even though standardization is of the utmost importance in order to facilitate clinical studies and for daily clinical practice. This work constitutes a joint procedural recommendation on FDG-PET/CT(A) imaging in large vessel vasculitis (LVV) and PMR from the Cardiovascular and Inflammation & Infection Committees of the European Association of Nuclear Medicine (EANM), the Cardiovascular Council of the Society of Nuclear Medicine and Molecular Imaging (SNMMI), and the PET Interest Group (PIG), and endorsed by the American Society of Nuclear Cardiology (ASNC). The aim of this joint paper is to provide recommendations and statements, based on the available evidence in the literature and consensus of experts in the field, for patient preparation, and FDG-PET/CT(A) acquisition and interpretation for the diagnosis and follow-up of patients with suspected or diagnosed LVV and/or PMR. This position paper aims to set an internationally accepted standard for FDG-PET/CT(A) imaging and reporting of LVV and PMR.
In baseball pitchers the elbow is exposed to high and repetitive loads (i.e. external valgus torque), caused by pitching a high number of balls in a practice session or game. This can result in ...overuse injuries like the ulnar collateral ligament (UCL) injury. To understand injury mechanisms, the effect of repetitive pitching on the elbow load magnitude and variability was investigated. In addition, we explored whether repetitive pitching affects elbow muscle activation during pitching. Fifteen pitchers threw each 60 to 110 balls. The external valgus torque and electromyography of three elbow muscles were quantified during each pitch. Linear mixed model analyses were performed to investigate the effect of repetitive pitching. On a group level, the linear mixed models showed no significant associations of repetitive pitching with valgus torque magnitude and variability and elbow muscle activity. Significant differences exist between pitchers in their individual trajectories in elbow valgus torque and muscle activity with repetitive pitching. This shows the importance of individuality in relation to repetitive pitching. In order to achieve effective elbow injury prevention in baseball pitching, individual characteristics of changes in elbow load and muscle activity in relation to the development of UCL injuries should be investigated.
Peripheral nerve injuries that induce gaps larger than 1-2 cm require bridging strategies for repair. Autologous nerve grafts are still the gold standard for such interventions, although alternative ...treatments, as well as treatments to improve the therapeutic efficacy of autologous nerve grafting are generating increasing interest. Investigations are still mostly experimental, although some clinical studies have been undertaken. In this review, we aim to describe the developments in bridging technology which aim to replace the autograft. A multi-disciplinary approach is of utmost importance to develop and optimise treatments of the most challenging peripheral nerve injuries.
The meninges contain adaptive immune cells that provide immunosurveillance of the central nervous system (CNS). These cells are thought to derive from the systemic circulation. Through single-cell ...analyses, confocal imaging, bone marrow chimeras, and parabiosis experiments, we show that meningeal B cells derive locally from the calvaria, which harbors a bone marrow niche for hematopoiesis. B cells reach the meninges from the calvaria through specialized vascular connections. This calvarial-meningeal path of B cell development may provide the CNS with a constant supply of B cells educated by CNS antigens. Conversely, we show that a subset of antigen-experienced B cells that populate the meninges in aging mice are blood-borne. These results identify a private source for meningeal B cells, which may help maintain immune privilege within the CNS.
Element- and orbital-selective x-ray absorption and magnetic circular dichroism measurements are carried out to probe the electronic structure and magnetism of Ir 5d electronic states in double ...perovskite Sr sub(2) MIrO sub(6) (M = Mg, Ca, Sc, Ti, Ni, Fe, Zn, In) and La sub(2) NiIrO sub(6) compounds. All the studied systems present a significant influence of spin-orbit interactions in the electronic ground state. In addition, we find that the Ir 5d local magnetic moment shows different character depending on the oxidation state despite the net magnetization being similar for all the compounds. Ir carries an orbital contribution comparable to the spin contribution for Ir super(4+) (5d super(5)) and Ir super(5+) (5d super(4)) oxides, whereas the orbital contribution is quenched for Ir super(6+) (5d super(3)) samples. Incorporation of a magnetic 3d atom allows getting insight into the magnetic coupling between 5d and 3d transition metals. Together with previous susceptibility and neutron diffraction measurements, the results indicate that Ir carries a significant local magnetic moment even in samples without a 3d metal. The size of the (small) net magnetization of these compounds is a result of predominant antiferromagnetic interactions between local moments coupled with structural details of each perovskite structure.
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