Pre-orchiectomy tumor marker levels should not be used for International Germ Cell Consensus Classification (IGCCCG) risk group assignment

PURPOSE To investigate whether the use of pre-orchiectomy instead of pre-chemotherapy tumor marker (TM) levels has an impact on the International Germ Cell Consensus Classification (IGCCCG) risk group assignment in patients with metastatic germ cell tumors (GCT). METHODS Demographic and clinical information of all patients treated for primary metastatic testicular non-seminomatous GCT in our tertiary care academic center were extracted from medical charts. IGCCCG risk group assignment was correctly performed with pre-chemotherapy marker levels and additionally with pre-orchiectomy marker levels. Agreement between pre-chemotherapy and pre-orchiectomy risk group assignments was assessed using Cohen's kappa. RESULTS Our cohort consisted of 83 patients. The use of pre-orchiectomy TMs resulted in an IGCCCG risk group upstaging in 12 patients (16%, 8 patients from good to intermediate risk and 4 patients from intermediate to poor risk) and a downstaging in 1 patient (1.2%, from intermediate- to good-risk). The agreement between pre-orchiectomy and pre-chemotherapy IGCCCG risk groups resulted in a Cohen's kappa of 0.888 (p < 0.001). CONCLUSIONS Using pre-orchiectomy TMs can result in incorrect IGCCCG risk group assignment, which in turn can impact on the clinical management and follow-up of patients with metastatic GCT. Thus, adherence to the IGCCCG standard using pre-chemotherapy TMs levels is recommended

Characterizing the turbulent drag properties of rough surfaces with a Taylor--Couette setup

Wall-roughness induces extra drag in wall-bounded turbulent flows. Mapping any given roughness geometry to its fluid dynamic behaviour has been hampered by the lack of accurate and direct measurements of skin-friction drag. Here the Taylor-Couette (TC) system provides an opportunity as it is a closed system and allows to directly and reliably measure the skin-friction. However, the wall-curvature potentially complicates the connection between the wall friction and the wall roughness characteristics. Here we investigate the effects of a hydrodynamically fully rough surface on highly turbulent, inner cylinder rotating, TC flow. We find that the effects of a hydrodynamically fully rough surface on TC turbulence, where the roughness height k is three orders of magnitude smaller than the Obukhov curvature length Lc (which characterizes the effects of curvature on the turbulent flow, see Berghout et al. arXiv: 2003.03294, 2020), are similar to those effects of a fully rough surface on a flat plate turbulent boundary layer (BL). Hence, the value of the equivalent sand grain height ks, that characterizes the drag properties of a rough surface, is similar to those found for comparable sandpaper surfaces in a flat plate BL. Next, we obtain the dependence of the torque (skin-friction drag) on the Reynolds number for given wall roughness, characterized by ks, and find agreement with the experimental results within 5 percent. Our findings demonstrate that global torque measurements in the TC facility are well suited to reliably deduce wall drag properties for any rough surface.Comment: 18 pages, 13 figure

Challenges at the marketing–operations interface in omni-channel retail environments

To compete in today’s omni-channel business context, it is essential for firms to co-ordinate their activities across channels and across different stages of the customer journey and the product flow. This requires firms to adopt an integrative approach, addressing each omni-channel design decision from a dual demand-side (marketing) and supply-side (operations) perspective. However, both in practice and in academic research, such an integrative approach is still in an immature stage. In this article, a framework is developed with the following key decision areas: (i) assortment & inventory, (ii) distribution & delivery and (iii) returns. These affect both the customer journey and the product flow. As a consequence of the resulting interdependencies between the firm’s functions, addressing the issues that arise in the three decision areas requires an integrated marketing and operations perspective. For each of the areas, the key decisions that affect or involve both the customer journey and product flow are identified first. Next, for each decision, the marketing and operational goals and the tensions that arise when these goals are not perfectly aligned are described. The opportunities for relieving these tensions are also discussed and possible directions for future research aimed at addressing these tensions and opportunities are presented.info:eu-repo/semantics/publishedVersio

Mast Cells Control Neutrophil Recruitment during T Cell–Mediated Delayed-Type Hypersensitivity Reactions through Tumor Necrosis Factor and Macrophage Inflammatory Protein 2

Polymorphonuclear leukocytes (PMNs) characterize the pathology of T cell–mediated autoimmune diseases and delayed-type hypersensitivity reactions (DTHRs) in the skin, joints, and gut, but are absent in T cell–mediated autoimmune diseases of the brain or pancreas. All of these reactions are mediated by interferon γ–producing type 1 T cells and produce a similar pattern of cytokines. Thus, the cells and mediators responsible for the PMN recruitment into skin, joints, or gut during DTHRs remain unknown. Analyzing hapten-induced DTHRs of the skin, we found that mast cells determine the T cell–dependent PMN recruitment through two mediators, tumor necrosis factor (TNF) and the CXC chemokine macrophage inflammatory protein 2 (MIP-2), the functional analogue of human interleukin 8. Extractable MIP-2 protein was abundant during DTHRs in and around mast cells of wild-type (WT) mice but absent in mast cell–deficient WBB6F1-KitW/KitW-v (KitW/KitW-v) mice. T cell–dependent PMN recruitment was reduced >60% by anti–MIP-2 antibodies and >80% in mast cell–deficient KitW/KitW-v mice. Mast cells from WT mice efficiently restored DTHRs and MIP-2–dependent PMN recruitment in KitW/KitW-v mice, whereas mast cells from TNF−/− mice did not. Thus, mast cell–derived TNF and MIP-2 ultimately determine the pattern of infiltrating cells during T cell–mediated DTHRs

Age- and gender-related normal left ventricular deformation assessed by cardiovascular magnetic resonance feature tracking

Background: Assessment of left (LV) ventricular function is one of the most important tasks of cardiovascular magnetic resonance (CMR). Impairment of LV deformation is a strong predictor of cardiovascular outcome in various cardiac diseases like ischemic heart disease or cardiomyopathies. The aim of the study was to provide reference values for myocardial deformation derived from the CMR feature tracking imaging (FTI) algorithm in a reference population of healthy volunteers. Methods: FTI was applied to standard short axis and 2-, 3- and 4-chamber views of vector-ECG gated CMR cine SSFP sequences of 150 strictly selected healthy volunteers (75 male/female) of three age tertiles (mean age 45.8yrs). Global peak and mean radial, circumferential and longitudinal endo- and myocardial systolic strain values as well as early diastolic strain rates were measured using FTI within a standard protocol on a 1.5T whole body MR scanner. Results: Global peak systolic values were 36.3 ± 8.7% for radial, −27.2 ± 4.0% for endocardial circumferential, −21.3 ± 3.3% for myocardial circumferential, −23.4 ± 3.4% for endocardial longitudinal and −21.6 ± 3.2% for myocardial longitudinal strain. Global peak values were -2.1 ± 0.5s−1 for radial, 2.1 ± 0.6s−1 for circumferential endocardial, 1.7 ± 0.5s−1 for circumferential myocardial, 1.8 (1.5-2.2)s−1 for longitudinal endocardial, 1.6 (1.4-2.0)s−1 for longitudinal myocardial early diastolic strain rates. Men showed a higher radial strain than women whereas the circumferential and longitudinal strains were lower resulting in less negative values. Circumferential and longitudinal strain rates were significantly higher in female subjects. Radial strain increased significantly with age whereas the diastolic function measured by the radial, circumferential and longitudinal strain rates showed a decrease. The coefficients of variation determined in ten further subjects, who underwent two CMR examinations within 12 days, were −4.8% for circumferential and −4.5% for longitudinal endocardial mean strains. Conclusions: Myocardial deformation analysis using FTI is a novel technique and robust when applied to standard cine CMR images providing the possibility of a reliable, objective quantification of global LV deformation. Since strain values and strain rates differed partly between genders as well as between age groups, the application of specific reference values as provided by this study is recommendable

SARS-CoV-2 Proteome-Wide Analysis Revealed Significant Epitope Signatures in COVID-19 Patients

The WHO declared the COVID-19 outbreak a public health emergency of international concern. The causative agent of this acute respiratory disease is a newly emerged coronavirus, named SARS-CoV-2, which originated in China in late 2019. Exposure to SARS-CoV-2 leads to multifaceted disease outcomes from asymptomatic infection to severe pneumonia, acute respiratory distress and potentially death. Understanding the host immune response is crucial for the development of interventional strategies. Humoral responses play an important role in defending viral infections and are therefore of particular interest. With the aim to resolve SARS-CoV-2-specific humoral immune responses at the epitope level, we screened clinically well-characterized sera from COVID-19 patients with mild and severe disease outcome using high-density peptide microarrays covering the entire proteome of SARS-CoV-2. Moreover, we determined the longevity of epitope-specific antibody responses in a longitudinal approach. Here we present IgG and IgA-specific epitope signatures from COVID-19 patients, which may serve as discriminating prognostic or predictive markers for disease outcome and/or could be relevant for intervention strategies

Improved Somatic Mutagenesis in Zebrafish Using Transcription Activator-Like Effector Nucleases (TALENs)

Zinc Finger Nucleases (ZFNs) made by Context-Dependent Assembly (CoDA) and Transcription Activator-Like Effector Nucleases (TALENs) provide robust and user-friendly technologies for efficiently inactivating genes in zebrafish. These designer nucleases bind to and cleave DNA at particular target sites, inducing error-prone repair that can result in insertion or deletion mutations. Here, we assess the relative efficiencies of these technologies for inducing somatic DNA mutations in mosaic zebrafish. We find that TALENs exhibited a higher success rate for obtaining active nucleases capable of inducing mutations than compared with CoDA ZFNs. For example, all six TALENs tested induced DNA mutations at genomic target sites while only a subset of CoDA ZFNs exhibited detectable rates of mutagenesis. TALENs also exhibited higher mutation rates than CoDA ZFNs that had not been pre-screened using a bacterial two-hybrid assay, with DNA mutation rates ranging from 20%–76.8% compared to 1.1%–3.3%. Furthermore, the broader targeting range of TALENs enabled us to induce mutations at the methionine translation start site, sequences that were not targetable using the CoDA ZFN platform. TALENs exhibited similar toxicity to CoDA ZFNs, with >50% of injected animals surviving to 3 days of life. Taken together, our results suggest that TALEN technology provides a robust alternative to CoDA ZFNs for inducing targeted gene-inactivation in zebrafish, making it a preferred technology for creating targeted knockout mutants in zebrafish

Efficient design and assembly of custom TALEN and other TAL effector-based constructs for DNA targeting

TALENs are important new tools for genome engineering. Fusions of transcription activator-like (TAL) effectors of plant pathogenic Xanthomonas spp. to the FokI nuclease, TALENs bind and cleave DNA in pairs. Binding specificity is determined by customizable arrays of polymorphic amino acid repeats in the TAL effectors. We present a method and reagents for efficiently assembling TALEN constructs with custom repeat arrays. We also describe design guidelines based on naturally occurring TAL effectors and their binding sites. Using software that applies these guidelines, in nine genes from plants, animals and protists, we found candidate cleavage sites on average every 35 bp. Each of 15 sites selected from this set was cleaved in a yeast-based assay with TALEN pairs constructed with our reagents. We used two of the TALEN pairs to mutate HPRT1 in human cells and ADH1 in Arabidopsis thaliana protoplasts. Our reagents include a plasmid construct for making custom TAL effectors and one for TAL effector fusions to additional proteins of interest. Using the former, we constructed de novo a functional analog of AvrHah1 of Xanthomonas gardneri. The complete plasmid set is available through the non-profit repository AddGene and a web-based version of our software is freely accessible online