The efficacy of recombinant thrombopoietin in murine and nonhuman primate models for radiation-induced myelosuppression and stem cell transplantation

Radiation-induced pancytopenia proved to be a suitable model system in mice and rhesus monkeys for studying thrombopoietin (TPO) target cell range and efficacy. TPO was highly effective in rhesus monkeys exposed to the mid-lethal dose of 5 Gy (300 kV x-rays) TBI, a model in which it alleviated thrombocytopenia, promoted red cell reconstitution, accelerated reconstitution of immature CD34+ bone marrow cells, and potentiated the response to growth factors such as GM-CSF and G-CSF. In contrast to the results in the 5 Gy TBI model, TPO was ineffective following transplantation of limited numbers of autologous bone marrow or highly purified stem cells in monkeys conditioned with 8 Gy TBI. In the 5 Gy model, a single dose of TPO augmented by GM-CSF 24 h after TBI was effective in preventing thrombocytopenia. The strong erythropoietic stimulation may result in iron depletion, and TPO treatment should be accompanied by monitoring of iron status. This preclinical evaluation thus identified TPO as a potential major therapeutic agent for counteracting radiation-induced pancytopenia and demonstrated pronounced stimulatory effects on the reconstitution of immature CD34+ hemopoietic cells with multilineage potential. The latter observation explains the potentiation of the hematopoietic responses to G-CSF and GM-CSF when administered concomitantly. It also predicts the effective use of TPO to accelerate reconstitution of immature hematopoietic cells as well as possible synergistic effects in vivo with various other growth factors acting on immature stem cells and their direct lineage-committed progeny. The finding that a single dose of TPO might be sufficient for a clinically significant response emphasizes its potency and is of practical relevance. The heterogeneity of the TPO response encountered in the various models used for evaluation points to multiple mechanisms operating on the TPO response and heterogeneity of its target cells. Mechanistic mouse studies made apparent that the response of multilineage cells shortly after TBI to a single administration of TPO is quantitatively more important for optimal efficacy than the lineage-restricted response obtained at later intervals after TBI and emphasized the importance of a relatively high dose of TPO to overcome initial c-mpl-mediated clearance. Further elucidation of mechanisms determining efficacy might very well result in a further improvement, e.g., following transplantation of limited numbers of stem cells. Adverse effects of TPO administration to myelosuppressed or stem cell transplanted experimental animals were not observed

Diversity of Wadden Sea macrofauna and meiofauna communities highest in DNA from extractions preceded by cell lysis

Metabarcoding of genetic material in environmental samples has increasingly been employed as a means to assess biodiversity, also of marine benthic communities. Current protocols employed to extract DNA from benthic samples and subsequent bioinformatics pipelines differ considerably. The present study compares three commonly deployed metabarcoding approaches against a morphological approach to assess benthic biodiversity in an intertidal bay in the Dutch Wadden Sea. Environmental DNA was extracted using three different approaches; extraction of extracellular DNA, extraction preceded by cell lysis of a sieved fraction of the sediment, and extraction of DNA directly from small amounts of sediment. DNA extractions after lysis of sieved sediment fractions best recovered the macrofauna diversity whereas direct DNA extraction of small amounts of sediment best recovered the meiofauna diversity. Extractions of extracellular DNA yielded the lowest number of OTUs per sample and hence an incomplete view of benthic biodiversity. An assessment of different bioinformatic pipelines and parameters was conducted using a mock sample with a known species composition. The RDP classifier performed better than BLAST for taxonomic assignment of the samples in this study. Novel metabarcodes obtained from local specimens were added to the SILVA 18S rRNA database to improve taxonomic assignment. This study provides recommendations for a general metabarcoding protocol for marine benthic surveys in the Wadden Sea

Erratum: Impact of an artificial structure on the benthic community composition in the southern North Sea: Assessed by a morphological and molecular approach

The following affiliation for Lise Klunder was not included in the earlier version of this article. This has now been added: Marine Evolution and Conservation, Groningen Institute of Evolutionary Life Sciences, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands.</p

Impact of an artificial structure on the benthic community composition in the southern North Sea:Assessed by a morphological and molecular approach

Man-made structures in the North Sea are known to act as artificial reefs by providing a habitat for sessile epifauna in a predominantly soft sediment environment. This epifauna is hypothesized to cast a so-called "shadow"over the soft sediment ecosystem by altering the nutrient composition in the overlying water column. In addition, the structure itself could alter currents and thereby influence the deposition and erosion of the sediments in the wake of the platform. This study aims to assess the long-Term effects of a gas platform in the southern North Sea on the surrounding benthic community by both morphological and molecular identification of benthic species. The species composition and a set of abiotic factors of the sediment around a gas platform were assessed along four transects. Differences for the abiotic factors were found in the closer vicinity of the platform in the direction corresponding to the predominant currents. The number of benthic fauna families found in the molecular approach were on average three times higher than for the morphological approach. Both approaches showed that small differences occurred primarily due to changes in sedimentary organic matter content. Differences in species composition were more pronounced between transects rather than between distances from the platform.</p

A molecular approach to explore the background benthic fauna around a hydrothermal vent and their larvae:Implications for future mining of deep-sea SMS deposits

Seafloor massive sulfide (SMS) deposits are commonly found at hydrothermal vents and recently gained the special interest of mining industries. These deposits contain valuable metals and methods are currently developed to mine deep sea SMS deposits. However, excavation of SMS deposits potentially pose a threat to benthic life at the mining site itself, and also in the surrounding environment with plumes of suspended sediment and fine-grained SMS debris created during deep sea mining activities being highlighted as one of the major threats to deep-sea benthic fauna. The benthic communities surrounding the vents are, however, poorly known. As they are often exposed to natural plumes studying such communities could provide valuable information on their resilience toward mining related plumes. The Rainbow hydrothermal vent site at the Mid-Atlantic Ridge is a site characterized by one of the largest continuous natural plumes, which is found persisting over an extensive area. Sediment and water samples were taken both upstream and downstream of the Rainbow hydrothermal vent. Approximately 25 km away from the vent reference sites were samples as well. In addition to detecting the plume itself, concentrations of major and trace-metals in the sediments were used as tracers for long time sustained plume influence. At all sites, we assessed benthic species composition and detected larvae. Metabarcoding methods were used to determine species composition. Benthic species composition in the sediment was shown to differ between all locations and was highly influenced by the plume's fall out. Arthropoda were more dominant closer to the vent whereas Annelida and Nematoda were more dominant at the reference locations. Conservation and restoration of all these communities after a deep sea mining event will be difficult due to the spatial variation of these benthic communities

MSSM Higgs-Boson Production at Hadron Colliders with Explicit CP Violation

Gluon fusion is the main production mechanism for Higgs bosons with masses up to several hundred GeV in $pp$ collisions at the CERN Large Hadron Collider. We investigate the effects of the CP-violating phases on the fusion process including both the sfermion-loop contributions and the one-loop induced CP-violating scalar-pseudoscalar mixing in the minimal supersymmetric standard model. With a universal trilinear parameter assumed, every physical observable involves only the sum of the phases of the universal trilinear parameter $A$ and the higgsino mass parameter $\mu$. The phase affects the lightest Higgs-boson production rate significantly through the neutral Higgs-boson mixing and, for the masses around the lightest stop-pair threshold, it also changes the production rate of the heavy Higgs bosons significantly through both the stop and sbottom loops and the neutral Higgs-boson mixing.Comment: 28 pages, 8 figures. Some references and comments added. Typos corrected. To appear in Phys. Rev.

Meta-analysis identifies seven susceptibility loci involved in the atopic March

Eczema often precedes the development of asthma in a disease course called the a 'atopic march'. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P=2.1 × 10 a'8) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P=5.3 × 10 a'9). Additional susceptibility loci identified

Psychology and aggression

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68264/2/10.1177_002200275900300301.pd

Postoperative intensive care unit stay after minimally invasive esophagectomy shows large hospital variation. Results from the Dutch Upper Gastrointestinal Cancer Audit

Introduction: The value of routine intensive care unit (ICU) admission after minimally invasive esophagectomy (MIE) has been questioned. This study aimed to investigate Dutch hospital variation regarding length of direct postoperative ICU stay, and the impact of this hospital variation on short-term surgical outcomes. Materials and methods: Patients registered in the Dutch Upper Gastrointestinal Cancer Audit (DUCA) undergoing curative MIE were included. Length of direct postoperative ICU stay was dichotomized around the national median into short ICU stay ( ≤ 1 day) and long ICU stay ( > 1 day). A case-mix corrected funnel plot based on multivariable logistic regression analyses investigated hospital variation. The impact of this hospital variation on short-term surgical outcomes was investigated using multilevel multivariable logistic regression analyses. Results: Between 2017 and 2019, 2110 patients from 16 hospitals were included. Median length of postoperative ICU stay was 1 day [hospital variation: 0–4]. The percentage of short ICU stay ranged from 0 to 91% among hospitals. Corrected for case-mix, 7 hospitals had statistically significantly higher short ICU stay rates and 6 hospitals had lower rates. ICU readmission, in-hospital/30-day mortality, failure to rescue, postoperative pneumonia, cardiac complications and anastomotic leakage were not associated with hospital variation in length of ICU stay. Total length of hospital stay was significantly shorter in hospitals with relatively short ICU stay. Conclusion: This study showed significant hospital variation in postoperative length of ICU stay after MIE. Short ICU stay was associated with shorter overall hospital admission and did not negatively impact short-term surgical outcomes. More selected use of ICU resources could result in a national significant cost reduction

Real-world outcomes of advanced melanoma patients not represented in phase III trials

The aim was to provide evidence on systemically treated patients with advanced melanoma not represented in phase III trials to support clinical decision-making. Analysis were performed on advanced melanoma patients diagnosed between 2014 and 2017 in the Netherlands, treated with immune- or targeted therapy, who met ≥1 trial exclusion criteria. These criteria were derived from the KEYNOTE-006 and CHECKMATE-067/-066 phase III trials. Prognostic importance of factors associated with overall survival (OS) was assessed with the Kaplan-Meier method, Cox models, predicted OS probabilities of prognostic subgroups and a conditional inference survival tree (CIST). A nationwide population-based registry was used as data source. Of 2536 systemically treated patients with advanced melanoma, 1004 (40%) patients were ineligible for phase IIII trials. Ineligible patients had a poorer median OS (mOS) compared to eligible patients (8.8 vs 23 months). Eligibility criteria strongly associated with OS in systemically treated ineligible patients were Eastern Cooperative Oncology Group Performance Score (ECOG PS) ≥2, brain metastases (BM) and lactate dehydrogenase (LDH) of >500 U/L. Patients with ECOG PS of ≥2 with or without symptomatic BM had a predicted mOS of 6.5 and 11.3 months and a 3-year survival probability of 9.3% and 23.6%, respectively. The CIST showed the strongest prognostic covariate for survival was LDH, followed by ECOG PS. The prognosis of patients with LDH of >500 U/L is poor, but long-term survival is possible. The prognosis of ineligible patients with advanced melanoma in real-world was very heterogeneous and highly dependent on LDH value, ECOG PS and symptomatic BM