MMP13 mediates cell cycle progression in melanocytes and melanoma cells: in vitro studies of migration and proliferation

Contains fulltext : 87376.pdf (publisher's version ) (Open Access)BACKGROUND: Melanoma cells are usually characterized by a strong proliferative potential and efficient invasive migration. Among the multiple molecular changes that are recorded during progression of this disease, aberrant activation of receptor tyrosine kinases (RTK) is often observed. Activation of matrix metalloproteases goes along with RTK activation and usually enhances RTK-driven migration. The purpose of this study was to examine RTK-driven three-dimensional migration of melanocytes and the pro-tumorigenic role of matrix metalloproteases for melanocytes and melanoma cells. RESULTS: Using experimental melanocyte dedifferentiation as a model for early melanomagenesis we show that an activated EGF receptor variant potentiates migration through three-dimensional fibrillar collagen. EGFR stimulation also resulted in a strong induction of matrix metalloproteases in a MAPK-dependent manner. However, neither MAPK nor MMP activity were required for migration, as the cells migrated in an entirely amoeboid mode. Instead, MMPs fulfilled a function in cell cycle regulation, as their inhibition resulted in strong growth inhibition of melanocytes. The same effect was observed in the human melanoma cell line A375 after stimulation with FCS. Using sh- and siRNA techniques, we could show that MMP13 is the protease responsible for this effect. Along with decreased proliferation, knockdown of MMP13 strongly enhanced pigmentation of melanocytes. CONCLUSIONS: Our data show for the first time that growth stimuli are mediated via MMP13 in melanocytes and melanoma, suggesting an autocrine MMP13-driven loop. Given that MMP13-specific inhibitors are already developed, these results support the evaluation of these inhibitors in the treatment of melanoma

Failure to Predict High-risk Kawasaki Disease Patients in a Population-based Study Cohort in Germany

Background: Diverse scores on high-risk Kawasaki disease (KD) patients have proven a good prognostic validity in the Japanese population. However, data on non-Japanese have been inconclusive. Do the Kobayashi, Egami and Sano scores or application of up-to-date statistical methods (Random Forest) predict response to standard intravenous immunoglobulin (IVIG) therapy and the risk of persistent coronary artery aneurysm (CAA) in patients with KD in a mainly Caucasian population in Germany? Methods: Data on 442 children (German population-based survey, 2013 and 2014) were used to assess the prognostic validity of the Kobayashi, Egami and Sano scores for being refractory to IVIG treatment and for predicting the risk of persistent CAA. Additionally, an up-to-date statistical approach (Random Forest) was applied to identify a potentially more valid score. Results: A total of 301 children were eligible for assessment of their response to IVIG treatment. Among those, 177 children were followed-up for 1 year to identify persistent CAA. Although all scores were significantly associated with being refractory to IVIG (relative risk range between 2.32 and 3.73), the prognostic properties were low (likelihood ratio positive: 1.83-4.57;sensitivity in the range of 0.28-0.53). None of the scores was a significant predictor of CAA 1 year after acute illness. Application of statistical analysis such as Random Forest did not yield a more valid score. Conclusions: None of the available scores appears to be appropriate for identifying high-risk Caucasian children with KD who might need intensified therapy

SARS-CoV-2 variants and the risk of pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 among children in Germany

Purpose To investigate the relationship between the risk of pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) in children and the predominance of different SARS-CoV-2 variants of concern (VOC) over time. Methods In relation to the Alpha, Delta, and Omicron VOC phases of the pandemic, the risk of developing PIMS-TS was calculated by analyzing data for rtPCR-confirmed SARS-CoV-2 infections reported to the German statutory notification system, along with data captured by a separate, national PIMS-TS registry. Both overall infection rates and age group-specific ratios of PIMS-TS during the different pandemic phases were calculated using the Alpha period as the baseline. Results The PIMS-TS rate changed significantly over time. When the Alpha VOC was dominant [calendar week (CW) 11 in March–CW 31 in August 2021], the PIMS-TS rate was 6.19 [95% confidence intervals (95% CI) 5.17, 7.20]. When Delta prevailed (CW 32 in August 2021–CW 4 in January 2022), the rate decreased to 1.68 (95% CI 1.49, 1.87). During the Omicron phase (CW 5 in January–CW 16 in April 2022), the rate fell further to 0.89 (95% CI 0.79, 1.00). These changes correspond to a decreased PIMS-TS rate of 73% (rate ratio 0.271, 95% CI 0.222; 0.332) and 86% (rate ratio 0.048, 95% CI 0.037; 0.062), respectively, in comparison to the Alpha period. Rate ratios were nearly identical for all age groups. Conclusion The data strongly suggest an association between the risk for PIMS-TS and the prevailing VOC, with highest risk related to Alpha and the lowest to Omicron. Given the uniformity of the decreased risk across age groups, vaccination against SARS-CoV-2 does not appear to have a significant impact on the risk of children developing PIMS-TS.Peer Reviewe

Impact of Nanocomposite Combustion Aerosols on A549 Cells and a 3D Airway Model

The use of nanomaterials incorporated into plastic products is increasing steadily. By using nano-scaled filling materials, thermoplastics, such as polyethylene (PE), take advantage of the unique properties of nanomaterials (NM). The life cycle of these so-called nanocomposites (NC) usually ends with energetic recovery. However, the toxicity of these aerosols, which may consist of released NM as well as combustion-generated volatile compounds, is not fully understood. Within this study, model nanocomposites consisting of a PE matrix and nano-scaled filling material (TiO$_{2}$, CuO, carbon nano tubes (CNT)) were produced and subsequently incinerated using a lab-scale model burner. The combustion-generated aerosols were characterized with regard to particle release as well as compound composition. Subsequently, A549 cells and a reconstituted 3D lung cell culture model (MucilAir™, Epithelix) were exposed for 4 h to the respective aerosols. This approach enabled the parallel application of a complete aerosol, an aerosol under conditions of enhanced particle deposition using high voltage, and a filtered aerosol resulting in the sole gaseous phase. After 20 h post-incubation, cytotoxicity, inflammatory response (IL-8), transcriptional toxicity profiling, and genotoxicity were determined. Only the exposure toward combustion aerosols originated from PE-based materials induced cytotoxicity, genotoxicity, and transcriptional alterations in both cell models. In contrast, an inflammatory response in A549 cells was more evident after exposure toward aerosols of nano-scaled filler combustion, whereas the thermal decomposition of PE-based materials revealed an impaired IL-8 secretion. MucilAir™ tissue showed a pronounced inflammatory response after exposure to either combustion aerosols, except for nanocomposite combustion. In conclusion, this study supports the present knowledge on the release of nanomaterials after incineration of nano-enabled thermoplastics. Since in the case of PE-based combustion aerosols no major differences were evident between exposure to the complete aerosol and to the gaseous phase, adverse cellular effects could be deduced to the volatile organic compounds that are generated during incomplete combustion of NC

New Class of Eigenstates in Generic Hamiltonian Systems

In mixed systems, besides regular and chaotic states, there are states supported by the chaotic region mainly living in the vicinity of the hierarchy of regular islands. We show that the fraction of these hierarchical states scales as $\hbar^{-\alpha}$ and relate the exponent $\alpha=1-1/\gamma$ to the decay of the classical staying probability $P(t)\sim t^{-\gamma}$. This is numerically confirmed for the kicked rotor by studying the influence of hierarchical states on eigenfunction and level statistics.Comment: 4 pages, 3 figures, Phys. Rev. Lett., to appea

Antimicrobial Use in Pediatric Oncology and Hematology: Protocol for a Multicenter Point-Prevalence Study With Qualitative Expert Panel Assessment

Background: Because infections are a major driver of morbidity and mortality in children with hematologic or oncologic diseases, antimicrobials are frequently prescribed in pediatric oncology practice. However, excess or inappropriate use of antimicrobials is directly linked to the emergence of antimicrobial resistance. Although point-prevalence studies have examined the extent of antimicrobial use, a comprehensive qualitative evaluation of individual antimicrobial prescriptions remains lacking. Objective: The aim of this study is to identify appropriate versus inappropriate antimicrobial use among pediatric cancer patients in a point-prevalence study, followed by an expert panel adjudication process and a subsequent report of these findings to participating centers. This study also aims to improve the quality of patient care by informing centers about discrepancies between internal standards of care and national guidelines. Methods: Our point-prevalence study is performed at pediatric cancer centers in Germany and Austria. All patients under 18 years old who are hospitalized at the time of the study are included. As a supplement to the point-prevalence study, an expert panel is qualitatively assessing each of the antimicrobial prescriptions at the participating centers to review local guidelines and compare them with national guidelines. Results: As of December 2021, the point-prevalence survey has been conducted at 30 sites and expert panel adjudication for qualitative assessment of each antimicrobial use is ongoing. Results of the study are expected in 2022. Conclusions: This is the first point-prevalence study conducted among pediatric cancer centers with an integrated, multistep, qualitative approach that assesses each antimicrobial prescription. The results of this study will inform possible interventions for internal guidelines and antimicrobial stewardship programs implemented at pediatric cancer centers. In addition, local guidelines will be compared with national guidelines. Furthermore, this study will contribute to the overall integration of antimicrobial stewardship principles and initiatives in pediatric oncology and hematology, thereby improving safety and quality of care for children and adolescents with cancer and blood disorders

Helden in der Schule. Akten der Tagung Kloster Banz 2014

Ausgehend von der Feststellung, dass die Integration mittelalterlicher Texte im Deutschunterricht in der Schulpraxis weitgehend ein Desiderat darstellt, präsentierten Beitragende aus Schule und Wissenschaft bei der Tagung „Helden in der Schule“ im Oktober 2014 ihre Projekte und Ideen zu und Erfahrungen mit der Implementation germanistisch-mediävistischer Inhalte im Deutschunterricht. Dabei reichen die Beiträge von allgemeinen Überlegungen zum Nutzen mittelalterlicher Literatur in der Schule über konkrete Unterrichtsentwürfe bis hin zur Umsetzung in der Waldorfschule und der Integration schulbezogener Lehrveranstaltungen in der Universität. Bei aller Verschiedenheit in den Herangehensweisen wird in allen Beiträgen eindrucksvoll deutlich gemacht, dass mittelalterliche Literatur auch im 21. Jahrhundert überaus lohnend in die Unterrichtspraxis einbezogen werden kann.Since medieval texts are not treated enough in school, lecturers working in school and university presented their projects, ideas and experiences concerning the implementation of German-mediavistic contents in German school lessons during the conference “Heroes in School” in October 2014. The topics concern general reflection about the profitability of medieval literature in school, concrete lesson plans, the implementation in Rudolf Steiner schools, the integration of seminars in university that deal with the work in school etc. All articles demonstrate that the integration of medieval literature in school worth the effort – also in the 21st century

Cross-sectional seroprevalence surveys of SARS-CoV-2 antibodies in children in Germany, June 2020 to May 2021

The rate of SARS-CoV-2 infections in children remains unclear due to many asymptomatic cases. We present a study of cross-sectional seroprevalence surveys of anti-SARS-CoV-2 IgG in 10,358 children recruited in paediatric hospitals across Germany from June 2020 to May 2021. Seropositivity increased from 2.0% (95% CI 1.6, 2.5) to 10.8% (95% CI 8.7, 12.9) in March 2021 with little change up to May 2021. Rates increased by migrant background (2.8%, 4.4% and 7.8% for no, one and two parents born outside Germany). Children under three were initially 3.6 (95% CI 2.3, 5.7) times more likely to be seropositive with levels equalising later. The ratio of seropositive cases per recalled infection decreased from 8.6 to 2.8. Since seropositivity exceeds the rate of recalled infections considerably, serologic testing may provide a more valid estimate of infections, which is required to assess both the spread and the risk for severe outcomes of SARS-CoV-2 infections

Enterococcal colonization of infants in a neonatal intensive care unit: associated predictors, risk factors and seasonal patterns

<p>Abstract</p> <p>Background</p> <p>During and shortly after birth, newborn infants are colonized with enterococci. This study analyzes predictors for early enterococcal colonization of infants in a neonatal intensive care unit and describes risk factors associated with multidrugresistant enterococci colonization and its seasonal patterns.</p> <p>Methods</p> <p>Over a 12-month period, we performed a prospective epidemiological study in 274 infants admitted to a neonatal intensive care unit. On the first day of life, we compared infants with enterococcal isolates detected in meconium or body cultures to those without. We then tested the association of enterococcal colonization with peripartal predictors/risk factors by using bivariate and multivariate statistical methods.</p> <p>Results</p> <p>Twenty-three percent of the infants were colonized with enterococci. The three most common enterococcal species were <it>E. faecium </it>(48% of isolates), <it>E. casseliflavus </it>(25%) and <it>E. faecalis </it>(13%). Fifty-seven percent of the enterococci found were resistant to three of five antibiotic classes, but no vancomycin-resistant isolates were observed. During winter/spring months, the number of enterococci and multidrug-resistant enterococci were higher than in summer/fall months (p = 0.002 and p < 0.0001, respectively). With respect to enterococcal colonization on the first day of life, predictors were prematurity (p = 0.043) and low birth weight (p = 0.011). With respect to colonization with multidrug-resistant enterococci, risk factors were prematurity (p = 0.0006), low birth weight (p < 0.0001) and prepartal antibiotic treatment (p = 0.019). Using logistic regression, we determined that gestational age was the only parameter significantly correlated with multidrug-resistant enterococci colonization. No infection with enterococci or multidrugresistant enterococci in the infants was detected. The outcome of infants with and without enterococcal colonization was the same with respect to death, necrotizing enterocolitis, intracerebral hemorrhage and bronchopulmonary dysplasia.</p> <p>Conclusion</p> <p>In neonatal intensive care units, an infant's susceptibility to early colonization with enterococci in general, and his or her risk for colonization with multidrug-resistant enterococci in particular, is increased in preterm newborns, especially during the winter/spring months. The prepartal use of antibiotics with no known activity against enterococci appears to increase the risk for colonization with multidrug-resistant enterococci.</p