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- Department of Nuclear Medicine, Philipps University Marburg, Marburg, Germany (1)
- Georg August University School of Science (1)
- Helmholtz Institute for RNA-based Infection Biology (HIRI), Josef-Schneider-Straße 2/D15, DE-97080 Wuerzburg, Germany (1)
- IZKF Nachwuchsgruppe Geweberegeneration für muskuloskelettale Erkrankungen (1)
- Institute of Cancer Research (ICR) London (1)
Objectives
Micro-computed tomography (μ-CT) and histology, the current gold standard methods for assessing the formation of new bone and blood vessels, are invasive and/or destructive. With that in mind, a more conservative tool, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), was tested for its accuracy and reproducibility in monitoring neovascularization during bone regeneration. Additionally, the suitability of blood perfusion as a surrogate of the efficacy of osteoplastic materials was evaluated.
Materials and methods
Sixteen rabbits were used and equally divided into four groups, according to the time of euthanasia (2, 3, 4, and 6 weeks after surgery). The animals were submitted to two 8-mm craniotomies that were filled with blood or autogenous bone. Neovascularization was assessed in vivo through DCE-MRI, and bone regeneration, ex vivo, through μ-CT and histology.
Results
The defects could be consistently identified, and their blood perfusion measured through DCE-MRI, there being statistically significant differences within the blood clot group between 3 and 6 weeks (p = 0.029), and between the former and autogenous bone at six weeks (p = 0.017). Nonetheless, no significant correlations between DCE-MRI findings on neovascularization and μ-CT (r =−0.101, 95% CI [−0.445; 0.268]) or histology (r = 0.305, 95% CI [−0.133; 0.644]) findings on bone regeneration were observed.
Conclusions
These results support the hypothesis that DCE-MRI can be used to monitor neovascularization but contradict the premise that it could predict bone regeneration as well.
Purpose
Biallelic pathogenic NBAS variants manifest as a multisystem disorder with heterogeneous clinical phenotypes such as recurrent acute liver failure, growth retardation, and susceptibility to infections. This study explores how NBAS-associated disease affects cells of the innate and adaptive immune system.
Methods
Clinical and laboratory parameters were combined with functional multi-parametric immunophenotyping methods in fifteen NBAS-deficient patients to discover possible alterations in their immune system.
Results
Our study revealed reduced absolute numbers of mature CD56dim natural killer (NK) cells. Notably, the residual NK cell population in NBAS-deficient patients exerted a lower potential for activation and degranulation in response to K562 target cells, suggesting an NK cell–intrinsic role for NBAS in the release of cytotoxic granules. NBAS-deficient NK cell activation and degranulation was normalized upon pre-activation by IL-2 in vitro, suggesting that functional impairment was reversible. In addition, we observed a reduced number of naïve B cells in the peripheral blood associated with hypogammaglobulinemia.
Conclusion
In summary, we demonstrate that pathogenic biallelic variants in NBAS are associated with dysfunctional NK cells as well as impaired adaptive humoral immunity.
Die quantitative Analyse der relativen DNA-Methylierung gilt als eine der vielversprechendsten Methoden der molekularen Altersschätzung. Viele Studien der letzten Jahre identifizierten geeignete Positionen im Genom, deren DNA-Methylierung sich altersabhängig verändert. Für den Einsatz dieser Methode in der Routine- bzw. Fallarbeit ist es von großer Bedeutung, angewandte Analysetechniken zu validieren. Als ein Teilaspekt dieser Validierung sollte die Vergleichbarkeit der Analyseergebnisse zur DNA-Methylierung mithilfe der Mini- und Pyrosequenzierung zwischen verschiedenen Laboren evaluiert werden. Die Arbeitsgruppe „Molekulare Altersschätzung“ der Deutschen Gesellschaft für Rechtsmedizin (DGRM) führte hierzu den ersten, technischen Ringversuch durch, der 4 Positionen in den Genen PDE4C, EDARADD, SST und KLF14 umfasste. Diese Marker waren in vorangegangenen Studien als altersabhängige Biomarker charakterisiert worden. Am Ringversuch nahmen 12 Labore teil, wobei jedes die Wahl zwischen der Minisequenzierung und/oder der Pyrosequenzierung für die quantitative Methylierungsanalyse hatte. Jedem teilnehmenden Labor wurden Blut- und Speichelproben von 3 Personen unterschiedlichen Alters übersandt. Die Wahl der Reagenzien für die Probenbearbeitung wurde den Teilnehmern freigestellt.
Die Ergebnisse der Minisequenzierung zeigten systematische Abweichungen zwischen den Laboren, die am ehesten auf die Verwendung unterschiedlicher Reagenzien und Analyseplattformen zurückzuführen sein können. Die Resultate der Pyrosequenzierung hingegen wiesen nicht auf systematische Abweichungen zwischen den Laboren hin, hier zeigte sich jedoch die Tendenz einer markerabhängigen Abweichung. Darüber hinaus konnten Unterschiede hinsichtlich technischer Probleme zwischen Laboren mit mehr Erfahrung in der jeweiligen Sequenzierungsmethode und Laboren mit weniger Erfahrung festgestellt werden. Sowohl die Beobachtung von systematischen als auch die von markerabhängigen Abweichungen lässt den Schluss zu, dass eine Übertragung von Analysemethoden zwischen Laboren grundsätzlich möglich ist, eine Anpassung des jeweiligen Modells zur Altersschätzung jedoch notwendig sein kann.
Systemic chemotherapy of pediatric recurrent ependymomas: results from the German HIT-REZ studies
(2021)
Purpose
Survival in recurrent ependymoma (EPN) depends mainly on the extent of resection achieved. When complete resection is not feasible, chemotherapy is often used to extend progression-free and overall survival. However, no consistent effect of chemotherapy on survival has been found in patients with recurrent EPN.
Methods
Systemic chemotherapeutic treatment of 138 patients enrolled in the German HIT-REZ-studies was analyzed. Survival depending on the use of chemotherapy, disease-stabilization rates (RR), duration of response (DOR) and time to progression (TTP) were estimated.
Results
Median age at first recurrence was 7.6 years (IQR: 4.0–13.6). At first recurrence, median PFS and OS were 15.3 (CI 13.3–20.0) and 36.9 months (CI 29.7–53.4), respectively. The Hazard Ratio for the use of chemotherapy in local recurrences in a time-dependent Cox-regression analysis was 0.99 (CI 0.74–1.33). Evaluable responses for 140 applied chemotherapies were analyzed, of which sirolimus showed the best RR (50%) and longest median TTP [11.51 (CI 3.98; 14.0) months] in nine patients, with the strongest impact found when sirolimus was used as a monotherapy. Seven patients with progression-free survival > 12 months after subtotal/no-resection facilitated by chemotherapy were found. No definitive survival advantage for any drug in a specific molecularly defined EPN type was found.
Conclusion
No survival advantage for the general use of chemotherapy in recurrent EPN was found. In cases with incomplete resection, chemotherapy was able to extend survival in individual cases. Sirolimus showed the best RR, DOR and TTP out of all drugs analyzed and may warrant further investigation.
Across Europe, calcareous grasslands become increasingly fragmented and their quality deteriorates through abandonment and land use intensification, both affecting biodiversity. Here, we investigated local and landscape effects on diversity patterns of several taxonomic groups in a landscape of highly fragmented calcareous grassland remnants. We surveyed 31 grassland fragments near Göttingen, Germany, in spring and summer 2017 for vascular plants, butterflies and birds, with sampling effort adapted to fragment area. Through regression modelling, we tested relationships between species richness and fragment size (from 314 to 51,395 m\(^2\)), successional stage, habitat connectivity and the per cent cover of arable land in the landscape at several radii. We detected 283 plant species, 53 butterfly species and 70 bird species. Of these, 59 plant species, 19 butterfly species and 9 bird species were grassland specialists. Larger fragments supported twice the species richness of plants than small ones, and hosted more species of butterflies, but not of birds. Larger grassland fragments contained more grassland specialist plants, but not butterfly or bird specialists. Increasing amounts of arable land in the landscape from 20 to 90% was related to the loss of a third of species of plants, and less so, of butterflies, but not of birds. Per cent cover of arable land negatively correlated to richness of grassland specialist plants and butterflies, but positively to grassland specialist birds. We found no effect by successional stages and habitat connectivity. Our multi-taxa approach highlights the need for conservation management at the local scale, complemented by measures at the landscape scale.
Optimization problems with composite functions consist of an objective function which is the sum of a smooth and a (convex) nonsmooth term. This particular structure is exploited by the class of proximal gradient methods and some of their generalizations like proximal Newton and quasi-Newton methods. The current literature on these classes of methods almost exclusively considers the case where also the smooth term is convex. Here we present a globalized proximal Newton-type method which allows the smooth term to be nonconvex. The method is shown to have nice global and local convergence properties, and some numerical results indicate that this method is very promising also from a practical point of view.
In this work, we present a multimodal approach to three-dimensionally quantify and visualize fiber orientation and resin-rich areas in carbon-fiber-reinforced polymers manufactured by vacuum infusion. Three complementary image modalities were acquired by Talbot–Lau grating interferometer (TLGI) X-ray microcomputed tomography (XCT). Compared to absorption contrast (AC), TLGI-XCT provides enhanced contrast between polymer matrix and carbon fibers at lower spatial resolutions in the form of differential phase contrast (DPC) and dark-field contrast (DFC). Consequently, relatively thin layers of resin, effectively indiscernible from image noise in AC data, are distinguishable. In addition to the assessment of fiber orientation, the combination of DPC and DFC facilitates the quantification of resin-rich areas, e.g., in gaps between fiber layers or at binder yarn collimation sites. We found that resin-rich areas between fiber layers are predominantly developed in regions characterized by a pronounced curvature. In contrast, in-layer resin-rich areas are mainly caused by the collimation of fibers by binder yarn. Furthermore, void volume around two adjacent 90°-oriented fiber layers is increased by roughly 20% compared to a random distribution over the whole specimen.
Background
Deregulated expression of MYC is a driver of colorectal carcinogenesis, suggesting that decreasing MYC expression may have significant therapeutic value. CIP2A is an oncogenic factor that regulates MYC expression. CIP2A is overexpressed in colorectal cancer (CRC), and its expression levels are an independent marker for long-term outcome of CRC. Previous studies suggested that CIP2A controls MYC protein expression on a post-transcriptional level.
Methods
To determine the mechanism by which CIP2A regulates MYC in CRC, we dissected MYC translation and stability dependent on CIP2A in CRC cell lines.
Results
Knockdown of CIP2A reduced MYC protein levels without influencing MYC stability in CRC cell lines. Interfering with proteasomal degradation of MYC by usage of FBXW7-deficient cells or treatment with the proteasome inhibitor MG132 did not rescue the effect of CIP2A depletion on MYC protein levels. Whereas CIP2A knockdown had marginal influence on global protein synthesis, we could demonstrate that, by using different reporter constructs and cells expressing MYC mRNA with or without flanking UTR, CIP2A regulates MYC translation. This interaction is mainly conducted by the MYC 5′UTR.
Conclusions
Thus, instead of targeting MYC protein stability as reported for other tissue types before, CIP2A specifically regulates MYC mRNA translation in CRC but has only slight effects on global mRNA translation. In conclusion, we propose as novel mechanism that CIP2A regulates MYC on a translational level rather than affecting MYC protein stability in CRC.
Formation and treatment of biofilms present a great challenge for health care and industry. About 80% of human infections are associated with biofilms including biomaterial centered infections, like infections of prosthetic heart valves, central venous catheters, or urinary catheters. Additionally, biofilms can cause food and drinking water contamination. Biofilm research focusses on application of experimental biofilm models to study initial adherence processes, to optimize physico-chemical properties of medical materials for reducing interactions between materials and bacteria, and to investigate biofilm treatment under controlled conditions. Exploring new antimicrobial strategies plays a key role in a variety of scientific disciplines, like medical material research, anti-infectious research, plant engineering, or wastewater treatment. Although a variety of biofilm models exist, there is a lack of standardization for experimental protocols, and designing experimental setups remains a challenge. In this study, a number of experimental parameters critical for material research have been tested that influence formation and stability of an experimental biofilm using the non-pathogenic model strain of Pseudomonas fluorescens. These parameters include experimental time frame, nutrient supply, inoculum concentration, static and dynamic cultivation conditions, material properties, and sample treatment during staining for visualization of the biofilm. It was shown, that all tested parameters critically influence the experimental biofilm formation process. The results obtained in this study shall support material researchers in designing experimental biofilm setups.
Therapy options for adrenal insufficiency and recommendations for the management of adrenal crisis
(2021)
Adrenal insufficiency (AI) is a life-threatening condition requiring life-long glucocorticoid (GC) substitution therapy, as well as stress adaptation to prevent adrenal crises. The number of individuals with primary and secondary adrenal insufficiency in Europe is estimated to be 20–50/100.000. A growing number of AI cases are due to side effects of GC treatment used in different treatment strategies for cancer and to immunotherapy in cancer treatment. The benefit of hormone replacement therapy is evident but long-term adverse effects may arise due to the non-physiological GC doses and treatment regimens used. Given multiple GC replacement formulations available comprising short-acting, intermediate, long-acting and novel modified-release hydrocortisone as well as subcutaneous formulations, this review offers a concise summary on the latest therapeutic improvements for treatment of AI and prevention of adrenal crises. As availability of various glucocorticoid formulations and access to expert centers across Europe varies widely, European Reference Networks on rare endocrine conditions aim at harmonizing treatment and ensure access to specialized patient care for individual case-by-case treatment decisions. To improve the availability across Europe to cost effective oral and parenteral formulations of hydrocortisone will save lives.