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EU-Projektnummer / Contract (GA) number
- 265432 (2)
Background CD30+ T-cell lymphoproliferations comprise a spectrum of clinically heterogeneous entities, including systemic anaplastic large cell lymphomas (ALK- and ALK+) and primary cutaneous CD30+ T-cell lymphoproliferative disorders. While all these entities are characterized by proliferation of highly atypical, anaplastic CD30+ T cells, the expression of T-cell specific antigens in the tumor cells is not consistently detectable. Design and Methods We evaluated biopsies from 19 patients with primary cutaneous CD30+ lymphoproliferative disorders, 38 with ALK- and 33 with ALK+ systemic anaplastic large cell lymphoma. The biopsies were examined for the expression of T-cell receptoraβ/CD3 complex (CD3γ, δ, ε, ζ), transcription factors regulating T-cell receptor expression (ATF1, ATF2, TCF-1, TCF-1a/LEF-1, Ets1), and molecules of T-cell receptor-associated signaling cascades (Lck, ZAP-70, LAT, bcl-10, Carma1, NFATc1, c-Jun, c-Fos, Syk) using immunohistochemistry. Results In comparison to the pattern in 20 peripheral T-cell lymphomas, not otherwise specified, we detected a highly disturbed expression of the T-cell receptor/CD3 complex, TCF-1, TCF- 1a/LEF-1, Lck, ZAP-70, LAT, NFATc1, c-Jun, c-Fos and Syk in most of the systemic anaplastic large cell lymphomas. In addition, primary cutaneous CD30+ lymphoproliferative disorders showed such a similar expression pattern to that of systemic anaplastic large cell lymphomas, that none of the markers we investigated can reliably distinguish between these CD30+ T-cell lymphoproliferations. Conclusions Severely altered expression of the T-cell receptor/CD3 complex, T-cell receptor-associated transcription factors and signal transduction molecules is a common characteristic of systemic and cutaneous CD30+ lymphoproliferations, although the clinical behavior of these entities is very different. Since peripheral T-cell lymphomas, not otherwise specified retain the full expression program required for functioning T-cell receptor signaling, the differential expression of a subset of these markers might be of diagnostic utility in distinguishing peripheral T-cell lymphomas, not otherwise specified from the entire group of CD30+ lymphoproliferations.
Background: Animal models of human inflammatory diseases have limited predictive quality for human clinical trials for various reasons including species specific activation mechanisms and the immunological background of the animals which markedly differs from the genetically heterogeneous and often aged patient population.
Objective: Development of an animal model allowing for testing therapeutics targeting pathways involved in the development of Atopic Dermatitis (AD) with better translatability to the patient.
Methods: NOD-scid IL2R \(\gamma^{null}\) mice engrafted with human peripheral blood mononuclear cells (hPBMC) derived from patients suffering from AD and healthy volunteers were treated with IL-4 and the antagonistic IL-4 variant R121/Y124D (Pitrakinra). Levels of human (h) IgE, amount of B-, T- and plasma-cells and ratio of CD4 : CD8 positive cells served as read out for induction and inhibition of cell proliferation and hIgE secretion. Results were compared to in vitro analysis.
Results: hIgE secretion was induced by IL-4 and inhibited by the IL-4 antagonist Pitrakinra in vivo when formulated with methylcellulose. B-cells proliferated in response to IL-4 in vivo; the effect was abrogated by Pitrakinra. IL-4 shifted CD4 : CD8 ratios in vitro and in vivo when hPBMC derived from healthy volunteers were used. Pitrakinra reversed the effect. Human PBMC derived from patients with AD remained inert and engrafted mice reflected the individual responses observed in vitro.
Conclusion: NOD-scid IL2R \(\gamma^{null}\) mice engrafted with human PBMC reflect the immunological history of the donors and provide a complementary tool to in vitro studies. Thus, studies in this model might provide data with better translatability from bench to bedside.
The development of ICT infrastructures has facilitated the emergence of new paradigms for looking at society and the environment over the last few years. Participatory environmental sensing, i.e. directly involving citizens in environmental monitoring, is one example, which is hoped to encourage learning and enhance awareness of environmental issues. In this paper, an analysis of the behaviour of individuals involved in noise sensing is presented. Citizens have been involved in noise measuring activities through the WideNoise smartphone application. This application has been designed to record both objective (noise samples) and subjective (opinions, feelings) data. The application has been open to be used freely by anyone and has been widely employed worldwide. In addition, several test cases have been organised in European countries. Based on the information submitted by users, an analysis of emerging awareness and learning is performed. The data show that changes in the way the environment is perceived after repeated usage of the application do appear. Specifically, users learn how to recognise different noise levels they are exposed to. Additionally, the subjective data collected indicate an increased user involvement in time and a categorisation effect between pleasant and less pleasant environments.
Animal models mimicking human diseases have been used extensively to study the pathogenesis of autoimmune diseases and the efficacy of potential therapeutics. They are, however, limited with regard to their similarity to the human disease and cannot be used if the antagonist and its cognate receptor require high similarity in structure or binding. Here, we examine the induction of oxazolone-mediated features of atopic dermatitis (AD) in NOD-scid IL2Rγnull mice engrafted with human peripheral blood mononuclear cells (PBMC). The mice developed the same symptoms as immunocompetent BALB/c mice. Histological alterations induced by oxazolone were characterized by keratosis, epithelial hyperplasia and influx of inflammatory cells into the dermis and epidermis. The cellular infiltrate was identified as human leukocytes, with T cells being the major constituent. In addition, oxazolone increased human serum IgE levels. The response, however, required the engraftment of PBMC derived from patients suffering from AD, which suggests that this model reflects the immunological status of the donor. Taken together, the model described here has the potential to evaluate the efficacy of therapeutics targeting human lymphocytes in vivo and, in addition, might be developed further to elucidate molecular mechanisms inducing and sustaining flares of the disease.
Animal models mimicking human diseases have been used extensively to study the pathogenesis of autoimmune diseases and the efficacy of potential therapeutics. They are, however, limited with regard to their similarity to the human disease and cannot be used if the antagonist and its cognate receptor require high similarity in structure or binding. Here, we examine the induction of oxazolone-mediated features of atopic dermatitis (AD) in NOD-scid IL2R \(γ^{null}\) mice engrafted with human peripheral blood mononuclear cells (PBMC). The mice developed the same symptoms as immunocompetent BALB/c mice. Histological alterations induced by oxazolone were characterized by keratosis, epithelial hyperplasia and influx of inflammatory cells into the dermis and epidermis. The cellular infiltrate was identified as human leukocytes, with T cells being the major constituent. In addition, oxazolone increased human serum IgE levels. The response, however, required the engraftment of PBMC derived from patients suffering from AD, which suggests that this model reflects the immunological status of the donor. Taken together, the model described here has the potential to evaluate the efficacy of therapeutics targeting human lymphocytes in vivo and, in addition, might be developed further to elucidate molecular mechanisms inducing and sustaining flares of the disease.
Background: miRNA profiles are promising biomarker candidates for a manifold of human pathologies, opening new avenues for diagnosis and prognosis. Beyond studies that describe miRNAs frequently as markers for specific traits, we asked whether a general pattern for miRNAs across many diseases exists.
Methods: We evaluated genome-wide circulating profiles of 1,049 patients suffering from 19 different cancer and non-cancer diseases as well as unaffected controls. The results were validated on 319 individuals using qRT-PCR.
Results: We discovered 34 miRNAs with strong disease association. Among those, we found substantially decreased levels of hsa-miR-144* and hsa-miR-20b with AUC of 0.751 ( 95% CI: 0.703-0.799), respectively. We also discovered a set of miRNAs, including hsa-miR-155*, as rather stable markers, offering reasonable control miRNAs for future studies. The strong downregulation of hsa-miR-144* and the less variable pattern of hsa-miR-155* has been validated in a cohort of 319 samples in three different centers. Here, breast cancer as an additional disease phenotype not included in the screening phase has been included as the 20th trait.
Conclusions: Our study on 1,368 patients including 1,049 genome-wide miRNA profiles and 319 qRT-PCR validations further underscores the high potential of specific blood-borne miRNA patterns as molecular biomarkers. Importantly, we highlight 34 miRNAs that are generally dysregulated in human pathologies. Although these markers are not specific to certain diseases they may add to the diagnosis in combination with other markers, building a specific signature. Besides these dysregulated miRNAs, we propose a set of constant miRNAs that may be used as control markers.
Objective: This study aims to critically evaluate the effectiveness and accuracy of a time safing and cost-efficient open-source algorithm for in-house planning of mandibular reconstructions using the free osteocutaneous fibula graft. The evaluation focuses on quantifying anatomical accuracy and assessing the impact on ischemia time.
Methods: A pilot study was conducted, including patients who underwent in-house planned computer-aided design and manufacturing (CAD/CAM) of free fibula flaps between 2021 and 2023. Out of all patient cases, we included all with postoperative 3D imaging in the study. The study utilized open-source software tools for the planning step, and three-dimensional (3D) printing techniques. The Hausdorff distance and Dice coefficient metrics were used to evaluate the accuracy of the planning procedure.
Results: The study assessed eight patients (five males and three females, mean age 61.75 ± 3.69 years) with different diagnoses such as osteoradionecrosis and oral squamous cell carcinoma. The average ischemia time was 68.38 ± 27.95 min. For the evaluation of preoperative planning vs. the postoperative outcome, the mean Hausdorff Distance was 1.22 ± 0.40. The Dice Coefficients yielded a mean of 0.77 ± 0.07, suggesting a satisfactory concordance between the planned and postoperative states. Dice Coefficient and Hausdorff Distance revealed significant correlations with ischemia time (Spearman's rho = −0.810, p = 0.015 and Spearman's rho = 0.762, p = 0.028, respectively). Linear regression models adjusting for disease type further substantiated these findings.
Conclusions: The in-house planning algorithm not only achieved high anatomical accuracy, as reflected by the Dice Coefficients and Hausdorff Distance metrics, but this accuracy also exhibited a significant correlation with reduced ischemia time. This underlines the critical role of meticulous planning in surgical outcomes. Additionally, the algorithm's open-source nature renders it cost-efficient, easy to learn, and broadly applicable, offering promising avenues for enhancing both healthcare affordability and accessibility.
The issue of sustainability is at the top of the political and societal agenda, being considered of extreme importance and urgency. Human individual action impacts the environment both locally (e.g., local air/water quality, noise disturbance) and globally (e.g., climate change, resource use). Urban environments represent a crucial example, with an increasing realization that the most effective way of producing a change is involving the citizens themselves in monitoring campaigns (a citizen science bottom-up approach). This is possible by developing novel technologies and IT infrastructures enabling large citizen participation. Here, in the wider framework of one of the first such projects, we show results from an international competition where citizens were involved in mobile air pollution monitoring using low cost sensing devices, combined with a web-based game to monitor perceived levels of pollution. Measures of shift in perceptions over the course of the campaign are provided, together with insights into participatory patterns emerging from this study. Interesting effects related to inertia and to direct involvement in measurement activities rather than indirect information exposure are also highlighted, indicating that direct involvement can enhance learning and environmental awareness. In the future, this could result in better adoption of policies towards decreasing pollution.
Rapid multiple-quantum three-dimensional fluorescence spectroscopy disentangles quantum pathways
(2019)
Coherent two-dimensional spectroscopy is a powerful tool for probing ultrafast quantum dynamics in complex systems. Several variants offer different types of information but typically require distinct beam geometries. Here we introduce population-based three-dimensional (3D) electronic spectroscopy and demonstrate the extraction of all fourth- and multiple sixth-order nonlinear signal contributions by employing 125-fold (1⨯5⨯5⨯5) phase cycling of a four-pulse sequence. Utilizing fluorescence detection and shot-to-shot pulse shaping in single-beam geometry, we obtain various 3D spectra of the dianion of TIPS-tetraazapentacene, a fluorophore with limited stability at ambient conditions. From this, we recover previously unknown characteristics of its electronic two-photon state. Rephasing and nonrephasing sixth-order contributions are measured without additional phasing that hampered previous attempts using noncollinear geometries. We systematically resolve all nonlinear signals from the same dataset that can be acquired in 8 min. The approach is generalizable to other incoherent observables such as external photoelectrons, photocurrents, or photoions.
Background
Even though the international combat against Neglected Tropical Diseases such as schistosomiasis or soil-transmitted helminthiases depends on reliable therapeutics, anthelminthic pharmacovigilance has been neglected on many national African drug markets. Therefore, quality and composition of Albendazole, Mebendazole and Praziquantel locally collected in Burkina Faso, Côte d’Ivoire, Ghana and Tanzania were analysed.
Methods
Samples of 88 different batches were obtained from randomly selected facilities. Sampling took place in Northwest Tanzania, Western Burkina Faso, Southeast Côte d’Ivoire and Southwest Ghana. Visual examination of both packaging and samples was performed according to the WHO ‘Be Aware’ tool. Products were then screened with the GPHF Minilab, consisting of tests of mass uniformity, disintegration times and thin-layer chromatography (TLC). Confirmatory tests were performed according to international pharmacopoeiae, applying assays for dissolution profiles and high-performance liquid chromatography (HPLC).
Findings
Despite minor irregularities, appearance of the products did not hint at falsified medicines. However, 19.6% of the brands collected in Ghana and Tanzania were not officially licensed for sale. Mass uniformity was confirmed in 53 out of 58 brands of tablets. 41 out of 56 products passed disintegration times; 10 out of the 15 failing products did not disintegrate at all. Evaluating TLC results, only 4 out of 83 batches narrowly missed specification limits, 18 batches slightly exceeded them. Not more than 46.3% (31 / 67) of the tablets assayed passed the respective pharmaceutical criteria for dissolution. HPLC findings confirmed TLC results despite shifted specification limits: 10 out of 83 tested batches contained less than 90%, none exceeded 110%.
Conclusion
In the four study countries, no falsified anthelminthic medicine was encountered. The active pharmaceutical ingredient was not found to either exceed or fall below specification limits. Galenic characteristics however, especially dissolution profiles, revealed great deficits.