Identifikation neuer klinischer Anwendungen für Saure Sphingomyelinase Inhibitoren

Acid sphingomyelinase is a lysosomal enzyme that catalyzes the hydrolysis of sphingomyelin to ceramide. Acid sphingomyelinase/ceramide have been implicated in the pathogenesis of a number of different diseases. Pharmacological inhibitors of acid sphingomyelinase are already in clinical use and are well tolerated. Thus, this study aimed to expand the existing applications of known acid sphingomyelinase inhibitors to acid sphingomyelinase/ceramide-related diseases with a currently unmet clinical treatment need. Farber disease is a rare lysosomal storage disorder caused by ceramide accumulation due to acid ceramidase deficiency. This study introduces a new mouse model to study FD that mirrors the human disease closely. Cross-breeding of these mice to acid sphingomyelinase-deficient mice reduced ceramide accumulation, improved disease manifestations and prolonged survival. Pharmacological inhibition of acid sphingomyelinase, however, failed due to unexpected, genotype-specific toxicity. In rheumatoid arthritis, an autoimmune disorder affecting predominantly the joints, ceramide levels in the synovial fluid of patients have been reported to be elevated. Using a mouse model of inflammatory arthritis, this study analyzed the role of acid sphingomyelinase in joint inflammation and shows that both genetic ablation and pharmacological inhibition of acid sphingomyelinase ameliorates arthritis severity.Das Enzym Saure Sphingomyelinase katalysiert die Hydrolyse von Sphingomyelin zu Ceramid. Saure Sphingomyelinase und Ceramid spielen eine Rolle in der Pathogenese einer Reihe verschiedener Erkrankungen. Pharmakologische Inhibitoren der Sauren Sphingomyelinase werden bereits in der Klinik eingesetzt und sind gut verträglich. Das Ziel dieser Arbeit war es deshalb, die Anwendungsgebiete dieser bereits eingesetzten Inhibitoren auf Erkrankungen zu erweitern, bei denen die Saure Sphingomyelinase und/oder Ceramid eine Rolle spielen und die bislang nur unzureichend behandelt werden können. Farber Lipogranulomatose ist eine seltene lysosomale Speichererkrankung, bei der es aufgrund einer Sauren Ceramidase-Defizienz zu einer Anreicherung von Ceramid kommt. Diese Arbeit stellt ein neues Mausmodell zur Erforschung der Erkrankung vor, dass den Phänotyp der humanen Erkrankung wiederspiegelt. Die Kreuzung dieser Mäuse mit Saure Sphingomyelinase-defizienten Mäusen reduzierte die Ceramid-Akkumulation, verbesserte die Symptome und verlängerte das Überleben der Farber-Mäuse. Die pharmakologische Inhibition scheiterte jedoch aufgrund unerwarteter, Genotyp-spezifischer Toxizität. Rheumatoide Arthritis ist eine Autoimmunerkrankung, die vor allem die Gelenke betrifft. In der Synovialflüssigkeit von Patienten mit dieser Erkrankung wurden erhöhte Ceramid-Spiegel festgestellt. Mithilfe eines Mausmodells für entzündliche Arthritis wurde in dieser Arbeit die Rolle der Sauren Sphingomyelinase bei Gelenkentzündungen untersucht. Sowohl durch genetische Deletion als auch durch pharmakologische Inhibition der sauren Sphingomyelinase konnte die Gelenkentzündung reduziert werden

Carcinogen metabolism, cigarette smoking, and breast cancer risk: a Bayes model averaging approach

BACKGROUND: Standard logistic regression with or without stepwise selection has the disadvantage of not incorporating model uncertainty and the dependency of estimates on the underlying model into the final inference. We explore the use of a Bayes Model Averaging approach as an alternative to analyze the influence of genetic variants, environmental effects and their interactions on disease. METHODS: Logistic regression with and without stepwise selection and Bayes Model Averaging were applied to a population-based case-control study exploring the association of genetic variants in tobacco smoke-related carcinogen pathways with breast cancer. RESULTS: Both regression and Bayes Model Averaging highlighted a significant effect of NAT1*10 on breast cancer, while regression analysis also suggested a significant effect for packyears and for the interaction of packyears and NAT2. CONCLUSIONS: Bayes Model Averaging allows incorporation of model uncertainty, helps reduce dimensionality and avoids the problem of multiple comparisons. It can be used to incorporate biological information, such as pathway data, into the analysis. As with all Bayesian analysis methods, careful consideration must be given to prior specification

Facets of Communication: Gap Junction Ultrastructure and Function in Cancer Stem Cells and Tumor Cells

Gap junction proteins are expressed in cancer stem cells and non-stem cancer cells of many tumors. As the morphology and assembly of gap junction channels are crucial for their function in intercellular communication, one focus of our review is to outline the data on gap junction plaque morphology available for cancer cells. Electron microscopic studies and freeze-fracture analyses on gap junction ultrastructure in cancer are summarized. As the presence of gap junctions is relevant in solid tumors, we exemplarily outline their role in glioblastomas and in breast cancer. These were also shown to contain cancer stem cells, which are an essential cause of tumor onset and of tumor transmission into metastases. For these processes, gap junctional communication was shown to be important and thus we summarize, how the expression of gap junction proteins and the resulting communication between cancer stem cells and their surrounding cells contributes to the dissemination of cancer stem cells via blood or lymphatic vessels. Based on their importance for tumors and metastases, future cancer-specific therapies are expected to address gap junction proteins. In turn, gap junctions also seem to contribute to the unattainability of cancer stem cells by certain treatments and might thus contribute to therapeutic resistance

Онтологическая функция мифа: миф как бытийная связь между "мифосом" и "логосом"

Показана необходимость пересмотра онтологического статуса мифа в связи с кризисом идеалов классического рационализма. Автор раскрывает смысл мифа как онтологической реальности на основе анализа взаимосвязи "мифоса" и "логоса". Выявляется роль "мифоса" в аспекте культурного смыслополагания

Representation of genetic association via attributable familial relative risks in order to identify polymorphisms functionally relevant to rheumatoid arthritis

The results from association studies are usually summarized by a measure of evidence of association (frequentist or Bayesian probability values) that does not directly reflect the impact of the detected signals on familial aggregation. This article investigates the possible advantage of a two-dimensional representation of genetic association in order to identify polymorphisms relevant to disease: a measure of evidence of association (the Bayes factor, BF) combined with the estimated contribution to familiality (the attributable sibling relative risk, λs). Simulation and data from the North American Rheumatoid Consortium (NARAC) were used to assess the possible benefit under several scenarios. Simulation indicated that the allele frequencies to reach the maximum BF and the maximum attributable λs diverged as the size of the genetic effect increased. The representation of BF versus attributable λs for selected regions of NARAC data revealed that SNPs involved in replicated associations clearly departed from the bulk of SNPs in these regions. In the 12 investigated regions, and particularly in the low-recombination major histocompatibility region, the ranking of SNPs according to BF differed from the ranking of SNPs according to attributable λs. The present results should be generalized using more extensive simulations and additional real data, but they suggest that a characterization of genetic association by both BF and attributable λs may result in an improved ranking of variants for further biological analyses

Temporal discrepancies in "rapid" HIV testing: explaining misdiagnoses at the point-of-care in Zimbabwe.

BACKGROUND: Rapid diagnostic tests have revolutionized the HIV response in low resource and high HIV prevalence settings. However, disconcerting levels of misdiagnosis at the point-of-care call for research into their root causes. As rapid HIV tests are technologies that cross borders and have inscribed within them assumptions about the context of implementation, we set out to explore the (mis)match between intended and actual HIV testing practices in Zimbabwe. METHODS: We examined actual HIV testing practices through participant observations in four health facilities and interviews with 28 rapid HIV testers. As time was identified as a key sphere of influence in thematic analyses of the qualitative data, a further layer of analysis juxtaposed intended (as scripted in operating procedures) and actual HIV testing practices from a temporal perspective. RESULTS: We uncover substantial discrepancies between the temporal flows assumed and inscribed into rapid HIV test kits (their intended use) and those presented by the high frequency testing and low resource and staffing realities of healthcare settings in Zimbabwe. Aside from pointing to temporal root causes of misdiagnosis, such as the premature reading of test results, our findings indicate that the rapidity of rapid diagnostic technologies is contingent on a slow, steady, and controlled environment. This not only adds a different dimension to the meaning of "rapid" HIV testing, but suggests that errors are embedded in the design of the diagnostic tests and testing strategies from the outset, by inscribing unrealistic assumptions about the context within which they used. CONCLUSION: Temporal analyses can usefully uncover difficulties in attuning rapid diagnostic test technologies to local contexts. Such insight can help explain potential misdiagnosis 'crisis points' in point-of-care testing, and the need for public health initiatives to identify and challenge the underlying temporal root causes of misdiagnosis

Acid Sphingomyelinase Deficiency Ameliorates Farber Disease

Farber disease is a rare lysosomal storage disorder resulting from acid ceramidase deficiency and subsequent ceramide accumulation. No treatments for Farber disease are clinically available, and affected patients have a severely shortened lifespan. We have recently reported a novel acid ceramidase deficiency model that mirrors the human disease closely. Acid sphingomyelinase is the enzyme that generates ceramide upstream of acid ceramidase in the lysosomes. Using our acid ceramidase deficiency model, we tested if acid sphingomyelinase could be a potential novel therapeutic target for the treatment of Farber disease. A number of functional acid sphingomyelinase inhibitors are clinically available and have been used for decades to treat major depression. Using these as a therapeutic for Farber disease, thus, has the potential to improve central nervous symptoms of the disease as well, something all other treatment options for Farber disease can’t achieve so far. As a proof-of-concept study, we first cross-bred acid ceramidase deficient mice with acid sphingomyelinase deficient mice in order to prevent ceramide accumulation. Double-deficient mice had reduced ceramide accumulation, fewer disease manifestations, and prolonged survival. We next targeted acid sphingomyelinase pharmacologically, to test if these findings would translate to a setting with clinical applicability. Surprisingly, the treatment of acid ceramidase deficient mice with the acid sphingomyelinase inhibitor amitriptyline was toxic to acid ceramidase deficient mice and killed them within a few days of treatment. In conclusion, our study provides the first proof-of-concept that acid sphingomyelinase could be a potential new therapeutic target for Farber disease to reduce disease manifestations and prolong survival. However, we also identified previously unknown toxicity of the functional acid sphingomyelinase inhibitor amitriptyline in the context of Farber disease, strongly cautioning against the use of this substance class for Farber disease patients

Scald Injury-Induced T Cell Dysfunction Can Be Mitigated by Gr1+ Cell Depletion and Blockage of CD47/CD172a Signaling

Infection is a common and severe complication of burn injury: Sepsis accounts for 47% of postburn mortality. Burn-induced T cell suppression likely contributes to the increased infection susceptibility in burn patients. However, little is known about the kinetics of T cell dysfunction after burn and its underlying mechanisms. In this study, we show in a murine scald injury model that T cell activation of both CD4+ and CD8+ T cells as well as T cell cytokine production is suppressed acutely and persistently for at least 11 days after burn injury. Purified T cells from scald-injured mice exhibit normal T cell functions, indicating an extrinsically mediated defect. We further show that T cell dysfunction after burn appears to be cell-to-cell contact dependent and can be ameliorated by depletion of myeloid-derived suppressor cells. These cells expand after burn injury, particularly a subset expressing the checkpoint inhibitor CD172a, and infiltrate germinal centers. Expression of CD172a appears to be driven by ingestion of immature reticulocytes. Immature reticulocytes are drastically increased in the spleen of scald mice and may contribute to immunosuppression through more direct mechanisms as well. Overall, our study newly identifies two cell populations, myeloid-derived suppressor cells and immature reticulocytes, as well as the CD47/CD172a-signaling pathways as mediators of T cell suppressors after burn and thus opens up new research opportunities in the search for new therapies to combat increased infection susceptibility and the associated morbidity and mortality in burn victims

Режимы лазерного восстановления оксида графена

Обработка светом (фотолитография) хорошо зарекомендовала себя в твердотельной электронике и на данный момент играет важную роль в микроэлектронной промышленности. С данной точки зрения представляется научный интерес работы по возможностям модификации пленок ОГ для получения гибкой, биосовместимой и "зеленой" электроникиPhotolithography is a powerfull instrument for designing a solid state electronics. Today is plays an important role in the microelectronic industry. Scientific interest of this work is on the possibilities of modifications of the graphene oxide film to obtain flexibility, biocompatible and "green" electronic