502 research outputs found

    EZH2 Inhibition as New Epigenetic Treatment Option for Pancreatic Neuroendocrine Neoplasms (PanNENs).

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    Pancreatic neuroendocrine neoplasms are epigenetically driven tumors, but therapies against underlying epigenetic drivers are currently not available in the clinical practice. We aimed to investigate EZH2 (Enhancer of Zest homolog) expression in PanNEN and the impact of EZH2 inhibition in three different PanNEN preclinical models. EZH2 expression in PanNEN patient samples (n = 172) was assessed by immunohistochemistry and correlated with clinico-pathological data. Viability of PanNEN cell lines treated with EZH2 inhibitor (GSK126) was determined in vitro. Lentiviral transduction of shRNA targeting EZH2 was performed in QGP1 cells, and cell proliferation was measured. Rip1TAG2 mice underwent GSK126 treatment for three weeks starting from week 10 of age. Primary cells isolated from PanNEN patients (n = 6) were cultivated in 3D as islet-like tumoroids and monitored for 10 consecutive days upon GSK126 treatment. Viability was measured continuously for the whole duration of the treatment. We found that high EZH2 expression correlated with higher tumor grade (p < 0.001), presence of distant metastases (p < 0.001), and shorter disease-free survival (p < 0.001) in PanNEN patients. Inhibition of EZH2 in vitro in PanNEN cell lines and in patient-derived islet-like tumoroids reduced cell viability and impaired cell proliferation, while inhibition of EZH2 in vivo in Rip1TAG2 mice reduced tumor burden. Our results show that EZH2 is highly expressed in high-grade PanNENs, and during disease progression it may contribute to aberrations in the epigenetic cellular landscape. Targeting EZH2 may represent a valuable epigenetic treatment option for patients with PanNEN

    Sequence and functional differences in the ATPase domains of CHD3 and SNF2H promise potential for selective regulability and drugability

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    Chromatin remodelers use the energy of ATP hydrolysis to regulate chromatin dynamics. Their impact for development and disease requires strict enzymatic control. Here, we address the differential regulability of the ATPase domain of hSNF2H and hCHD3, exhibiting similar substrate affinities and enzymatic activities. Both enzymes are comparably strongly inhibited in their ATP hydrolysis activity by the competitive ATPase inhibitor ADP. However, the nucleosome remodeling activity of SNF2H is more strongly affected than that of CHD3. Beside ADP, also IP6 inhibits the nucleosome translocation of both enzymes to varying degrees, following a competitive inhibition mode at CHD3, but not at SNF2H. Our observations are further substantiated by mutating conserved Q‐ and K‐residues of ATPase domain motifs. The variants still bind both substrates and exhibit a wild‐type similar, basal ATP hydrolysis. Apart from three CHD3 variants, none of the variants can translocate nucleosomes, suggesting for the first time that the basal ATPase activity of CHD3 is sufficient for nucleosome remodeling. Together with the ADP data, our results propose a more efficient coupling of ATP hydrolysis and remodeling in CHD3. This aspect correlates with findings that CHD3 nucleosome translocation is visible at much lower ATP concentrations than SNF2H. We propose sequence differences between the ATPase domains of both enzymes as an explanation for the functional differences and suggest that aa interactions, including the conserved Q‐ and K‐residues distinctly regulate ATPase‐dependent functions of both proteins. Our data emphasize the benefits of remodeler ATPase domains for selective drugability and/or regulability of chromatin dynamics

    Collateralized loan obligations (CLOs) : an analysis of CLO risk today compared to CDOs during the global financial crisis

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    Since the Global Financial Crisis (GFC), structured credit has attracted public notice. While the issuance of subprime mortgage CDOs has declined after the GFC, other forms of securitization have grown substantially – in particular, collateralized loan obligations (CLOs). Those instruments invest in leveraged loans, meaning bank loans to highly indebted companies. In 2018 and 2019, prominent public figures, institutions and the financial press voiced concerns over leveraged loans and CLOs and the way they bear upon financial stability. This dissertation compares the current CLO market with that of subprime CDOs during the GFC, examining the structure and function of both instruments. An analytical framework of factors that helped cause and/or accelerate the GFC is established and then applied to CLOs. The results of this study show that CLOs today are less complex than CDOs were in the run-up to the GFC and tend not to be leveraged by using short-term repo financing. However, similar to CDOs, the credit quality of the underlying assets in CLOs is deteriorating while credit rating agencies persist in misstating the underlying default probabilities. Overall, “irrational exuberance” in the CLO market seems less accentuated than in the CDO markets before the GFC. However, investors and policymakers should anticipate substantial losses in these markets caused by the current global recession.Desde a crise financeira de 2008 que o crĂ©dito estruturado tem vindo a atrair a atenção pĂșblica. Embora a emissĂŁo de CDOs tenha diminuĂ­do apĂłs a crise do subprime, outras formas de securitização cresceram substancialmente desde entĂŁo - particularmente, obrigaçÔes de emprĂ©stimos colateralizados (CLOs). Estes instrumentos sĂŁo caracterizados como emprĂ©stimos bancĂĄrios a empresas de alto risco, particularmente endividadas e com baixa notação financeira. Em 2018 e 2019, figuras pĂșblicas de destaque, instituiçÔes e imprensa financeira manifestaram preocupação com tais emprĂ©stimos alavancados e CLOs e com a forma como estes podem influenciar a estabilidade financeira. Esta dissertação compara o mercado actual dos CLOs com o de CDOs subprime durante a crise de 2008, examinando a estrutura e função de ambos os instrumentos. Para tal, Ă© estabelecida uma estrutura analĂ­tica de fatores que causaram ou aceleraram a crise do subprime, e em seguida, a mesma Ă© aplicada aos CLOs. Como resultado, os CLOs sĂŁo menos complexos do que os CDOs e tendem a nĂŁo ser alavancados usando financiamento a curto prazo. No entanto, paralelamente aos CDOs, a qualidade de crĂ©dito dos ativos subjacentes nos CLOs tem vindo a deteriozar-se ao mesmo tempo que as agĂȘncias de classificação de risco de crĂ©dito prosseguem com a distorção das probabilidades subjacentes de falĂȘncia. No geral, a “exuberĂąncia irracional” no mercado dos CLOs aparenta ser menos acentuada do que nos mercados de CDO antes da crise do subprime. No entanto, investidores e decisores polĂ­ticos poderĂŁo antecipar perdas substanciais nesses mercados causadas pela recessĂŁo global actual

    3D Primary Cell Culture: A Novel Preclinical Model For Pancreatic Neuroendocrine Tumors (PanNETs)

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    Molecular mechanisms underlying the development and progression of PanNET are still insufficiently understood. Efficacy of currently approved PanNET therapies is limited. While novel treatment options are being developed, patient stratification permitting more personalized treatment selection in PanNET is yet not feasible since no predictive markers are established. The lack of representative in vitro and in vivo models as well as the rarity and heterogeneity of PanNET are prevailing reasons for this. In this study, we describe an in vitro 3D human primary PanNET culture system as a novel preclinical model for more personalized therapy selection. We present a screening platform allowing multi-center sample collection and drug screening in 3D cultures of human primary PanNET cells. We demonstrate that primary cells isolated from PanNET patients and cultured in vitro form islet-like tumoroids. Islet-like tumoroids retain the neuroendocrine phenotype and are viable for at least two weeks in culture with high success rate (86%). Viability can be monitored continuously allowing for a per-well normalization. In a proof-of-concept study, islet-like tumoroids were screened with three clinically approved therapies for PanNET: Sunitinib, everolimus and temozolomide. Islet-like tumoroids display varying in vitro response profiles to distinct therapeutic regimes. Treatment response of islet-like tumoroids (IC50) differs also between patient samples. We believe that the presented human PanNET screening platform is suitable for personalized drug testing in a larger patient cohort and a broader application will help in identifying novel markers predicting treatment response and in refining PanNET therapy

    Mechanics of the stomach: a review of an emerging field of biomechanics

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    Mathematical and computational modeling of the stomach is an emerging field of biomechanics where several complex phenomena, such as gastric electrophysiology, fluid mechanics of the digesta, and solid mechanics of the gastric wall, need to be addressed. Developing a comprehensive multiphysics model of the stomach that allows studying the interactions between these phenomena remains one of the greatest challenges in biomechanics. A coupled multiphysics model of the human stomach would enable detailed in-silico studies of the digestion of food in the stomach in health and disease. Moreover, it has the potential to open up unprecedented opportunities in numerous fields such as computer-aided medicine and food design. This review article summarizes our current understanding of the mechanics of the human stomach and delineates the challenges in mathematical and computational modeling which remain to be addressed in this emerging area.Funding from the German Research Foundation (Deutsche Forschungsgemeinschaft) within the Project CY 75/3-1 (“Computational Multiphysics Modeling of the Postprandial Human Stomach”)

    Post-imperialism, postcolonialism and beyond: towards a periodisation of cultural discourse about colonial legacies

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    Taking German history and culture as a starting point, this essay suggests a historical approach to reconceptualising different forms of literary engagement with colonial discourse, colonial legacies and (post-) colonial memory in the context of Comparative Postcolonial Studies. The deliberate blending of a historical, a conceptual and a political understanding of the ‘postcolonial’ in postcolonial scholarship raises problems of periodisation and historical terminology when, for example, anti-colonial discourse from the colonial period or colonialist discourse in Weimar Germany are labelled ‘postcolonial’. The colonial revisionism of Germany’s interwar period is more usefully classed as post-imperial, as are particular strands of retrospective engagement with colonial history and legacy in British, French and other European literatures and cultures after 1945. At the same time, some recent developments in Francophone, Anglophone and German literature, e.g. Afropolitan writing, move beyond defining features of postcolonial discourse and raise the question of the post-postcolonial

    Outcome von Kindern nach Cochlea-Implantat-Versorgung in AbhÀngigkeit von weiteren Behinderungen und vom Lebensalter

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    Hintergrund: Nach Cochlea-Implantat (CI)-Versorgung bei Kindern dient die Bestimmung der AufblĂ€hkurve (ABK), sowie des Sprachverstehens als Maß um den Erfolg der CI-Versorgung zu beurteilen. Die Hörleistung kann mit dem jeweiligen Höralter, oder mit Kindern gleichen Lebensalters verglichen werden. In der vorliegenden Studie soll untersucht werden, ob die Schwellen der ABK in der Erstanpassungsphase (audioverbale Therapie/AVT) sich zwischen jĂŒngeren und Ă€lteren Kindern unterscheiden.Material und Methoden: Es wurden Gruppen in AbhĂ€ngigkeit vom Alter zum Zeitpunkt der Ersteinstellung (bis 16. Lebensmonat/30.-60. Lebensmonat) und dem Vorhandensein von Begleitbehinderungen (monosymptomatische cochleĂ€re Schwerhörigkeit/ Schwerhörigkeit mit Begleitbehinderungen) gebildet und die ABK verglichen. Alle Kinder sammelten zuvor mit HörgerĂ€ten Hörerfahrungen.Ergebnisse: Bei den Kindern mit monosymptomatischer Schwerhörigkeit lag die 1. ABK bei den spĂ€ter implantierten Kindern besser als bei den jĂŒngeren. Bei den Kindern mit Begleitbehinderungen unterschied sich die 1. ABK nur wenig in beiden Altersgruppen, die jĂŒngeren schnitten etwas besser ab. Alle Kinder, mit und ohne Begleitbehinderungen, konnten sich wĂ€hrend der 1. AVT verbessern, die Ă€lteren rascher. WĂ€hrend der 2. AVT verbesserten sich erneut alle Kinder, die jĂŒngeren stĂ€rker.Diskussion: Dass die 1. ABK in der 1. AVT bei den Ă€lteren Kindern bei geringeren LautstĂ€rken lag, ist auf mehr Hörerfahrungen und das höhere Lebensalter zurĂŒckzufĂŒhren. Die 1. ABK lagen in dem LautstĂ€rkebereich, in dem normalhörende Neugeborene Hörreaktionen zeigen. Vor allem fĂŒr die höheren Frequenzen zeigten die spĂ€ter operierten Kinder große Fortschritte. Im Vergleich zu normalhörenden Kindern gleichen Lebensalters lag die ABK am Ende der 1. AVT unabhĂ€ngig vom Implantationsalter um 30-40 dB schlechter. Vergleicht man die 1. ABK aller Kinder, dann fĂ€llt das Ergebnis bei Kindern mit Begleitbehinderungen insbesondere bei den Ă€lteren ungĂŒnstiger aus. Am Ende der 2. AVT lagen die Kinder mit Begleitbehinderungen ebenfalls etwas schlechter.Fazit: FĂŒr die korrekte Bewertung der ABK bei CI-versorgten Kindern sind das Lebensalter, eine Begleitbehinderung und die Zeit seit der Ersteinstellung zu berĂŒcksichtigen. Die vorliegenden Daten erlauben eine Einordnung

    Elektrische Momente von Molekeln

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