22,999 research outputs found
NEW INSIGHTS OF MIR-145 FUNCTION AND REGULATION IN HUMAN BREAST CANCER.
No full textmiR-145 is down-regulated in the majority of human cancers, including breast cancer (BC).
However, its role remains largely unknown. Here, I provide evidence for miR-145 induced
anti-proliferative and pro-apoptotic effect in several BC cell lines, which was not detected in
BC cells lacking a functional TP53 gene and exhibiting an estrogen receptor alfa (ESR1)
negative status. I found that miR-145 anti-proliferative effects were dependent upon TP53
activation and that activation of TP53 could in turn stimulates miR-145 expression. I also
found that miR-145 could repress the expression of ESR1 protein by direct interaction with
two sites within its gene coding sequence. My findings support the existence of a positive
regulatory loop where miR-145 directly targets ESR1 and indirectly activates TP53, which in
turn sustains miR-145 expression and reinforces miR-145 overall effects on proliferation and
apoptosis
MicroRNA profiling in B cell non-Hodgkin Lymphoma : focus on the role of MYC
No full textNon-Hodgkinlymfoon is een kwaadaardige vorm van kanker die uitgaat van de lymfeklieren. De ziekte wordt gekenmerkt door specifieke chromosoomafwijkingen en door afwijkende patronen van genexpressie. Onderzoek naar miRNAs (MicroRNAs, moleculen die de expressie van genen reguleren tijdens cellulaire processen zoals celdeling en de vorming van nieuwe cellen) heeft bijgedragen aan een betere kennis van het ontstaan van de ziekte, maar er is nog veel onduidelijk. Jan Lukas Robertus onderzocht de rol van MicroRNAs in twee vormen van lymfklierkanker.
Robertus deed onderzoek naar twee vormen van Non-Hodgkinlymfoom, het veel voorkomende diffuus grootcellig B-lymfoom (DLBCL) en het minder vaak voorkomende Burkitt lymfoom (BL). Hij wist twee specifieke miRNAs te identificeren waarmee een subgroep van DLBCL (namelijk die in de testikels en het centrale zenuwstelsel) gekarakteriseerd kan worden. Verder ontdekte de promovendus dat verschillende lymfoom-subtypes verschillende miRNA-expressieprofielen laten zien. Tot slot toonde hij de rol van zeven specifieke miRNAs aan die een belangrijke rol spelen in de groei van Burktitt Lymfoom-cellen.
Most non-Hodgkin lymphoma (NHL) subtypes are characterized by specific chromosomal aberrations and aberrant gene expression patterns, some of which have been shown to be particularly relevant to their pathogenesis. In the past decade, research on microRNAs (miRNAs) has further contributed to knowledge about the pathogenesis of NHL, but the picture is far from complete. MiRNAs are a group of regulatory small RNAs that belong to the non-coding RNA family. MiRNAs can post-trancriptionally regulate the expression of their target genes, which include oncogenes and tumor suppressor genes, and as such contribute to tumorigenesis. Studies on miRNAs might therefore further improve our understanding of the molecular abnormalities that underlie the pathogenesis of lymphomas and cancer in general. This thesis focused on the role of miRNAs in the pathogenesis of lymphomas, in particular that of diffuse large B cell lymphoma (DLBCL) and Burkitt lymphoma (BL). We identified two miRNAs that characterize the testicular and CNS DLBCL cases. We further showed marked differences in the expression pattern of the oncogenic miRNA cluster, miR-17~92 with miR-92 being the most abundant miRNA in most cases, and miR-19b being the most significantly induced miRNA as compared to their normal counterparts. We further established specific miRNA expression profiles in different NHL subtypes and showed that the profile of BL is strongly defined by MYC. Finally, we identified seven MYC regulated miRNAs that have a remarkably strong impact on growth of BL cells.
microRNA expression and function in Embryonic Stem Cells: miR-100, miR-137 and miR-34a are required for ESC differentiation
No full textGiven their capacity to self-renew and differentiate efficiently into the different cell types, Embryonic Stem Cells (ESCs) provide a valid model to understand the complex network of signaling interactions in the mammalian embryo and open up new possibilities for cell therapy. So a deeper understanding of the molecular mechanisms that regulate generation, self-renewal and differentiation of ESCs is become crucial not only to fulfill their clinical promise but also to get insight into the molecular mechanisms controlling early events of mammalian development. The emergence of microRNAs (microRNAs) as potent regulators of gene expression at the post-transcriptional level has broad implications in all facets of biology, including ESCs and early development.
In recent years, the role of microRNAs in ESCs and mammalian embryogenesis has begun to be explored but specific roles of the microRNAs in the regulation of ESC specific fate are still largely unknown. In this context, our interest is to identify microRNAs regulating ESC functions. We performed a systematic comparison of microRNA expression in undifferentiated versus differentiating mouse ESCs. We report that different microRNAs are increased upon the induction of differentiation. We compared the entire list of candidate mRNA targets of upregulated microRNAs with that of mRNA dowregulated in ESCs upon the induction of differentiation. Among the candidate targets emerged from this analysis, we found three genes Smarca5, Jarid1b and Sirt1, previously demonstrated to be necessary to sustain the undifferentiated phenotype in ESCs. On this basis, we first demonstrated that Smarca5 is a direct target of miR-100, Jarid1b of miR-137 and confirmed previously published data demonstrating that Sirt1 is a direct target of miR-34a in a different context. The suppression of these three microRNAs by anti-miRs caused block of ESC differentiation induced by LIF withdrawal. On the other hand, the overexpression of the three microRNAs resulted in an altered expression of differentiation markers. These results demonstrated that miR-100, miR-137 and miR-34a are required for proper differentiation of ESCs, and that they function by targeting, among the others, the mRNAs of Smarca5, Jarid1b and Sirt1.
In conclusion, we have characterized a subset of microRNAs that are necessary for proper differentiation of mouse ESCs. The identification of microRNAs that are up-regulated upon the induction of ESC differentiation suggests that they suppress, directly or indirectly, the expression of genes necessary to maintain ESCs in the undifferentiated state. The identification of targets of the microRNAs that we have studied may provide tools to drive ESC differentiation towards specific lineages
Serum microRNA-21 as marker for necroinflammation in hepatitis C patients with and without hepatocellular carcinoma
No full textBackground: MicroRNA-21 (miR-21) is up-regulated in tumor tissue of patients with malignant diseases, including hepatocellular carcinoma (HCC). Elevated concentrations of miR-21 have also been found in sera or plasma from patients with malignancies, rendering it an interesting candidate as serum/plasma marker for malignancies. Here we correlated serum miR-21 levels with clinical parameters in patients with different stages of chronic hepatitis C virus infection (CHC) and CHC-associated HCC.
Methodology/Principal Findings: 62 CHC patients, 29 patients with CHC and HCC and 19 healthy controls were prospectively enrolled. RNA was extracted from the sera and miR-21 as well as miR-16 levels were analyzed by quantitative real-time PCR; miR-21 levels (normalized by miR-16) were correlated with standard liver parameters, histological grading and staging of CHC. The data show that serum levels of miR-21 were elevated in patients with CHC compared to healthy controls (P<0.001); there was no difference between serum miR-21 in patients with CHC and CHC-associated HCC. Serum miR-21 levels correlated with histological activity index (HAI) in the liver (r = −0.494, P = 0.00002), alanine aminotransferase (ALT) (r = −0.309, P = 0.007), aspartate aminotransferase (r = −0.495, P = 0.000007), bilirubin (r = −0.362, P = 0.002), international normalized ratio (r = −0.338, P = 0.034) and γ-glutamyltransferase (r = −0.244, P = 0.034). Multivariate analysis revealed that ALT and miR-21 serum levels were independently associated with HAI. At a cut-off dCT of 1.96, miR-21 discriminated between minimal and mild-severe necroinflammation (AUC = 0.758) with a sensitivity of 53.3% and a specificity of 95.2%.
Conclusions/Significance: The serum miR-21 level is a marker for necroinflammatory activity, but does not differ between patients with HCV and HCV-induced HCC
Die Bedeutung von microRNAs für die Funktion von Endothelzellen
No full textDicer and Drosha are the major enzymes involved in microRNA processing. Using siRNA targeting Dicer and Drosha, thereby downregulating a substantial number of microRNAs in EC, we demonstrate a crucial role of both enzymes in angiogenic processes. Interestingly, Dicer inhibition exerts more profound effects on processes like migration and viability of EC in comparison to Drosha inhibition. Moreover, Dicer effects in vivo angiogenesis, a process which is unaffected by Drosha. This discrepancy might be partially due to the involvement of Dicer in other cellular processes like heterochromatin formation and to the fact that Dicer and Drosha target mainly different subsets of microRNAs. In addition, we identified miR-92a as a novel endogenous repressor of the angiogenic program in EC, which impairs their angiogenic functions in vitro and in vivo. Consistent with these data, blocking miR-92a by systemic infusion of antagomirs enhances neovascularization and functional recovery after ischemia in vivo. At first sight, the anti-angiogenic function of miR-92a in EC appears to contradict the previously identified anti-apoptotic and pro-angiogenic activities of the miR-17~92 cluster in tumor cells. However, this apparent discrepancy might be well rationalized by a predominant function of miR-18a and miR-19a in tumor cells, which are responsible for the tumorigenic and non-cell autonomous pro-angiogenic functions of the miR-17~92 cluster. Instead, miR-92a expression is specifically upregulated in ischemic tissues and appears to cell-autonomously repress the angiogenic potential of EC. Among the various targets and verified regulated genes identified by microarray, we confirmed the downregulation of Integrin a5 in vitro and in vivo. The relevance of this miR-92a target is evidenced by severe vascular defects in the absence of Integrin a5. In addition, endothelial miR-92a interferes with the expression pattern of genes controlling key EC functions at various levels, some of which, e.g. eNOS, might be secondarily affected by directly targeted genes. Obviously, our data do not formally exclude effects of antagomir-92a on perivascular and other cell types, but surely include effects on EC. Regardless of this, the capacity of miR-92a to target various downstream effectors might be an advantage of miRNA-based therapeutic strategies and may overcome the limited therapeutic capacity of single growth factor or single gene therapies in ischemic diseases, since the highly organized process of vessel growth, maturation and functional maintenance is well known to require the fine-tuned regulation of a set of genes.Angiogenese, die Bildung von Kapillaren aus bereits existierenden Gefäßen, ist ein wichtiger physiologischer Prozess zur Wundheilung und Wiederherstellung des Blutflusses nach Verletzung. Das Ziel der vorliegenden Arbeit war die genaue Untersuchung der Rolle von microRNAs in angiogenen Prozessen. MicroRNAs sind kleine, einzelsträngige RNA Moleküle, welche die Genexpression durch Bindung an die messenger RNA (mRNA) von Zielgenen und darauffolgenden Degradierung der mRNA oder Repression der Translation regulieren. Die Inhibition der microRNA-prozessierenden Enzyme Dicer und Drosha in Endothelzellen führt zu einer Dysregulation der microRNA Expression und zu einer signifikanten Reduktion der Angiogenese in vitro. Im Gegensatz zu Drosha, dessen Inhibition keinen Effekt auf die in vivo Angiogenese zeigt, führt die Inhibition von Dicer auch in einem in vivo Angiogenese-Modell zu einer deutliche reduzierten Einsprossung von Gefäßen. Zusammenfassend sprechen diese Daten für eine wichtige Rolle von microRNAs in der Endothelzellbiologie. Der zweite Teil der vorliegenden Arbeit beschränkte sich auf die Untersuchung einer, in Endothelzellen hoch exprimierten microRNA, miR-92a. MiR-92a ist ein Mitglied des miR-17-92 Clusters, für den bereits eine Rolle in der Tumorangiogenese beschrieben ist. Die Überexpression der miR-92a in Endothelzellen führt zu einer signifikanten Hemmung der Angiogenese, sowie reduzierter Adhäsion und Migration auf Fibronektin. Zudem wird die Einsprossung von Gefäßen in Matrigel Plugs deutlich gehemmt. In Übereinstimmung hierzu führt die systemische Hemmung der miR-92a mit Hilfe von modifizierten antisense Oligoribonukleotiden (Antagomir-92a) im Mausmodell zu einer Stimulation der Einsprossung von Gefäßen in Matrigel Plugs. In klinisch relevanten Modellen, wie dem Hinterlaufischämie-Modell und dem akuten Myokardinfarkt-Modell, führt die Behandlung mit Antagomir-92a zu einer funktionelle Verbesserung. Immunohistologische Analysen ergaben, dass in den Antagomir-92a behandelten Tieren sowohl die Anzahl der Kapillaren als auch der größeren Gefäße deutlich erhöht ist. Obwohl wir einen direkten Effekt der Antagomir-92a Behandlung auf die Myozyten zum jetzigen Zeitpunkt nicht auschließen können, weisen unsere Daten definitiv auf eine Stimulation der Angiogenese hin. Nachdem wir sowohl in vitro als auch in vivo zeigen konnten, dass miR-92a maßgeblich an angiogenen Prozessen beteiligt ist, stellten wir uns die Frage nach den zugrunde liegenden Zielgenen. Es zeigte sich, dass miR-92a neben einer größeren Anzahl pro-angiogener Faktoren die Integrin Untereinheit a5 sowohl in vitro als auch in vivo reguliert. Desweiteren konnten wir mit Hilfe eines Luciferase Assays die direkte Regulation von Integrin a5 durch miR-92a zeigen. Zusammenfassend deuten diese Daten daraufhin, dass Integrin a5 ein Schlüsselregulator der Antagomir-92a-vermittelten Angiogenese ist und somit unmittelbar an der Verbesserung nach Hinterlaufischämie und akutem Myokardinfarkt beteiligt ist
Jan Kapr's contribution to contemporary music : an essay about a composer and teacher
No full textThis creative project is a treatise on a leading personality of Czechoslovakian musical life, the composer, Jan Kapr. The author discusses the following:1. The complicated development of Kapr's career and work, 2. Kapr's method of organization of musical material in a composition, as described in his book Constants,3. His former and current style which is demonstrated in two of his compositions, Concert Variations, for flute and string orchestra and Testimonies for four solo instruments,4. Two of his recent works, Exercises for Gydli and the Symphony No. 7, Country of Childhood.Thesis (M.A.
Going Beyond Counting First Authors in Author Co-citation Analysis
No full textThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
ELEVEN FACES OF JAN GOGOL, JR.
No full textAuthor Jan Rendl in his thesis attempts to look at the world of ideas and educator Jan
Gogola ml. through the eleven chapters in which each chapter somehow characterizes itself by Jan Gogola ml. and each of them somehow determines its creative ideas of it through the metaphor of a football match when Jan Gogola, with its characters, movies himself a teammate, as well as defensively. It gives goals with their situations as well as occasionally digging his opponents ankles.
Jan Gogola ml. thus embodies one stage of the Department of Documentary Film at FAMU, which often stands at the intersection between teaching activities and Karel Vachek among students who applied by them during their seminars psychological methods that work must be peculiarly associated with the author of the film
Dr. Jan French – Faculty Author Interview
No full textDr. Jan French, Assistant Professor of Anthropology, discusses her new book, Legalizing Identities: Becoming Black or Indian in Brazil’s Northeast, which shows how law can successfully serve as the impetus for the transformation of cultural practices and collective identity
Jan Bernátek - organ works
No full textThis graduation thesis provides a more detailed view on compositoins of Jan Bernátek.The aim is to present this less well-known temporary czech author,who makes use of the organ in the majority of his work
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