339 research outputs found
IGFBP2 Is a Potential Master Regulator Driving the Dysregulated Gene Network Responsible for Short Survival in Glioblastoma Multiforme
No full textOnly 2% of glioblastoma multiforme (GBM) patients respond to standard therapy and survive beyond 36 months (long-term survivors, LTS), while the majority survive less than 12 months (short-term survivors, STS). To understand the mechanism leading to poor survival, we analyzed publicly available datasets of 113 STS and 58 LTS. This analysis revealed 198 differentially expressed genes (DEGs) that characterize aggressive tumor growth and may be responsible for the poor prognosis. These genes belong largely to the Gene Ontology (GO) categories “epithelial-to-mesenchymal transition” and “response to hypoxia.” In this article, we applied an upstream analysis approach that involves state-of-the-art promoter analysis and network analysis of the dysregulated genes potentially responsible for short survival in GBM. Binding sites for transcription factors (TFs) associated with GBM pathology like NANOG, NF-κB, REST, FRA-1, PPARG, and seven others were found enriched in the promoters of the dysregulated genes. We reconstructed the gene regulatory network with several positive feedback loops controlled by five master regulators [insulin-like growth factor binding protein 2 (IGFBP2), vascular endothelial growth factor A (VEGFA), VEGF165, platelet-derived growth factor A (PDGFA), adipocyte enhancer-binding protein (AEBP1), and oncostatin M (OSMR)], which can be proposed as biomarkers and as therapeutic targets for enhancing GBM prognosis. A critical analysis of this gene regulatory network gives insights into the mechanism of gene regulation by IGFBP2 via several TFs including the key molecule of GBM tumor invasiveness and progression, FRA-1. All the observations were validated in independent cohorts, and their impact on overall survival has been investigated
Computational identification of key regulators in two different colorectal cancer cell lines
No full textTranscription factors (TFs) are gene regulatory proteins that are essential for an effective regulation of the transcriptional machinery. Today, it is known that their expression plays an important role in several types of cancer. Computational identification of key players in specific cancer cell lines is still an open challenge in cancer research. In this study, we present a systematic approach which combines colorectal cancer (CRC) cell lines, namely 1638N-T1 and CMT-93, and well-established computational methods in order to compare these cell lines on the level of transcriptional regulation as well as on a pathway level, i.e., the cancer cell-intrinsic pathway repertoire. For this purpose, we firstly applied the Trinity platform to detect signature genes, and then applied analyses of the geneXplain platform to these for detection of upstream transcriptional regulators and their regulatory networks. We created a CRC-specific position weight matrix (PWM) library based on the TRANSFAC database (release 2014.1) to minimize the rate of false predictions in the promoter analyses. Using our proposed workflow, we specifically focused on revealing the similarities and differences in transcriptional regulation between the two CRC cell lines, and report a number of well-known, cancer-associated TFs with significantly enriched binding sites in the promoter regions of the signature genes. We show that, although the signature genes of both cell lines show no overlap, they may still be regulated by common transcription factors in CRC. Based on our findings, we suggest that canonical Wnt signaling is activated in 1638N-T1, but inhibited in CMT-93 through cross-talks of Wnt signaling with the VDR signaling pathway and/or LXR-related pathways. Furthermore, our findings provide indication of several master regulators being present such as MLK3 and Mapk1 (ERK2) which might be important in cell proliferation, migration, and invasion of 1638N-T1 and CMT-93, respectively. Taken together, we provide new insights into the invasive potential of these cell lines, which can be used for development of effective cancer therapy
A Bioinformatics Pipeline for Identifying Dysregulated Pathways in Cancer from Comparative RNA-Seq Transcriptome Analysis
No full textKrebs ist eine multifaktorielle Erkrankung, die während des invasiven Tumorwachstums
genetische und epigenetische Veränderungen durchläuft. So wurden zahlreiche Tumor-
proben mit Hilfe von Hochdurchsatz-Sequenzierungstechnologien wie Microarray und
RNA-Sequenzierung (RNA-Seq) profiliert, um ihre Transkriptome zu erhalten. Es bleibt
jedoch eine schwierige Aufgabe, solche hochdimensionalen Daten zu entschlüsseln, um
dysregulierte Signalwege zu identifizieren. Um diese Lücke zu schließen, werden bioin-
formatische Pipelines benötigt, die die Fehlregulierung von Genen aufdecken, indem sie
kausale regulatorische Verbindungen zwischen Transkriptionsfaktoren (TFs) und ihren Ziel-
genen herstellen. TFs sind Proteine, die die Genexpression steuern, indem sie kurze Motive,
so genannte Transkriptionsfaktor-Bindungsstellen (TFBS), in DNA-Regulationsregionen
wie z.B. Promotoren, Enhancern und Silencern erkennen.
Ziel dieser Arbeit war es daher, eine Bioinformatik-Pipeline für den Vergleich von
Phänotypen auf der Grundlage von RNA-Seq zu entwickeln und zu bewerten. Die einzel-
nen Arbeitsabläufe der Pipeline umfassen Methoden in der RNA-Seq-Datenanalyse, der
Promotoranalyse, der umfassenden Funktionsanalyse und der Master-Regulator-Analyse
(MRA), wodurch differenziell exprimierte Gene (DEG), TFs, biologische Prozesse und
Master-Regulatoren (MR) identifiziert werden. Für die Promoter-Analyse wird ein diskri-
minierender Motiv-Entdeckungsansatz mit dem Boruta feature selection-Algorithmus
vorgeschlagen, der zwei DEG-Promotersequenzdatensätze auf der Grundlage von TFBS-
Mustern unterscheidet. Darüber hinaus wird ein Gengruppierungsansatz vorgeschlagen,
bei dem Jensen-Shannon-Divergenz (JSD), Hauptkomponentenanalyse (PCA) und der
k-Means-Algorithmus verwendet werden. Dieser Ansatz gruppiert die DEG-Promotoren
auf der Grundlage von TFBS-Mustern, welche mit den diskriminierenden Motiven zusam-
menhängen. Die erhaltenen Gengruppen werden dann einer funktionalen Kategorisierung
mit Hilfe der Gene Ontology (GO) und einer MRA unterzogen.
Die Nützlichkeit der Pipeline wurde anhand von drei heterogenen Genexpressionsstu-
dien demonstriert, die sich durch eine unterschiedliche Aktivität der Signalwege bei Krebs
auszeichnen. Im Verlauf der Promotoranalyse zeigten die Ergebnisse, dass die auf der Rang-
folge basierenden Wichtigkeitsscores von Boruta verwendet werden können, um biologisch
relevante TFs zu identifizieren. Darüber hinaus wiesen die Ergebnisse auf klar getrennte
Gengruppen hin, die durch eindeutig signifikante GO-Begrifflichkeiten und MRs gekennze-
ichnet sind. Zusammenfassend lässt sich sagen, dass die Pipeline einen nützlichen bioinfor-
matischen Rahmen für die vergleichende Untersuchung von Phänotypen auf der Grundlage
von RNA-Seq bietet, um Variationen in der Transkriptionsregulation und im Repertoire der
Signalwege aufzudecken.Cancer is characterized as a multifactorial disease which undergoes genetic and epige-
netic changes during invasive tumor growth. Thus, numerous tumor samples have been
profiled using high-throughput sequencing technologies such as microarray and RNA
sequencing (RNA-Seq) to obtain their transcriptomes. However, disentangling such high-
dimensional data to identify dysregulated signaling pathways remains a difficult task.
To close this gap, bioinformatics pipelines are needed to uncover gene misregulation by
establishing causal regulatory links between transcription factors (TFs) and their target
genes. TFs are proteins that control gene expression by recognizing short motifs called
transcription factor binding sites (TFBSs) in DNA regulatory regions like promoters, en-
hancers, and silencers.
To this end, the goal of this thesis was to establish and evaluate a bioinformatics pipeline
for comparing phenotypes based on RNA-Seq. The individual workflows of the pipeline
comprise methods in RNA-Seq data analysis, promoter analysis, comprehensive functional
categorization, and master regulator analysis (MRA), thereby identifying differentially
expressed genes (DEGs), TFs, biological processes, and master regulators (MRs). For
promoter analysis, a discriminative motif discovery approach using the Boruta feature
selection algorithm is proposed, which distinguishes two DEG promoter sequence datasets
based on TFBS patterns. In addition, a gene clustering approach is proposed using the
Jensen-Shannon divergence (JSD), principal component analysis (PCA), and the k-means
algorithm, which groups DEG promoters based on TFBS patterns related to the discrimi-
native motifs. The gene clusters obtained are subjected to Gene Ontology (GO) functional
categorization and MRA.
The utility of the pipeline was demonstrated using three heterogenous gene expression
studies that are characterized by distinct signaling pathway activity in cancer. In the course
of promoter analysis, the results indicated that Boruta’s ranking-based importance scores
can be used to identify biologically relevant TFs. Furthermore, the results indicated clearly
separated gene clusters characterized by uniquely significant GO terms and MRs.
In conclusion, the pipeline provides a useful bioinformatics framework for the comparative
study of phenotypes based on RNA-Seq to reveal variations in transcriptional regulation
and pathway repertoire.2022-04-1
Consensus molecular subtyping of colorectal carcinoma brain metastases reveals a metabolic signature associated with poor patient survival
No full textThe transcriptomic classification of primary colorectal cancer (CRC) into distinct consensus molecular subtypes (CMSs) is a well‐described strategy for patient stratification. However, the molecular nature of CRC metastases remains poorly investigated. To this end, this study aimed to identify and compare organotropic CMS frequencies in CRC liver and brain metastases. Compared to reported CMS frequencies in primary CRC, liver metastases from CRC patients were CMS4‐enriched and CMS3‐depleted, whereas brain metastases mainly clustered as CMS3 and rarely as CMS4. Regarding overall survival rates, CMS4 was the most favorable subtype for patients with hepatic lesions, followed by CMS1 and CMS2. The survival of patients with brain metastases did not correlate with CMS. However, we identified a CMS3‐related metabolic gene signature, specifically upregulated in central nervous system (CNS)‐infiltrating CRC, as a negative prognostic marker and potential tumor progressor. In summary, subtyping of CRC metastases revealed an organotropic CMS distribution in liver and brain with impact on patient survival. CNS‐infiltrating CRC samples were enriched for CMS3 and predictive metabolic biomarkers, suggesting metabolic dysregulation of CRC cells as a prerequisite for metastatic colonization of the brain.Bundesministerium für Bildung und Forschung https://doi.org/10.13039/50110000234
Darius I and the Daric
No full textThe author describes the place of the daric in the development of the coinage of Sardes, and links its weight with that of the Babylonian shekel of Darius I. He explores the question of exchange between the earlier electrum and the gold and silver issues struck at Sardes under the Persians, suggesting that there was a significant fall in the value of silver over the second half of the 6th. Century BC.L'auteur étudie la place du darique dans le développement du monnayage à Sardes, et lie son poids avec celui du shekel babylonien de Darius Ier. Il examine le problème de l'échange entre les monnaies en électrum de la période précédente et l'argent monnayé à Sardes à l'époque perse. Il suggère une baisse significative de la valeur de l'argent dans la deuxième moitié du VIe siècle av. J.-C.Price Martin J. Darius I and the Daric. In: Revue des Études Anciennes. Tome 91, 1989, n°1-2. L'or perse et l'histoire grecque, sous la direction de Raymond Descat. pp. 9-13
Darius Versus Xerxem: The images of Darius I And Xerxes In Old-Persian texts and in the works of Aeschylus and Herodotus
No full text© The Author(s) 2017. This article considers the development of the images of Persian Kings Darius I and Xerxes in Persia and Ancient Greece. The authors deal with self-representation of these monarchs in their inscriptions as well as perception of them in the ancient tradition represented by Aeschylus and Herodotus. They come to the conclusion that though Darius and Xerxes represented themselves as equals, they were perceived in ancient tradition as contrasting persons. It was most evident in Aeschylus' Persians who idealized Darius and represented Xerxes as the person mainly responsible for all misdeeds and failures of the Persians in their campaign against the Greeks. Herodotus contrasted Xerxes with Darius only on a few specific occasions, so the opposition between two Persian kings in his work is less evident than in Aeschylus' play. At the same time Herodotus' image of Xerxes is much more prejudiced and negative than that of Darius. However, there is a similarity in the representation of both Persian kings by Aeschylus and Herodotus: Darius is depicted as an administrator more than a warrior, Xerxes was a warrior par excellence
Darius Versus Xerxem: The images of Darius I And Xerxes In Old-Persian texts and in the works of Aeschylus and Herodotus
No full text© The Author(s) 2017. This article considers the development of the images of Persian Kings Darius I and Xerxes in Persia and Ancient Greece. The authors deal with self-representation of these monarchs in their inscriptions as well as perception of them in the ancient tradition represented by Aeschylus and Herodotus. They come to the conclusion that though Darius and Xerxes represented themselves as equals, they were perceived in ancient tradition as contrasting persons. It was most evident in Aeschylus' Persians who idealized Darius and represented Xerxes as the person mainly responsible for all misdeeds and failures of the Persians in their campaign against the Greeks. Herodotus contrasted Xerxes with Darius only on a few specific occasions, so the opposition between two Persian kings in his work is less evident than in Aeschylus' play. At the same time Herodotus' image of Xerxes is much more prejudiced and negative than that of Darius. However, there is a similarity in the representation of both Persian kings by Aeschylus and Herodotus: Darius is depicted as an administrator more than a warrior, Xerxes was a warrior par excellence
Intralesional TLR4 agonist treatment strengthens the organ defense against colonizing cancer cells in the brain
No full textAbstract
Brain metastasis in breast cancer remains difficult to treat and its incidence is increasing. Therefore, the development of new therapies is of utmost clinical relevance. Recently, toll-like receptor (TLR) 4 was correlated with IL6 expression and poor prognosis in 1 215 breast cancer primaries. In contrast, we demonstrated that TLR4 stimulation reduces microglia-assisted breast cancer cell invasion. However, the expression, prognostic value, or therapeutic potential of TLR signaling in breast cancer brain metastasis have not been investigated. We thus tested the prognostic value of various TLRs in two brain-metastasis gene sets. Furthermore, we investigated different TLR agonists, as well as MyD88 and TRIF-deficient microenvironments in organotypic brain-slice ex vivo co-cultures and in vivo colonization experiments. These experiments underline the ambiguous roles of TLR4, its adapter MyD88, and the target nitric oxide (NO) during brain colonization. Moreover, analysis of the gene expression datasets of breast cancer brain metastasis patients revealed associations of TLR1 and IL6 with poor overall survival. Finally, our finding that a single LPS application at the onset of colonization shapes the later microglia/macrophage reaction at the macro-metastasis brain-parenchyma interface (MMPI) and reduces metastatic infiltration into the brain parenchyma may prove useful in immunotherapeutic considerations.Deutsche Forschungsgemeinschaft https://doi.org/10.13039/501100001659Bundesministerium für Bildung und Forschung https://doi.org/10.13039/50110000234
Syntenin Controls Extracellular Vesicle‐Induced Tumour Migration by Regulating the Expression of Adhesion Proteins on Small Extracellular Vesicles
No full textABSTRACT Despite extensive proof for the tumour‐supporting function of cancer‐derived small extracellular vesicles (sEVs), attributions of pathological effects to specific sEV subpopulations are poorly described. In this study, we aimed to characterise a distinct sEV species under the control of Syntenin, a key regulator of endosomal sEV biogenesis, regarding its proteomic cargo and pro‐tumourigenic functions. Using mass spectrometry (MS), we detected 178 down‐ and 236 up‐regulated proteins on sEVs from breast cancer cells upon Syntenin knockout (KO). Pathway enrichment analysis suggested that Syntenin depletion was particularly associated with adhesion‐related processes. Accordingly, sEVs from Syntenin‐deficient 4T1 and MCF‐7 breast cancer cells showed a reduced expression of several focal adhesion and cell–cell junction proteins. Syntenin silencing reduced the Fibronectin‐binding capacity of sEVs from both cell lines, which was mediated by sEV‐associated Integrin alpha‐V/beta‐3 (αVβ3). Compared to sEVs from wildtype cells, Syntenin KO sEVs showed decreased tropism towards the Fibronectin‐rich liver microenvironment in vivo, provided less adhesive support for 4T1 cells and thereby failed to induce cancer cell migration, which appeared to be independent of EV uptake. In summary, this study revealed that Syntenin has a large‐scale effect on the proteomic cargo of sEVs and regulates their adhesive, organotropic and pro‐migratory properties in breast cancer
Causes of recurrence in laparoscopic inguinal hernia repair (vol 22, pg 975, 2018)
No full textIn the original publication, affiliation 3 was incorrectly published for the author 'Darius Ashrafi'. The correct affiliation should read as 'Department of Surgery, Sunshine Coast University Hospital, Birtinya, QLD, Australia
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