1,720,972 research outputs found
Identification of signaling pathways activated by cancer-associated fibroblasts leading to Akt activation in colon cancer cells
No full textMaster thesis - University of Veterinary Medicine Vienna - 2020With 10.2 % of all cancer types, colorectal cancer (CRC) is the third most common cancer in both sexes and accounts for 900,000 deaths per year worldwide. These numbers show the urgency of effective treatment strategies for this cancer type. In the past, most research studies focused on cancer cells themselves and how they can be targeted to treat cancer. Over the last 20 years, this perspective has considerably changed and studies additionally focused on the tumor microenvironment – also called the tumor stroma. There is now compelling evidence that the tumor stroma is critically involved in cancer initiation and progression. The tumor microenvironment is composed of extracellular matrix and many different cell types with cancer-associated fibroblasts (CAFs) being the most abundant cells. These cells can promote cancer progression by interacting with cancer cells directly or by modulating other stromal cells and components. In previous studies, we found that especially CAF-derived insulin-like growth factor (IGF)-2 is an important factor in CRC carcinogenesis. We could show that stromaderived IGF-2 signals via the IGF-1 receptor (IGF-1-R) and leads to increased p-Akt levels in CRC cells which is an accepted risk factor for CRC development and progression. However, these studies also demonstrated that IGF-2 is only partially responsible for Akt activation by CAFs indicating that other stromal factors than IGF-2 are present in the CAF secretome and mediate Akt activation. Thus, the aim of this study was to identify these other CAF-derived factors next to IGF-2 or additional pathways other than the IGF-1-R signaling which are responsible for full Akt activation. Inhibition of these CAF-induced signaling pathways might serve as future therapeutic route to target pro-tumorigenic CAF/colon cancer cell interactions. Therefore, a medium throughput screen with a 378 small molecules kinase inhibitor library was assessed to pinpoint potential inhibitors which downregulate CAF-dependent p-Akt upregulation in HCT116 colon cancer cells. As expected by the previous IGF-2 results, we found several promising IGF-1 receptor/insulin receptor inhibitors but also c-Met and JAK inhibitors which substantially inhibited Akt phosphorylation. These inhibitors were further validated and hits with the best Akt inhibitory effect and target selectivity for each of the three kinases (OSI-906, JNJ-38877605 and Fedratinib) were examined in further experiments. Phenotypic assays were performed to test the impact of the inhibitors on CAF-activated colon cancer cell proliferation, migration and invasion. Indeed, the inhibitors significantly impaired these cellular functions in vitro. With these results, we might contribute to the identification of novel therapeutic targets to interfere with the pro-tumorigenic effects of the tumor stroma/cancer cell interaction.Masterarbeit - Veterinärmedizinische Universität Wien - 2020Das kolorektale Karzinom (KRK) ist der dritthäufigste Krebstyp bei Frauen und Männern und ist weltweit für 900.000 Todesfalle pro Jahr verantwortlich. Die Häufigkeit dieser Erkrankung zeigt die Dringlichkeit effektive Therapiemöglichkeiten zu finden. Obwohl sich frühere Studien eher auf die Krebszellen selbst fokussierten, ist es in den letzten 20 Jahren zu einem Umdenken gekommen. Es wurde gezeigt, dass die Tumor Mikroumgebung – auch Tumor Stroma genannt – einen großen Teil zur Krebsentstehung und -fortschreitung beitragt. Die Tumor Mikroumgebung besteht aus der extrazellularen Matrix und vielen verschiedenen Zelltypen, wobei Tumor-assoziierte Fibroblasten (TAFs) die am häufigsten vorkommenden Zellen sind. TAFs können den Krebsverlauf zugunsten der Krebszellen beeinflussen indem sie mit Krebszellen direkt interagieren oder andere Stromakomponenten regulieren. In vorhergehenden Studien konnten wir bereits zeigen, dass der von TAFs sezernierte Insulinlike growth factor (IGF)-2 wesentlich zur kolorektalen Karzinogenese beitragt. Dabei bindet stromales IGF-2 an den IGF-1 Rezeptor und führt zu erhöhten p-Akt Mengen in KRK Zellen was ein allgemein anerkannter Risikofaktor für die Entstehung und das Fortschreiten eines KRK ist. Allerdings führte eine Blockierung des IGF-1 Rezeptors oder die direkte Inhibierung von IGF-2 zu keiner vollständigen p-Akt Inhibition, sondern lediglich zu einer verminderten Aktivierung. Daher war das Ziel dieser Arbeit weitere von TAFs sekretierte Faktoren oder von TAFs induzierte Signalwege zu finden, die zu einer vollständigen Akt Aktivierung fuhren und deren Inhibierung eine mögliche, zukünftige Krebstherapie darstellt. Zu diesem Zweck wurde ein Durchsatz-Screening mit 378 verschiedenen Kinase Inhibitoren durchgeführt um Inhibitoren zu finden, die TAF induzierte p-Akt Aktivierung in HCT116 KRK Zellen herabregulieren. Wie durch die vorausgegangene Studie erwartet, wurden mehrere IGF-1 Rezeptoren/Insulin Inhibitoren aber auch c-Met und JAK Inhibitoren gefunden, die p-Akt wirksam inhibieren konnten. Diese Inhibitoren wurden in verschiedenen Experimenten validiert und der wirksamste jeder Kategorie mit der höchsten Selektivitat (OSI-906, JNJ-38877605 und Fedratinib) wurde in weiteren Experimenten eingesetzt. In phenotypischen Experimenten wurde der Einfluss der Inhibitoren auf die Zellproliferation, -migration und -invasion von TAFaktivierten Krebszellen getestet. Wir konnten mit diesen Experimenten zeigen, dass die Inhibitoren diese Zellfunktionen in vitro signifikant beeinträchtigen. Diese Resultate können zur Identifikation von neuen therapeutischen Angriffspunkten beitragen, die die Kommunikation zwischen TAFs und KRK Zellen beeinträchtigen und somit das Voranschreiten der Krebserkrankungen verhindern.Master thesis - University of Veterinary Medicine Vienna - 2020With 10.2 % of all cancer types, colorectal cancer (CRC) is the third most common cancer in both sexes and accounts for 900,000 deaths per year worldwide. These numbers show the urgency of effective treatment strategies for this cancer type. In the past, most research studies focused on cancer cells themselves and how they can be targeted to treat cancer. Over the last 20 years, this perspective has considerably changed and studies additionally focused on the tumor microenvironment – also called the tumor stroma. There is now compelling evidence that the tumor stroma is critically involved in cancer initiation and progression. The tumor microenvironment is composed of extracellular matrix and many different cell types with cancer-associated fibroblasts (CAFs) being the most abundant cells. These cells can promote cancer progression by interacting with cancer cells directly or by modulating other stromal cells and components. In previous studies, we found that especially CAF-derived insulin-like growth factor (IGF)-2 is an important factor in CRC carcinogenesis. We could show that stromaderived IGF-2 signals via the IGF-1 receptor (IGF-1-R) and leads to increased p-Akt levels in CRC cells which is an accepted risk factor for CRC development and progression. However, these studies also demonstrated that IGF-2 is only partially responsible for Akt activation by CAFs indicating that other stromal factors than IGF-2 are present in the CAF secretome and mediate Akt activation. Thus, the aim of this study was to identify these other CAF-derived factors next to IGF-2 or additional pathways other than the IGF-1-R signaling which are responsible for full Akt activation. Inhibition of these CAF-induced signaling pathways might serve as future therapeutic route to target pro-tumorigenic CAF/colon cancer cell interactions. Therefore, a medium throughput screen with a 378 small molecules kinase inhibitor library was assessed to pinpoint potential inhibitors which downregulate CAF-dependent p-Akt upregulation in HCT116 colon cancer cells. As expected by the previous IGF-2 results, we found several promising IGF-1 receptor/insulin receptor inhibitors but also c-Met and JAK inhibitors which substantially inhibited Akt phosphorylation. These inhibitors were further validated and hits with the best Akt inhibitory effect and target selectivity for each of the three kinases (OSI-906, JNJ-38877605 and Fedratinib) were examined in further experiments. Phenotypic assays were performed to test the impact of the inhibitors on CAF-activated colon cancer cell proliferation, migration and invasion. Indeed, the inhibitors significantly impaired these cellular functions in vitro. With these results, we might contribute to the identification of novel therapeutic targets to interfere with the pro-tumorigenic effects of the tumor stroma/cancer cell interaction
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe 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
Die Rolle des FGF23-Signalwegs in der Pathogenese von renaler und cardialer Fibrose in einem chronischen Niereninsuffizienz-Modell in der Maus
No full textFibroblast-growth-factor-23 (FGF23) is a bone-derived hormone causing an augmented renal phosphate excretion and the suppression of the synthesis of active vitamin D in the kidney. Therefore, it is a major regulator of the phosphate homeostasis. In distal renal tubules, FGF23 activates a with-no-lysin-kinase-4 (WNK4) signalling pathway leading to an augmented membrane expression of Na+:Cl—cotransporter (NCC) and transient-receptor-potential-vannilloid-5 (TRPV5) and therefore to an increased urinary sodium and calcium retention. In chronic kidney disease (CKD) the decrease in glomerular filtration rate (GFR) leads to a progressive accumulation of FGF23. In the process of CKD FGF23 can reach several-fold higher serum levels as in physiological circumstances. Increased FGF23 serum levels are correlate positively with higher risk of cardiovascular diseases and higher incidence and prevalence of left ventricular hypertrophy (LVH). In contrast, CKD and LVH are not common findings in diseases which are characterised by primary chronically elevated FGF23 levels. Therefore, it is still uncertain whether FGF23 is just a biomarker of an inadequate phosphate homeostasis or a modulator of pathological processes during the progression of CKD. Furthermore, there are controversial data describing the role of FGF23 in the development of LVH. This study reveals that the genotype Fgf23-/-/VDRΔ/Δ leads to a significant reduced renal and cardiac fibrosis compared to WT mice with 5/6 nephrectomy (5/6 Nx) -induced CKD. To measure the collagen levels, heart and kidney slices from mice were stained with picrosirius red. The amount of collagen was shown to be equal between VDRΔ/Δ and WT mice with induced CKD. Thus, FGF23 was identified as an essential factor promoting the interstitial fibrosis of renal and left ventricular cardiac tissue in a mouse model with 5/6 Nx-induced CKD.Diplomarbeit - Veterinärmedizinische Universität Wien - 2020Fibroblast-growth-factor-23 (FGF23) ist ein aus Knochen freigesetztes Hormon, welches durch erhöhte renale Phosphatausscheidung und einer verminderten Synthese von aktivem Vitamin D an der Regulierung des Phosphatserumspiegels maßgeblich beteiligt ist. Darüber hinaus erhöht FGF23 über eine Signalkaskade, in die unter anderem With-No-Lysin-Kinase-4 (WNK4) involviert ist, durch erhöhte Membranexpression von Na+:Cl—Cotransporter (NCC) und Transient-Rezeptor-Potential-Vannilloid-5 (TRPV5), die Natrium- und Kalziumreabsorption im distalen Tubulus der Nieren. Bei chronischer Niereninsuffizienz (CNI) kommt es durch Abnahme der glomerulären Filtrationsrate (GFR) zu einem progressiven Anstieg der FGF23 Serumkonzentrationen, die dann bis zu einem Vielfachen über dem Normalniveau liegen können. Erhöhte FGF23 Serumkonzentrationen bei CNI führen zu einem erhöhten Risiko von kardiovaskulären Erkrankungen und korrelieren mit einer erhöhten Inzidenz und Prävalenz von linksventrikulärer Hypertrophie (LVH). Auf der anderen Seite sind CNI und LVH bei Patienten, die an Krankheiten leiden, welche durch primär chronisch erhöhte FGF23 Serumkonzentrationen charakterisiert sind, keine typischen Begleiterscheinungen. Daher ist es immer noch nicht vollständig geklärt, ob FGF23 einen Biomarker für eine entgleiste Phosphathomöostase darstellt oder ob es ein aktiver Modulator von pathologischen Prozessen bei der Progression von CNI ist. Des Weiteren gibt es Aufgrund kontroverser Daten Unklarheiten, ob und in welchem Zusammenhang erhöhte FGF23 Serumkonzentrationen und die Entstehung von LVH stehen. Wir konnten zeigen, dass in mit Picro-Sirius-Red gefärbten histologischen Präparaten, von Nieren und Herzen von Mäusen, in welchen zuvor durch 5/6 Nephrektomie (5/6 Nx) eine CNI induziert wurde, der Genotyp Fgf23-/-/VDRΔ/Δ signifikant geringere Kollagenniveaus gegenüber WT bedingte. Bezüglich VDRΔ/Δ Mäusen und WT Mäusen mit induzierter CNI war kein Unterschied im Kollagengehalt feststellbar. Dadurch konnten wir FGF23 als einen wesentlichen Faktor identifizieren, welcher die interstitielle Fibrosierung sowohl des Nierengewebes als auch des linken Ventrikels in einem Mausmodell der 5/6 Nx induzierten CNI vorantreibt
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Investigating the tumor microenvironment of liver metastases
No full textMaster thesis - University of Veterinary Medicine Vienna - 2023The diagnosis of liver metastases dramatically worsens prognosis in patients with gastrointestinal cancer. Histologically, two major growth pattern of liver metastases were described: replacement and encapsulated. Replacement-type metastases are characterized by direct contact between hepatocytes and tumor cells. In encapsulated metastases a fibrotic capsule separates the liver from the tumor. Importantly, encapsulated metastases are linked to improved survival. Our study explored the role of the tumor microenvironment in pancreatic and colorectal cancer liver metastases (PCLM and CRLM, respectively). We used multiplex RNA in situ hybridization to characterize the distribution of stromal cells within the capsule of encapsulated CRLM. The results revealed a zonal expression of the fibrotic marker genes COL1A1, DCN, FN1 and PDGFRA. In a CRLM cohort including 263 patients pre-operative chemotherapy treatment was associated with a higher degree of encapsulation. Similarly, we show that chemotherapy induces capsule formation in murine CRLM. In murine replacement-type liver metastases, we detected Stat3 phosphorylation (pStat3) at the invasion front, suggesting activation of the IL-6/JAK/STAT3 signalling axis. Unexpectedly, treatment with IL-6 blocking antibodies did not affect the pStat3 signal. I further established a co-culture system combining hepatocytes and pancreatic cancer cells. Preliminary data indicate that tumor cell addition alone does not induce apoptosis in neighbouring hepatocytes in vitro. Together, we gave new insights into the process of capsule formation in encapsulated liver metastases and provided evidence that STAT3 signaling is activated in the perimetastatic liver of replacement-type. In summary, our findings provide insights into the complex tumor microenvironment of liver metastases.Masterarbeit - Veterinärmedizinische Universität Wien - 2023Die Diagnose von Lebermetastasen bei Patienten mit gastrointestinalen Tumoren wie Bauchspeicheldrüsen- oder Dickdarmkrebs führt zu einer erheblichen Verschlechterung der Überlebensprognose. Histologisch wurden hauptsächlich zwei Wachstumsmuster von Lebermetastasen beschrieben: „Replacement“ und „Encapsulated“. Aggressive "Replacement"-Metastasen zeigen direkten Zellkontakt zwischen Hepatozyten und Tumorzellen. "Encapsulated"-Metastasen sind von einer fibrotischen Kapsel umgeben. Das „Encapsulated“ Wachstumsmuster ist mit einer besseren Überlebensrate assoziiert. Ziel unserer Studie war es, die Tumor-Mikroumgebung in Lebermetastasen von Bauchspeicheldrüsen- und Darmkrebs zu untersuchen. Mittels Multiplex-RNA-in-situ-Hybridisierung konnten wir eine zonale Expression der fibrotischen Markergene COL1A1, DCN, FN1, PDGFRA in der Kapsel von kolorektalen Lebermetastasen (KRLM) zeigen. In einer klinischen Kohorte von 263 KRLM Patienten war eine präoperative Chemotherapie mit einem höheren Anteil vom „Encapsulated“-Wachstumsmuster verbunden. Wir konnten diese Ergebnisse in einem Mausmodell bestätigen. Des Weiteren haben wir Phosphorylierung von Stat3 (pStat3) im perimetastatischen Lebergewebe von murinen Lebermetastasen gezeigt, was auf Aktivierung des IL-6/JAK/STAT3-Signalweges hinweist. Unerwarteterweise hatte die Behandlung von Mäusen mit IL-6 blockierenden Antikörpern keinen Einfluss auf das pStat3-Signal in der perimetastatischen Leber. Im weiteren Verlauf haben ich ein Co-Kultur-System etabliert, mit dem zelluläre Interaktionen zwischen Hepatozyten und Tumorzellen untersucht werden können. Vorläufige Ergebnisse weisen darauf hin, dass das Vorhandensein von Tumorzellen allein keine Apoptose in benachbarten Hepatozyten auslöst. Zusammenfassend gewannen wir neue Erkenntnisse zur Kapselbildung bei weniger aggressiven Lebermetastasen und zeigten, dass Lebermetastasen vom "Replacement"-Typ durch eine Aktivierung von STAT3 im perimetastatischen Lebergewebe gekennzeichnet sind. Unsere Ergebnisse liefern Einblicke in die komplexe Tumormikroumgebung von Lebermetastasen gastrointestinaler Tumore.Master thesis - University of Veterinary Medicine Vienna - 2023The diagnosis of liver metastases dramatically worsens prognosis in patients with gastrointestinal cancer. Histologically, two major growth pattern of liver metastases were described: replacement and encapsulated. Replacement-type metastases are characterized by direct contact between hepatocytes and tumor cells. In encapsulated metastases a fibrotic capsule separates the liver from the tumor. Importantly, encapsulated metastases are linked to improved survival. Our study explored the role of the tumor microenvironment in pancreatic and colorectal cancer liver metastases (PCLM and CRLM, respectively). We used multiplex RNA in situ hybridization to characterize the distribution of stromal cells within the capsule of encapsulated CRLM. The results revealed a zonal expression of the fibrotic marker genes COL1A1, DCN, FN1 and PDGFRA. In a CRLM cohort including 263 patients pre-operative chemotherapy treatment was associated with a higher degree of encapsulation. Similarly, we show that chemotherapy induces capsule formation in murine CRLM. In murine replacement-type liver metastases, we detected Stat3 phosphorylation (pStat3) at the invasion front, suggesting activation of the IL-6/JAK/STAT3 signalling axis. Unexpectedly, treatment with IL-6 blocking antibodies did not affect the pStat3 signal. I further established a co-culture system combining hepatocytes and pancreatic cancer cells. Preliminary data indicate that tumor cell addition alone does not induce apoptosis in neighbouring hepatocytes in vitro. Together, we gave new insights into the process of capsule formation in encapsulated liver metastases and provided evidence that STAT3 signaling is activated in the perimetastatic liver of replacement-type. In summary, our findings provide insights into the complex tumor microenvironment of liver metastases
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
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