11 research outputs found
Effekt von Adiposität auf die Entstehung von Mutationssignaturen in Magen-Darm Krebs
No full textKrebs entsteht aus normalem Gewebe, durch die Ansammlung von Mutationen, welche die Funktionalität der zellulären Signalwege verändern. Die Prozesse der DNA-Schädigung und -Reparatur (DDR) stehen im Mittelpunkt vieler Krebsmerkmale und stellen gleichzeitig ein Hindernis und eine Hilfe für die Krebsentwicklung dar. Um die Komplexität der Krebsentstehung zu begreifen, ist ein systematisches dafür Verständnis erforderlich, wie DDR-Prozesse unter bestimmten Bedingungen zur Entwicklung von genomischer Instabilität beitragen. Die mathematischen und computergestützten Konzepte der Mutationssignaturen hat die systematische Entdeckung biologisch aussagekräftiger Signaturen ermöglicht, welche spezifischen Mutationsprozessen zuzuschreiben sind und so den Entwicklungsprozess bösartiger Erkrankungen beschreiben. Die Analyse von Mutationssignaturen in DNA-Sequenz Daten von Krebspatienten hat die Entdeckung von Mutationssignaturen für verschiedene Mutationstypen vorangetrieben. Während einige Signaturen eine erklärbare Ätiologie haben und sogar im klinischen Kontext einsetzbar sind, bleibt die Ursache vieler anderer Signaturen unbekannt. Um die Ätiologie unbekannter Signaturen aufzuklären, haben sich Bottom-up In-vivo oder In-vitro Studien als nützlich erwiesen. Da DNA Reparatur Prozesse ihre Wirkung gewebespezifisch entfalten, ist es immer wichtiger geworden, DNA-Reparatur und Mutagenese auch gewebespezifisch zu untersuchen, was durch die Entwicklung von organoid-basierten Kultursystemen möglich geworden ist. Wir haben die neusten technischen Vorteile von Ex-vivo-Kultursystemen mit der Analyse von Mutationssignaturen kombiniert, um uns auf die Untersuchung von Mutationsprozessen bei der Entstehung von Adiposität bedingtem Krebs zu konzentrieren. Epidemiologisch gesehen ist Fettleibigkeit ein anerkannter Risikofaktor, der die Wahrscheinlichkeit der Entstehung von Krebs, insbesondere im Darmtrakt, erhöht. insbesondere für den Darmtrakt. Obwohl bereits erforscht wurde, dass Fettleibigkeit die Homöostase und Signalwege von Darmstammzellen - den Ursprungszellen für Darmkrebs - verändert, bleibt unklar, wie genau Adiposität zur Entwicklung von Magen-Darm-Krebs beiträgt. In dieser Studie haben wir ein Mausmodell für ernährungsbedingte Fettleibigkeit in einem genetischen Wildtyp-Hintergrund verwendet (C57/BL6). So konnten wir genomweite Mutationen in Darmstammzellen nach 48-wöchiger Exposition gegenüber einer fettreichen Ernährung zu beobachten. Durch die klonale Expansion einzelner Stammzellen in organoider Kultur und der Analyse der Genomsequenzen ermittelten wir, dass die Mutationssignaturen bei Mäusen mit fettreicher Ernährung denen einer Standarddiät ähneln und normale Prozesse der Alterung, der Zellreplikation und des oxidativen Stresses widerspiegeln. Unsere Studie kommt zu dem Schluss, dass eine fettreiche Ernährung allein, ohne andere Stressfaktoren wie chemische Exposition oder Treibermutationen, nicht ausreicht, um einen Anstieg der genomischen Instabilität zu bewirken.Cancer evolves from normal tissue through acquiring adaptive mutations which rewire the functionality of inherent cellular pathways. The process of DNA damage and repair (DDR) is at the center of many cancer hallmarks and at once is a barrier and an aid for cancer development. Unraveling the complexity of cancer etiologies requires a systematic understanding of how DDR processes lead to the development of genomic instability under certain conditions. The mathematical and computational framework of mutational signatures has enabled the systematic discovery of biologically meaningful signatures attributable to specific mutational processes which reveal the evolution of malignancies. The analysis of mutational signatures in large cancer cohorts has sparked the discovery of mutational signatures of various mutational types. While some signatures have an explainable etiology and are even clinically actionable, the cause of many other signatures remains unknown. Too elucidate the etiology of unknown signatures, bottom-up in-vivo or in-vitro studies have proven useful. Since DDR processes exert their effect in a tissue specific manner, it has furthermore become increasingly important to study DNA repair and mutagenesis in a tissue specific manner, which has been made possible by the development of organoid based culturing systems. We combined the recent technical advantages in both, ex-vivo culturing systems and mutational signature analysis, to focus on studying mutational processes in the development of obesity associated cancer. Epidemiologically obesity is a well-recognized risk factor increasing the chance of cancer development, especially for gastrointestinal organs. Although it has been shown that diet induced obesity changes the homeostasis of intestinal stem cells – the cell of origin for intestinal cancers – it remains unclear how specifically obesity contributes to the development of gastrointestinal cancers. In this study, we used a mouse model of diet induced obesity on a wild type C57/BL6 background to observe the mutational landscape of intestinal stem cells after a 48-week exposure to a high-fat diet. By clonally expanding single stem cells in organoid culture, and obtaining whole genome sequences, we found that single base substitution and insertion/deletion signatures present in the mice on the high-fat diet were similar to those on a standard diet and reflected normal processes of aging, cellular replication, and oxidative stress. Our study concludes that high fat diet alone, in the absence of other stressors such as chemical exposure or driver gene mutations, is not enough to induce an increase in genomic instability.Abweichender Titel laut Übersetzung der Verfasserin/des VerfassersDissertation Medizinische Universität Wien 202
Las condiciones de la competencia en el norte del país
Get PDFThe description of the actors and principal preferences in the northern states of Mexico constitutes the basic core of this article. In it, its author studies the singular characteristics that prevail in this part of the country in so far as to the political conceptions, including, as well, the different life-styles that differ, strongly in some instances, from the rest of the country. Likewise, profiles of the main political personalities of this zone, such as Francisco Barrio and Fernando Canales Clariond are reviewed, giving forth, according to the author, images of honest and efficient men, archetypes of the middle-class mentality. The analysis ends by comparing to the forces that the panismo has achieved in the northern states of the country, based mainly on the articulate discourse linked to the personalities of its inhabitants to its weakness in the southern states where it has not been able to develop the appropriate discourse.La descripción de los actores y las preferencias políticas en el norte de México, constituyen la parte fundamental de este artículo. En él, la autora analiza las singulares características que se dan en esta región del país en cuanto a las concepciones políticas e, incluso, estilos de vida que divergen, en ocasiones fuertemente, de los del resto de la República. Asimismo, se tocan algunos de los perfiles de los principales personajes políticos de esa zona, como Francisco Barrio y Femando Canales Clariond, que proyectan, afirma la autora, imágenes de hombres honestos y eficientes, arquetipos afines al pensamiento de la clase media. El escrito concluye contrastando la fuerza que el panismo ha cobrado en los estados del norte del país —basada, en buena medida, en un discurso articulado que se vincula a la personalidad de sus habitantes— con su debilidad en la zona sur, donde no ha logrado desarrollar un discurso apropiado
Los cambios y las permanencias: las elecciones presidenciales del año 2000
No full textEn este artículo se hace un análisis del proceso electoral del 2 de julio de 2000 a partir de cuatro perspectivas: Ias peculiaridades del presidencialismo en México, los rasgos que distinguen a estas elecciones presidenciales de Ias dos anteriores, Ias reformas electorales y el equilibrio de la competencia y los cambios en la fisonomía de los partidos y la articulación del sistema de partidos. Al final del mismo se hacen algunas recomendaciones para la permanencia de la democracia en México.This essay provides a review of the general election of July 2, 2000, in Mexico, since four perspectives of analysis: the particular features of the presidential system of this country; the elements that distinguish this presidential election from the two former processes; the electoral reform and the guarantees for a fair competition, and the changes in the parties' internal organization and party system. At the end of this essay the author provides some recommendations for the preservation of democracy in Mexico
Los cambios y las permanencias. Las elecciones presidenciales del año 2000
No full textThis essay provides a review of the general election of July 2, 2000, in Mexico, since four perspectives of analysis: the particular features of the presidential system of this country; the elements that distinguish this presidential election from the two former processes; the electoral reform and the guarantees for a fair competition,and the changes in the parties’ internal organization and party system. At the end of this essay the author provides some recommendations for the preservation of democracy in MexicoEn este artículo se hace un análisis del proceso electoral del 2 de julio de 2000 a partir de cuatro perspectivas: las peculiaridades del presidencialismo en México, los rasgos que distinguen a estas elecciones presidenciales de las dos anteriores, las reformas electorales y el equilibrio de la competencia y los cambios en la fisonomía de los partidos y la articulación del sistema de partidos. Al final del mismo se hacen algunas recomendaciones para la permanencia de la democracia en MéxicoUniversidad Nacional Autónoma de México. Instituto de Investigaciones Histórica
Pan-cancer analysis of the interplay between mutational signatures and cellular signaling
No full textSummary: Cancer is a multi-faceted disease with intricate relationships between mutagenic processes, alterations in cellular signaling, and the tissue microenvironment. To date, these processes have been largely studied in isolation. A systematic understanding of how they interact and influence each other is lacking. Here, we present a framework for systematically characterizing the interaction between pairs of mutational signatures and between signatures and signaling pathway alterations. We applied this framework to large-scale data from TCGA and PCAWG and identified multiple positive and negative interactions, both cross֊tissue and tissue֊specific, that provide new insights into the molecular routes observed in tumorigenesis and their respective drivers. This framework allows for a more fine-grained dissection of common and distinct etiology of mutational signatures. We further identified several interactions with both positive and negative impacts on patient survival, demonstrating their clinical relevance and potential for improving personalized cancer care
Relating mutational signature exposures to clinical data in cancers via signeR 2.0
No full textAbstract Background Cancer is a collection of diseases caused by the deregulation of cell processes, which is triggered by somatic mutations. The search for patterns in somatic mutations, known as mutational signatures, is a growing field of study that has already become a useful tool in oncology. Several algorithms have been proposed to perform one or both the following two tasks: (1) de novo estimation of signatures and their exposures, (2) estimation of the exposures of each one of a set of pre-defined signatures. Results Our group developed signeR, a Bayesian approach to both of these tasks. Here we present a new version of the software, signeR 2.0, which extends the possibilities of previous analyses to explore the relation of signature exposures to other data of clinical relevance. signeR 2.0 includes a user-friendly interface developed using the R-Shiny framework and improvements in performance. This version allows the analysis of submitted data or public TCGA data, which is embedded in the package for easy access. Conclusion signeR 2.0 is a valuable tool to generate and explore exposure data, both from de novo or fitting analyses and is an open-source R package available through the Bioconductor project at ( https://doi.org/10.18129/B9.bioc.signeR )
Supervision and continuing professional development: Supervisors' hopes for meaningful, supervision-supported CPD.
Get PDFContinuing professional development (CPD) is now embedded into the New Zealand Association of Counsellors (NZAC) practices, such as its members' supervision, processes for membership renewal and applications for annual practicing certificates. Since its implementation in 2017, a number of developments have been made to NZAC CPD requirements, and in 2020 the process went online. During the same year, six experienced supervisors participated in a small-scale study in which they were interviewed about their experiences of the CPD process and its effects on supervision. The research project was part of a postgraduate paper in professional supervision and worked to introduce and engage researcher-students, all of whom were experienced counselling practitioners, in a supervised collaborative project. This article offers a review of literature on CPD and supervision, and presents the new findings about supervisors' hopes for meaningful, supervision-supported CPD. The findings highlighted limitations with current competencies for CPD and questioned these competencies as reflecting dominant Pākehā constructions of counselling and therefore, having effects for Māori practitioners. The study also revealed a tension between treating professional development as a requirement to be accounted for and hopes for supervision as a space to reflect on and shape future professional development. [ABSTRACT FROM AUTHOR] Copyright of New Zealand Journal of Counselling is the property of New Zealand Association of Counsellors and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.
Clickable Cisplatin Derivatives as Versatile Tools to Probe the DNA Damage Response to Chemotherapy
No full textCisplatin induces DNA crosslinks that are highly cytotoxic. Hence, platinum complexes are frequently used in the treatment of a broad range of cancers. Efficiency of cisplatin treatment is limited by the tumor-specific DNA damage response to the generated lesions. We reasoned that better tools to investigate the repair of DNA crosslinks induced by cisplatin would therefore be highly useful in addressing drug limitations. Here, we synthesized a series of cisplatin derivatives that are compatible with click chemistry, thus allowing visualization and isolation of DNA-platinum crosslinks from cells to study cellular responses. We prioritized one alkyne and one azide Pt(II) derivative, Pt-alkyne-53 and Pt-azide-64, for further biological characterization. We demonstrate that both compounds bind DNA and generate DNA lesions and that the viability of treated cells depends on the active DNA repair machinery. We also show that the compounds are clickable with both a fluorescent probe as well as biotin, thus they can be visualized in cells, and their ability to induce crosslinks in genomic DNA can be quantified. Finally, we show that Pt-alkyne-53 can be used to identify DNA repair proteins that bind within its proximity to facilitate its removal from DNA. The compounds we report here can be used as valuable experimental tools to investigate the DNA damage response to platinum complexes and hence might shed light on mechanisms of chemoresistance
Mutational landscape of intestinal crypt cells after long-term in vivo exposure to high fat diet
No full textAbstract Obesity is a modifiable risk factor in cancer development, especially for gastrointestinal cancer. While the etiology of colorectal cancer is well characterized by the adenoma-carcinoma sequence, it remains unclear how obesity influences colorectal cancer development. Dietary components of a high fat diet along with obesity have been shown to modulate the cancer risk by perturbing the homeostasis of intestinal stem cells, yet how adiposity impacts the development of genomic instability has not been studied. Mutational signatures are a powerful way to understand how a complex biological response impacts genomic stability. We utilized a mouse model of diet-induced obesity to study the mutational landscape of intestinal crypt cells after a 48-week exposure to an experimental high fat diet in vivo. By clonally enriching single crypt derived cells in organoid culture and obtaining whole genome sequences, we analyzed and compared the mutational landscape of intestinal epithelial cells from normal diet and high fat diet mice. Single nucleotide substitution signatures and indel signatures present in our cohort are found equally active in both diet groups and reflect biological processes of normal aging, cellular replication, and oxidative stress induced during organoid culturing. Thus, we demonstrate that in the absence of activating mutations or chemical exposure, high fat diet alone is not sufficient to increase genomic instability
DataSheet_1_Clickable Cisplatin Derivatives as Versatile Tools to Probe the DNA Damage Response to Chemotherapy.pdf
No full textCisplatin induces DNA crosslinks that are highly cytotoxic. Hence, platinum complexes are frequently used in the treatment of a broad range of cancers. Efficiency of cisplatin treatment is limited by the tumor-specific DNA damage response to the generated lesions. We reasoned that better tools to investigate the repair of DNA crosslinks induced by cisplatin would therefore be highly useful in addressing drug limitations. Here, we synthesized a series of cisplatin derivatives that are compatible with click chemistry, thus allowing visualization and isolation of DNA-platinum crosslinks from cells to study cellular responses. We prioritized one alkyne and one azide Pt(II) derivative, Pt-alkyne-53 and Pt-azide-64, for further biological characterization. We demonstrate that both compounds bind DNA and generate DNA lesions and that the viability of treated cells depends on the active DNA repair machinery. We also show that the compounds are clickable with both a fluorescent probe as well as biotin, thus they can be visualized in cells, and their ability to induce crosslinks in genomic DNA can be quantified. Finally, we show that Pt-alkyne-53 can be used to identify DNA repair proteins that bind within its proximity to facilitate its removal from DNA. The compounds we report here can be used as valuable experimental tools to investigate the DNA damage response to platinum complexes and hence might shed light on mechanisms of chemoresistance.</p
