Cancer proteogenomics : connecting genotype to molecular phenotype

The central dogma of molecular biology describes the one-way road from DNA to RNA and finally to protein. Yet, how this flow of information encoded in DNA as genes (genotype) is regulated in order to produce the observable traits of an individual (phenotype) remains unanswered. Recent advances in high-throughput data, i.e., ‘omics’, have allowed the quantification of DNA, RNA and protein levels leading to integrative analyses that essentially probe the central dogma along all of its constituent molecules. Evidence from these analyses suggest that mRNA abundances are at best a moderate proxy for proteins which are the main functional units of cells and thus closer to the phenotype. Cancer proteogenomic studies consider the ensemble of proteins, the so-called proteome, as the readout of the functional molecular phenotype to investigate its influence by upstream events, for example DNA copy number alterations. In typical proteogenomic studies, however, the identified proteome is a simplification of its actual composition, as they methodologically disregard events such as splicing, proteolytic cleavage and post-translational modifications that generate unique protein species – proteoforms. The scope of this thesis is to study the proteome diversity in terms of: a) the complex genetic background of three tumor types, i.e. breast cancer, childhood acute lymphoblastic leukemia and lung cancer, and b) the proteoform composition, describing a computational method for detecting protein species based on their distinct quantitative profiles. In Paper I, we present a proteogenomic landscape of 45 breast cancer samples representative of the five PAM50 intrinsic subtypes. We studied the effect of copy number alterations (CNA) on mRNA and protein levels, overlaying a public dataset of drug- perturbed protein degradation. In Paper II, we describe a proteogenomic analysis of 27 B-cell precursor acute lymphoblastic leukemia clinical samples that compares high hyperdiploid versus ETV6/RUNX1-positive cases. We examined the impact of the amplified chromosomes on mRNA and protein abundance, specifically the linear trend between the amplification level and the dosage effect. Moreover, we investigated mRNA-protein quantitative discrepancies with regard to post-transcriptional and post-translational effects such as mRNA/protein stability and miRNA targeting. In Paper III, we describe a proteogenomic cohort of 141 non-small cell lung cancer clinical samples. We used clustering methods to identify six distinct proteome-based subtypes. We integrated the protein abundances in pathways using protein-protein correlation networks, bioinformatically deconvoluted the immune composition and characterized the neoantigen burden. In Paper IV, we developed a pipeline for proteoform detection from bottom-up mass- spectrometry-based proteomics. Using an in-depth proteomics dataset of 18 cancer cell lines, we identified proteoforms related to splice variant peptides supported by RNA-seq data. This thesis adds on the previous literature of proteogenomic studies by analyzing the tumor proteome and its regulation along the flow of the central dogma of molecular biology. It is anticipated that some of these findings would lead to novel insights about tumor biology and set the stage for clinical applications to improve the current cancer patient care

Crisis of representation in Chile?: the institutional connection

This article analyzes the challenges to democratic representation in contemporary Chile, with an institutional focus. I argue that the post-authoritarian model of politics was deeply constrained by institutions and practices inherited by democratic authorities and reinforced by the model of transitional politics and its series of informal institutions, which first facilitated, but then hindered democratic performance. While this does not point to a regime-threatening crisis, there are deep challenges to representation and a desire for a different model of politics that is more capable of resolving conflicts and satisfying citizen demands. I posit that, until now, Chile's formal and informal institutions have privileged stability over representation, accountability, and legitimacy. Consequently, it has fallen to social movements to set the agenda for change aimed at addressing Chile's deeper problems of political and social inequality. I argue that institutional reforms are a necessary, yet insufficient, antidote to current challenges of representation.Este artículo analiza los desafíos a la representación democrática en Chile contemporáneo, con un enfoque institucional. Sostengo que el modelo político post-autoritario estaba profundamente restringido y limitado por las instituciones y prácticas heredadas por las autoridades democráticas y reforzadas por el modelo de la política transicional y su serie de instituciones informales, que primero facilitó, pero luego obstaculizó el desempeño democrático. Si bien esto no necesariamente señaliza una crisis amenazadora del régimen, hay retos profundos a la representación y el deseo de un modelo político diferente que tenga una capacidad mayor de resolver conflictos y satisfacer las demandas ciudadanas. Postulo que, hasta ahora, las instituciones formales e informales de Chile han privilegiado la estabilidad sobre la representación, la rendición de cuentas y la legitimidad. En consecuencia, corresponde a los movimientos sociales fijar la agenda de cambio encaminada a abordar los problemas más profundos de desigualdad política y social en Chile. Sostengo que las reformas institucionales son un antídoto necesario, pero insuficiente, para los desafíos actuales de la representación

Nombramientos públicos como instituciones informales: lecciones del cuoteo en Chile, 1990-2018

This paper engages existing research on informal institutions in Latin America, by analyzing informal institutions related to public appointments in Chile with particular reference to what is known as the cuoteo. We extend the analysis from the national to the regional and local levels by considering how these informal institutions shape politics. Our research reveals that the nature and function of the cuoteo change according to the level of government at which it operates. Through this analysis we show how the decline of the cuoteo can lead to the erosion of its ability to contribute to the operation of high-quality formal institutions. We combine a review of literature with the analysis of 132 interviews in six regions of Chile

RODIN project, Topology Optimization 2.0?

RODIN project is an attempt to propose a new kind of topology optimization tools. It has been motivated by the combination of two events: (1) the industrials demands for getting past serious limits identified in the available tools, (2) the advent of a new mathematical approach in the mid 2000's presenting very interesting properties. This project has been launched in July 2012 and is supported by French public funding. It is a collaborative project that gathers ten partners (ranging from academics to software editors and industrials end-users) and firmly aims at overcoming technical and scientific locks in the area of topology optimization. RODIN is therefore an ambitious and risky project that will possibly mark the birth of a new numerical tool

Party Strategies, Constituency Links, and Legislative Speech

This article examines how parties organize legislative speech. Electoral incentives and legislative institutions affect speech participation. When electoral systems create personal vote-seeking incentives, parties are less concerned with screening speeches and more supportive of members seeking to garner name recognition. But in many countries, legislative rules and norms constrain opportunities for individual position taking during the lawmaking debates. We argue that parties resolve this dilemma by organizing speech participation into nonlegislative speeches and lawmaking debates. In each instance, different types of legislators are more likely to speak. We examine the case of Chile and test the implications of our theory with data on congressional speeches

Comparing candidate selection:A feminist institutionalist approach

This contribution evaluates the theoretical and methodological challenges ofresearching the gendered dynamics of candidate selection in comparativeperspective. It argues that comparative studies should take into account not only thegendered nature of political parties and their wider institutional context, but mustalso investigate the informal aspects of the selection process and their genderedconsequences. The article explores these dynamics by revisiting original in-depthresearch on the candidate selection process in two different settings – Thailand andScotland. Using a common analytical framework, the article reflects on this workand points to two key aspects of the interaction between formal and informal rules –the gendered consequences of informal party recruitment and of local influenceover candidate selection – which are critically important for understanding thecontinuity of male political dominance and female under-representation. The articleconcludes by outlining a research agenda for comparative work on gender, institutionsand candidate selection and pointing to future directions for work in this area.Political parties and women’s political representation: The role of bureaucratized candidate selection procedure

Proteogenomics and Hi-C reveal transcriptional dysregulation in high hyperdiploid childhood acute lymphoblastic leukemia.

Hyperdiploidy, i.e. gain of whole chromosomes, is one of the most common genetic features of childhood acute lymphoblastic leukemia (ALL), but its pathogenetic impact is poorly understood. Here, we report a proteogenomic analysis on matched datasets from genomic profiling, RNA-sequencing, and mass spectrometry-based analysis of >8,000 genes and proteins as well as Hi-C of primary patient samples from hyperdiploid and ETV6/RUNX1-positive pediatric ALL. We show that CTCF and cohesin, which are master regulators of chromatin architecture, display low expression in hyperdiploid ALL. In line with this, a general genome-wide dysregulation of gene expression in relation to topologically associating domain (TAD) borders were seen in the hyperdiploid group. Furthermore, Hi-C of a limited number of hyperdiploid childhood ALL cases revealed that 2/4 cases displayed a clear loss of TAD boundary strength and 3/4 showed reduced insulation at TAD borders, with putative leukemogenic effects