KRAS mutations of the lung adenocarcinoma genome and their impact on inflammation

Der maligne Pleuraerguss (MPE) ist ein bedeutendes klinisches Problem, das häufig durch Adenokarzinome verursacht wird. Obwohl sich die verschiedenen Pleuratumoren in ihrer Fähigkeit, einen MPE zu erzeugen, stark unterscheiden, sind die kritischen biologischen Pfade, die die MPE-Bildung bestimmen, schlecht definiert. Ein besseres Verständnis der Tumor-Host-Interaktionen, die zu MPE führen, könnte zu neuen Behandlungsmethoden für diese Erkrankung führen. In dieser Arbeit werden neue Mausmodelle des MPE vorgestellt, die dann eingesetzt werden, um zu entdecken, dass Karzinomzellen, die KRAS-Mutationen beherbergen, MPE produzieren, während Zellen ohne solche Mutationen kein MPE produzieren. Zu diesem Zweck zeigten Zellen des Lewis-Lungenkarzinoms (LLC), des Kolon-Adenokarzinoms (MC38) und des malignen Pleuramesothelioms (AE17), die potente Induktoren des MPE sind, mutierte Kras-Allele, nicht-kanonische Nuklearfaktor (NF)-κB Aktivierung, die durch Inhibitor der NF-κΒ Kinase α (IKKα) vermittelt wird, Überexpression von proinflammatorischen Chemokinen und die Fähigkeit zur Rekrutierung spezifischer myeloischer Untergruppen von Zellen im Pleuraraum, einschließlich Mastzellen, Makrophagen und Neutrophilen. Im Gegensatz dazu wiesen Hautmelanom- (B16F10) und Pankreas-Adenokarzinom-Zellen (PANO2) der Maus keine Kras-Mutationen auf, es fehlten alternative NF-κΒ-Signalwege und Chemokin-Expression, und sie waren nicht in der Lage, myeloische Zellen anzuziehen und MPE in syngenen Mäusen zu bilden. Die RNAi-vermittelte Stilllegung von Kras oder IKKα in MPE-kompetenten Zellen hob die MPE-Bildung und die alternative NF-κΒ-Aktivierung auf, während diese Phänomene in MPE-defekten Zellen nach mutierter Kras-Überexpression rekonstituiert wurden. MPE-enthaltende myeloide Zellen versorgten das pleurale Tumormilieu mit Interleukin-1β (IL-1β), das die IKKα Aktivität und die Chemokin-Sekretion von Tumorzellen pepepetuierte und dadurch die MPE-assoziierte Entzündung aufrechterhielt. Die Behandlung von Mäusen mit Deltarasin, einem neuartigen KRAS-Blocker, Imatinib mesylat, einem Mastzellen- und cKIT-Signal inhibitor, oder mit 17-DMAG (Alvespimycin), einem dualen IKKα/IKKβ-Inhibitor, begrenzte die MPE-Entwicklung. Diese Arbeit etablierte experimentelle Werkzeuge, die zum besseren Verständnis der Pathophysiologie des MPE eingesetzt werden können, identifizierte einen Entzündungszyklus, der durch Tumorzellen und das KRAS-Onkogen initiiert und durch Immunzellen und IL-1β perpetuiert wird, und schuf die Grundlagen für zukünftige zielgerichtete Therapien der Erkrankung.Malignant pleural effusion (MPE) is a significant clinical problem commonly caused by adenocarcinomas. Although different pleural tumors vary widely in their ability to produce MPE, the critical pathways that determine MPE formation are poorly defined. Improved understanding of tumor-host interactions that lead to MPE could lead to novel treatments for the condition. In this work, novel mouse models of MPE are put forth, which are subsequently employed to discover that carcinoma cells harboring KRAS mutations produce MPE while cells without such do not. To this end, Lewis lung carcinoma (LLC), colon adenocarcinoma (MC38), and malignant pleural mesothelioma (AE17) cells that are potent inducers of MPE displayed mutant Kras alleles, non-canonical nuclear factor (NF)-κB activation mediated via inhibitor of NF-κΒ kinase α (IKKα), overexpression of proinflammatory chemokines, and capability for the recruitment of specific myeloid cell subsets to the pleural space, including mast cells, macrophages, and neutrophils. In contrast, mouse skin melanoma (B16F10) and pancreatic adenocarcinoma (PANO2) cells did not have Kras mutations, lacked alternative NF-κΒ signaling and chemokine expression, and were incapable of attracting myeloid cells and of forming MPE in syngeneic mice. RNAi-mediated silencing of Kras or IKKα in MPE-competent cells abrogated MPE formation and alternative NF-κΒ activation, while these phenomena were reconstituted in MPE-defective cells after mutant Kras overexpression. MPE-contained myeloid cells fed the pleural tumor milieu with interleukin-1β (IL-1β), which peprpetuated IKKα activity and chemokine secretion by tumor cells, thereby sustaining MPE-associated inflammation. Treatment of mice with deltarasin, a novel KRAS blocker, imatinib mesylate, a mast cell and cKIT signaling inhibitor, or with 17-DMAG (alvespimycin), a dual IKKα/IKKβ inhibitor, limited MPE development. This work established experimental tools that can be used to better understand the pathophysiology of MPE, identified an inflammatory loop initiated by tumor cells and the KRAS oncogene and perpetuated by immune cells and IL-1β, and set the foundations for future targeted therapeutics of the condition

A hierarchical time-splitting approach for solving finite-time optimal control problems

We present a hierarchical computation approach for solving finite-time optimal control problems using operator splitting methods. The first split is performed over the time index and leads to as many subproblems as the length of the prediction horizon. Each subproblem is solved in parallel and further split into three by separating the objective from the equality and inequality constraints respectively, such that an analytic solution can be achieved for each subproblem. The proposed solution approach leads to a nested decomposition scheme, which is highly parallelizable. We present a numerical comparison with standard state-of-the-art solvers, and provide analytic solutions to several elements of the algorithm, which enhances its applicability in fast large-scale applications

The impact of investor horizon on say-on-pay voting

Shareholder investment horizons have a significant impact on say-on-pay voting patterns. Short-term investors are more likely to avoid expressing opinion on executive pay proposals by casting an abstaining vote. They vote against board proposals on pay only in cases where the CEO already receives excessive pay levels. In contrast, long-term investors typically cast favourable votes. According to our findings, this is due to effective monitoring rather than collusion with the management. Overall, investor heterogeneity in terms of investment horizons helps explain say-on-pay voting, in particular the low levels of say-on-pay dissent, which have recently raised questions over the efficiency of this corporate governance mechanism

Distributed Optimization and Control using Operator Splitting Methods

The significant progress that has been made in recent years both in hardware implementations and in numerical computing has rendered real-time optimization-based control a viable option when it comes to advanced industrial applications. At the same time, the field of big data has emerged, seeking solutions to problems that classical optimization algorithms are incapable of providing. Though for different reasons, both application areas triggered interest in revisiting the family of optimization algorithms commonly known as decomposition schemes or operator splitting methods. This lately revived interest in these methods can be mainly attributed to two characteristics: Com- putationally low per-iteration cost along with small memory footprint when it comes to embedded applications, and their capacity to deal with problems of vast scales via decomposition when it comes to machine learning-related applications. In this thesis, we design decomposition methods that tackle both small-scale centralized control problems and larger-scale multi-agent distributed control problems. In addition to the classical objective of devising faster methods, we also delve into less usual aspects of operator splitting schemes, which are nonetheless critical for control. In the centralized case, we propose an algorithm that uses decomposition in order to exactly solve a classical optimal control problem that could otherwise be solved only approximately. In the multi-agent framework, we propose two algorithms, one that achieves faster convergence and a second that reduces communication requirements

Από τον θρίαμβο στη διάσπαση. Αιτίες των ενδοκυβερνητικών διαφωνιών στην Ένωση Κέντρου (1964-1965)

Η παρούσα εργασία στοχεύει στην ανάδειξη των αιτιών που προκάλεσαν τις ενδοκυβερνητικές διαφωνίες στην Ένωση Κέντρου κατά την περίοδο 1964-1965. Οι διαφωνίες αυτές εντοπίζονται σχεδόν σε όλους τους τομείς: από την έλλειψη συνοχής του κόμματος, τη δυσαρέσκεια για την εσωτερική λειτουργία κόμματος και κυβέρνησης, τις διαφορετικές προσεγγίσεις για την οικονομία, το Κυπριακό, τις Ένοπλες Δυνάμεις, αλλά και προσωπικές διαφορές. Επίκεντρο της διαμάχης αποτέλεσε η συμμετοχή στην κυβέρνηση του Ανδρέα Παπανδρέου και η έντονη δραστηριότητά του. Επίσης, κομβικός ήταν ο ρόλος των εκδοτικών συγκροτημάτων. Με τη συγκεκριμένη ανάλυση επιχειρείται να καταδειχθεί ότι η πτώση και η διάσπαση της Ένωσης Κέντρου τον Ιούλιο του 1965 ήταν απόρροια πρωτίστως μιας ακολουθίας εσωτερικών διεργασιών και αλληλοσυγκρούσεων και όχι ένα ξαφνικό γεγονός.This paper aims to highlight the causes of intragovernmental disputes within the Centre Union party during the period of1964 to 1965. These disagreements can be traced in almost all areas: The lack of coherence of the party, dissatisfaction with the internal functioning of the party and the government, the different approaches to the economy, the Cyprus issue, the Armed Forces, but also personal differences. The focus of the disputes was on Andreas Papandreou’s presence and intense activity within the government. Furthermore, the role of the many prominent newspaper editors was crucial. This analysis shows that break-up of July 1965 was primarily the result of a sequence of internal processes and conflicts and not a sudden event

Dust-scattering rings of GRB 221009A as seen by the Neil Gehrels Swift satellite: can we count them all?

We present the first results for the dust-scattering rings of GRB 221009A, coined as the GRB of the century, as observed by the Neil Gehrels Swift satellite. We perform analysis of both time resolved observations and stacked data. The former approach enable us to study the expansion of the most prominent rings, associate their origin with the prompt X-ray emission of the GRB and determine the location of the dust layers. The stacked radial profiles increase the signal-to-noise ratio of the data and allows detection of fainter and overlapping peaks in the angular profile. We find a total of 16 dust concentrations (with hints of even more) that span about 15 kpc in depth and could be responsible for the highly structured X-ray angular profiles. By comparing the relative scattered fluxes of the five most prominent rings we show that the layer with the largest amount of dust is located at about 0.44 kpc away from us. We finally compare the location of the dust layers with results from experiments that study the 3D structure of our Galaxy via extinction or CO radio observations, and highlight the complementarity of dust X-ray tomography to these approaches.Comment: 12 pages, 10 figures, accepted for publication in MNRAS. New version contains updated tables/figures after correction of a numerical erro

Solving the Infinite-horizon Constrained LQR Problem using Accelerated Dual Proximal Methods

This work presents an algorithmic scheme for solving the infinite-time constrained linear quadratic regulation problem. We employ an accelerated version of a popular proximal gradient scheme, commonly known as the Forward-Backward Splitting (FBS), and prove its convergence to the optimal solution in our infinite-dimensional setting. Each iteration of the algorithm requires only finite memory, is computationally cheap, and makes no use of terminal invariant sets; hence, the algorithm can be applied to systems of very large dimensions. The acceleration brings in ‘optimal’ convergence rates O(1/k2) for function values and O(1/k) for primal iterates and renders the proposed method a practical alternative to model predictive control schemes for setpoint tracking. In addition, for the case when the true system is subject to disturbances or modelling errors, we propose an efficient warm-starting procedure, which significantly reduces the number of iterations when the algorithm is applied in closed-loop. Numerical examples demonstrate the approach

Solving the infinite-horizon constrained LQR problem using splitting techniques

This paper presents a method to solve the constrained infinite-time linear quadratic regulator (LQR) problem. We use an operator splitting technique, namely the alternating minimization algorithm (AMA), to split the problem into an unconstrained LQR problem and a projection step, which are solved repeatedly, with the solution of one influencing the other. The first step amounts to the solution of a system of linear equations (with the possibility to pre-factor) and the second step is a simple clipping. Therefore, each step can be carried out efficiently. The scheme is proven to converge to the solution to the infinite-time constrained LQR problem and is illustrated by numerical examples

Solving the infinite-horizon constrained LQR problem using splitting techniques

This paper presents a method to solve the constrained infinite-time linear quadratic regulator (LQR) problem. We use an operator splitting technique, namely the alternating minimization algorithm (AMA), to split the problem into an unconstrained LQR problem and a projection step, which are solved repeatedly, with the solution of one influencing the other. The first step amounts to the solution of a system of linear equations (with the possibility to pre-factor) and the second step is a simple clipping. Therefore, each step can be carried out efficiently. The scheme is proven to converge to the solution to the infinite-time constrained LQR problem and is illustrated by numerical examples