no / Predictive toxicology is concerned with the development of models that are able to predict the toxicity of chemicals. A reliable prediction of toxic effects of chemicals in living systems is highly desirable in cosmetics, drug design or food protection to speed up the process of chemical compound discovery while reducing the need for lab tests. There is an extensive literature associated with the best practice of model generation and data integration but management and automated identification of relevant models from available collections of models is still an open problem. Currently, the decision on which model should be used for a new chemical compound is left to users. This paper intends to initiate the discussion on automated model identification. We present an algorithm, based on Pareto optimality, which mines model collections and identifies a model that offers a reliable prediction for a new chemical compound. The performance of this new approach is verified for two endpoints: IGC50 and LogP. The results show a great potential for automated model identification methods in predictive toxicology.

In recent years, techniques that had been developed for the combination of unification algorithms for equational theories were extended to combining constraint solvers. These techniques inherited an old deficit that was already present in the ombination of equational theories which makes them rather unsuitable for pratical use: The underlying combination algorithms are highly non-deterministic. This paper is concerned with the pratical problem of how to optimise the combination method of Baader and Schulz. We present two optimisation methods,called the iterative and the deductive method. The iterative method reorders and localises the non-deterministic decisions. The deductive method uses specific algorithms for the components to reach certain decisions deterministically. Run time tests of our implementation indicate that the optimised combination method yields combined decision procedures that are efficient enough to be used in practice.

A major obstacle in the implementation of adoptive cell therapy (ACT) for solid tumors is CD8+ T cell quantity and functional quality. In order to address this issue, the ACT field has directed considerable effort toward the generation of less-differentiated memory T cells (Tm), which demonstrate superior effector function and engraftment over effector T cells. An obstacle in using Tm for ACT is their requirement for in vivo activation before full effector function can be acquired. We sought to determine if a rhabdovirus expressing a defined tumor antigen (i.e. a rhabdoviral oncolytic vaccine) could activate adoptively-transferred Tm in vivo and eliminate established tumors. We used ex vivo cultured DUC18 TCR-transgenic Tm combined with a rhabdoviral oncolytic vaccine to target established CMS5 fibrosarcomas in both balb/c and NRG mice, and we compared the efficacy of the combination treatment versus monotherapies. Our data demonstrate that the rhabdoviral oncolytic vaccine was capable of expanding adoptively-transferred Tm in order to eliminate established tumors. Furthermore, synergy between ACT and oncolytic vaccination was required for optimal therapeutic outcome. Interestingly, we observed a population of endogenous, tumor-primed lymphocytes which appeared to be required for complete tumor elimination and subsequent memory formation. This was in contrast to the current consensus in the ACT field which is that endogenous lymphocytes are detrimental to therapeutic outcome, thus necessitating lymphodepletion prior to the commencement of therapy. Our data suggest that endogenous lymphocytes may be a beneficial cell population which is overlooked by current approaches to ACT. / Thesis / Master of Science (MSc) / Current approaches to the T cell therapy of cancer are hindered by poor cell quality. It is simple to grow higher quality T cells, but it is difficult to grow very large numbers of them. Furthermore, higher quality T cells need a signal in order to “switch on” before they can start killing cancer cells. Here, we use a cancer-targeting virus as a signal for these cells to activate, grow to very large numbers in the patient, and destroy their tumor. Our vaccine also switches on other immune cells in the patient, which help guarantee the destruction of the tumor. The significance of this work is that it will improve T cell therapy for cancer by opening the possibility of using higher-quality T cells which are much better at killing cancer than the currently used type of T cells.

Die Rheumatoide Arthritis (RA) ist eine multifaktoriell bedingte Autoimmunerkrankung, die durch entzündlichen Gelenksbefall charakterisiert ist. Unter fehlender oder ungenügender therapeutischer Intervention nimmt die Erkrankung einen progressiven Verlauf, der zu Gelenkdestruktionen und damit zu zunehmender Behinderung, sowie Arbeitsunfähigkeit führt. Neben den Einschränkungen in der Gelenkfunktion können in jedem Krankheitsstadium Allgemeinsymptome und vielfältige extraartikuläre Manifestationen auftreten, sodass die Erkrankung mit einer verkürzten Lebenserwartung bzw. erhöhter Mortalität assoziiert ist. Obwohl in den letzten Jahren deutliche Fortschritte in der Therapie erzielt wurden, ist eine definitive Heilung nicht möglich. Gemäß der EULAR-Guidelines von 2019 ist Methotrexat (MTX) weiterhin als „anchor drug“ in der RA das Erstlinienmedikament der Wahl. Bei Therapieversagen von MTX und dem Fehlen von negativen Prognoseparametern kann als Zweitlinientherapie ein anderes konventionelles DMARD (csDMARD) in Monotherapie oder Kombination eingesetzt werden. Eine der Optionen ist Leflunomid (LEF), das in Studien seine Wirksamkeit als DMARD und seine Überlegenheit gegenüber Placebo bewiesen hat. Es ist aber nach wie vor nicht wirklich geklärt, ob Patienten im klinischen Alltag tatsächlich von einer Therapie mit LEF oder LEF/MTX profitieren, insbesondere nach dem Versagen einer Erstlinientherapie mit MTX. Dazu wurde in der vorliegenden Untersuchung der Alltagseinsatz und Nutzen von LEF sowohl in Monotherapie als auch in Kombination mit MTX analysiert. Es handelt sich um eine historisch prospektive Kohortenstudie mit Patienten der Rheumatologischen Ambulanz des Universitätsklinikums Dresden. Es erfolgte die Einteilung der Studienkohorte (n=158) in zwei Untergruppen. In der erweiterten LEF-Kohorte (eLEF) befanden sich alle Patienten, welche zu einem beliebigen Zeitpunkt zwischen 2007 und 2015 mit LEF (n=103) oder mit LEF/MTX (n=49) behandelt worden waren. In der post MTX-Kohorte (pMTX-Gruppe) befanden sich alle Patienten, die nach dem Versagen einer Erstlinientherapie mit MTX zwischen 2007 und 2015 mit LEF (n=39) oder LEF/MTX (n=16) als Zweitlinientherapie behandelt worden waren. Es wurde das Therapieüberleben mittels Kaplan-Meier-Kurven, sowie der klinische Verlauf im ersten Jahr mittels Scoresystemen (CDAI) erfasst. Zudem wurden Nebenwirkungen, Absetzgründe und radiographischer Progress analysiert. Sowohl in der eLEF-Gruppe als auch in der pMTX-Gruppe lag ein signifikant schlechteres Gesamttherapieüberleben in Kombinationstherapie von LEF/MTX im Vergleich zur Monotherapie mit LEF vor (eLEF p=0,004; pMTX p=0,002; Signifikanzniveau p=0,05). Im klinischen Verlauf zeigten sich keine signifikanten Unterschiede, lediglich der Startscorewert der Kombinationstherapie war signifikant höher als unter Monotherapie. Beide Therapieregime konnten eine durchschnittliche Verbesserung von moderater zu niedriger Krankheitsaktivität, aber nicht bis in Remission erreichen. Insgesamt lag eine hohe Abbrecherzahl innerhalb des ersten Behandlungsjahres unabhängig vom Therapieregime vor. Der wichtigste Absetzgrund war (außer in der pMTX-Gruppe unter LEF/MTX) Wirkversagen, von dem etwa jeder zweite Patient betroffen war. Der andere wesentliche Absetzgrund waren Nebenwirkungen, hier war etwa jeder vierte bis fünfte Patient betroffen. Zudem traten unter Kombinationstherapie mehr Nebenwirkungen als unter Monotherapie auf. Radiographischer Progress spielte in der vorliegenden Kohorte keine relevante Rolle. Zusammenfassend zeigt die vorliegende Studie Hinweise, dass die Kombinationstherapie der Monotherapie nicht überlegen ist. Daher wäre durchaus vertretbar, bei einem Therapiewechsel primär eine Monotherapie anzustreben, was sich unter Berücksichtigung des langjährigen Therapiebedarfs und des höheren Patientenalters positiv auf Interaktionen mit anderen Medikamenten, auf Nebenwirkungen und auf die Compliance der Patienten auswirken könnte. Zugleich könnten Kosten gespart werden. Aufgrund des längerfristig nicht überzeugenden Verlaufes, sollte ein Wechsel auf ein zweites csDMARD (oder die Etablierung einer Kombinationstherapie) nach Versagen von MTX entsprechend der Leitlinien der EULAR nur bei Fehlen negativer Prognosefaktoren und in höherem Lebensalter, sowie mit einem engmaschigen Therapiemonitoring (klinisch, laborchemisch, radiologisch) erfolgen. Dennoch ist bei weltweitem Auftreten der Erkrankung die Medikation mit LEF weiterhin eine preisgünstigere Alternative für die Länder, wo zusätzliche Ressourcen knapp sind.:Inhaltsverzeichnis V Abbildungen VIII Tabellen X Glossar XII Akürzungsverzeichnis XIX 1 Einleitung und Fragestellung 1 2 Die Rheumatoide Arthritis (RA) 3 2.1 Epidemiologie 3 2.2 Ätiologie 4 2.2.1 Genetische Veränderungen 4 2.2.2 Epigenetische Veränderungen 5 2.2.3 Nicht genetische Faktoren/Umwelt 5 2.3 Pathophysiologie/Pathogenese 8 2.3.1 Synovium 8 2.3.2 Weitere Antikörper 12 2.3.3 Krankheitsverlauf 12 2.4 Klinisches Bild 14 2.4.1 Gelenkbefall 14 2.4.2 Differentialdiagnosen 16 2.4.3 Extraartikuläre Manifestationen 19 2.4.4 Sonderformen 23 2.5 Diagnostik 23 2.5.1 Labor 24 2.5.2 Bildgebung 25 2.6 Therapie 27 2.6.1 Medikamentöse Basistherapie 27 2.6.2 Weitere Aspekte zum Einsatz von bDMARDs/ tsDMARDs 32 2.6.3 Einschätzung der Krankheitsaktivität 33 2.6.4 Ko-Medikation und begleitende nichtmedikamentöse Therapien 36 2.7 Prognose 37 2.7.1 Komorbiditäten 39 2.7.2 Mortalität 40 3 Leflunomid (LEF) 42 3.1 Wirkmechanismus 42 3.2 Pharmakologische Aspekte 43 3.3 Arzneimittelinteraktionen 44 3.4 Wirksamkeit 45 3.4.1 Klinisch 45 3.4.2 Radiologischer Progress 46 3.4.3 Kombinationstherapien 47 3.5 Nebenwirkungen 48 3.5.1 Spezielle Nebenwirkungen 49 3.6 Praktische Anwendung 55 3.7 Kontraindikationen 56 4 Studienergebnisse 58 4.1 Material und Methoden 58 4.2 Patientenpool und Vergleichsgruppen 59 4.2.1 Weitere Subgruppen 64 4.2.2 Patientencharakteristika 66 4.2.3 Nachverfolgung 67 4.3 Therapieüberleben 68 4.3.1 Ergebnisübersicht: Therapie- und Patientengruppen 68 4.3.2 Ergebnisübersicht möglicher Einflussfaktoren 69 4.4 Therapieverlauf im ersten Jahr 78 4.4.1 Ergebnisübersicht CDAI 78 4.4.2 Ergebnisübersicht SDAI 80 4.4.3 Ergebnisübersicht DAS28 81 4.4.4 Entzündungsparameter 83 4.4.5 Therapiewirksamkeit und Therapieabbruch 87 4.4.6 Vorliegen von Prognosefaktoren 89 4.5 Nebenwirkungen 93 4.5.1 Ergebnisübersicht eLEF-Gruppe 93 4.5.2 Ergebnisübersicht pMTX 96 4.6 Absetzgründe 100 4.6.1 Ergebnisübersicht 100 4.7 Röntgenprogress 103 4.7.1 Ergebnisübersicht 103 5 Interpretation und Diskussion 105 5.1 Therapieüberleben 105 5.2 Therapieverlauf im ersten Jahr 108 5.3 Nebenwirkungen 111 5.4 Therapievergleiche 113 5.5 Röntgenprogress 115 6 Schlussfolgerung 117 7 Anhang 120 7.1 Zusäzliche Abbildungen zu Kapitel 2 120 7.2 Zusäzliche Analysen zu Kapitel 4 122 7.2.1 LEF-Erstlinie 122 7.2.2 Therapieüberleben: Zusätzliche Vergleiche in Abhängigkeit der Therapie 123 7.2.3 Therapieüberleben in Abhängigkeit vom Zeitpunkt der Kombinationstherapie 126 7.2.4 Therapieverlauf im ersten Jahr: Statistische Tests 128 7.2.5 Zusammenhang zwischen CRP bzw. BSG und CDAI für pMTX 133 7.2.6 Nebenwirkungen in Abhängigkeit vom Serostatus 134 7.2.7 pMTX-LM-L-Gruppe 135 7.3 Zusäzliche Analysen zu Kapitel 5 136 7.3.1 LEF und Prednisolon 136 8 Literaturverzeichnis 139 / Rheumatoid arthritis (RA) is a multifactorial autoimmune disease characterized by inflammatory joint involvement. In the absence or inadequacy of therapeutic intervention, the disease takes a progressive course, leading to joint destruction, increasing disability, and incapacity to work. In addition to limitations in joint function, general symptoms and multiple extra-articular manifestations may occur at any stage of the disease, so that the disease is associated with a shortened life expectancy and increased mortality. Although significant advances in therapy have been made in recent years, a definitive cure is not possible. According to the 2019 EULAR guidelines, Methotrexate (MTX) remains the first-line drug of choice as the 'anchor drug' in RA. In case of treatment failure of MTX and the absence of poor prognostic factors, another conventional DMARD (csDMARD) can be used as second-line therapy in monotherapy or combination. One of the options is Leflunomide (LEF), which has demonstrated its efficacy as a DMARD and its superiority to placebo in trials. However, it is still not really clear whether patients actually benefit from therapy with LEF or LEF/MTX in daily clinical practice, especially after failure of first-line therapy with MTX. To this end, the present study analyzed the everyday use and benefit of LEF both in monotherapy and in combination with MTX. It is a historical prospective cohort study with patients of the Rheumatologic Outpatient Clinic of the University Hospital of Dresden. The study cohort (n=158) was divided into two subgroups. The extended LEF cohort (eLEF) included all patients who had been treated with LEF (n=103) or with LEF/MTX (n=49) at any time between 2007 and 2015. The post MTX cohort (pMTX group) included all patients who had been treated with LEF (n=39) or LEF/MTX (n=16) as second-line therapy after failure of first-line MTX between 2007 and 2015. Treatment survival was assessed using Kaplan-Meier curves, and clinical outcome in the first year was assessed using scoring systems (CDAI). In addition, side effects, discontinuation reasons, and radiographic progression were analyzed. In both the eLEF group and the pMTX group, there was a significantly worse overall therapy survival in combination therapy of LEF/MTX compared to monotherapy with LEF (eLEF p=0.004; pMTX p=0.002; significance level p=0.05). There were no significant differences in the clinical course, only the start score of the combination therapy was significantly higher than under monotherapy. Both therapy regimens were able to achieve an average improvement from moderate to low disease activity, but not to remission. Overall, a high dropout rate was present within the first year of treatment regardless of the therapy regimen. The main discontinuation reason (except in the pMTX group on LEF/MTX) was efficacy failure, affecting approximately one in two patients. The other major reason for discontinuation was side effects, affecting approximately one in four to five patients. In addition, more side effects occurred with combination therapy than with monotherapy. Radiographic progression did not play a relevant role in the present cohort. In summary, the present study shows some evidence that combination therapy is not superior to monotherapy. Therefore, it would be quite justifiable to aim primarily for monotherapy when changing therapy, which could have a positive effect on interactions with other drugs, on side effects, and on patient compliance, taking into account the long-term need for therapy and the higher patient age. At the same time, costs could be saved. Due to the unconvincing course in the longer term, a switch to a second csDMARD (or the establishment of a combination therapy) after failure of MTX should, according to the EULAR guidelines, only be made in the absence of poor prognostic factors and at an higher age, as well as with close-meshed therapy monitoring (clinical, laboratory, radiological). Nevertheless, with worldwide occurrence of the disease, medication with LEF continues to be a less expensive alternative for countries where additional resources are scarce.:Inhaltsverzeichnis V Abbildungen VIII Tabellen X Glossar XII Akürzungsverzeichnis XIX 1 Einleitung und Fragestellung 1 2 Die Rheumatoide Arthritis (RA) 3 2.1 Epidemiologie 3 2.2 Ätiologie 4 2.2.1 Genetische Veränderungen 4 2.2.2 Epigenetische Veränderungen 5 2.2.3 Nicht genetische Faktoren/Umwelt 5 2.3 Pathophysiologie/Pathogenese 8 2.3.1 Synovium 8 2.3.2 Weitere Antikörper 12 2.3.3 Krankheitsverlauf 12 2.4 Klinisches Bild 14 2.4.1 Gelenkbefall 14 2.4.2 Differentialdiagnosen 16 2.4.3 Extraartikuläre Manifestationen 19 2.4.4 Sonderformen 23 2.5 Diagnostik 23 2.5.1 Labor 24 2.5.2 Bildgebung 25 2.6 Therapie 27 2.6.1 Medikamentöse Basistherapie 27 2.6.2 Weitere Aspekte zum Einsatz von bDMARDs/ tsDMARDs 32 2.6.3 Einschätzung der Krankheitsaktivität 33 2.6.4 Ko-Medikation und begleitende nichtmedikamentöse Therapien 36 2.7 Prognose 37 2.7.1 Komorbiditäten 39 2.7.2 Mortalität 40 3 Leflunomid (LEF) 42 3.1 Wirkmechanismus 42 3.2 Pharmakologische Aspekte 43 3.3 Arzneimittelinteraktionen 44 3.4 Wirksamkeit 45 3.4.1 Klinisch 45 3.4.2 Radiologischer Progress 46 3.4.3 Kombinationstherapien 47 3.5 Nebenwirkungen 48 3.5.1 Spezielle Nebenwirkungen 49 3.6 Praktische Anwendung 55 3.7 Kontraindikationen 56 4 Studienergebnisse 58 4.1 Material und Methoden 58 4.2 Patientenpool und Vergleichsgruppen 59 4.2.1 Weitere Subgruppen 64 4.2.2 Patientencharakteristika 66 4.2.3 Nachverfolgung 67 4.3 Therapieüberleben 68 4.3.1 Ergebnisübersicht: Therapie- und Patientengruppen 68 4.3.2 Ergebnisübersicht möglicher Einflussfaktoren 69 4.4 Therapieverlauf im ersten Jahr 78 4.4.1 Ergebnisübersicht CDAI 78 4.4.2 Ergebnisübersicht SDAI 80 4.4.3 Ergebnisübersicht DAS28 81 4.4.4 Entzündungsparameter 83 4.4.5 Therapiewirksamkeit und Therapieabbruch 87 4.4.6 Vorliegen von Prognosefaktoren 89 4.5 Nebenwirkungen 93 4.5.1 Ergebnisübersicht eLEF-Gruppe 93 4.5.2 Ergebnisübersicht pMTX 96 4.6 Absetzgründe 100 4.6.1 Ergebnisübersicht 100 4.7 Röntgenprogress 103 4.7.1 Ergebnisübersicht 103 5 Interpretation und Diskussion 105 5.1 Therapieüberleben 105 5.2 Therapieverlauf im ersten Jahr 108 5.3 Nebenwirkungen 111 5.4 Therapievergleiche 113 5.5 Röntgenprogress 115 6 Schlussfolgerung 117 7 Anhang 120 7.1 Zusäzliche Abbildungen zu Kapitel 2 120 7.2 Zusäzliche Analysen zu Kapitel 4 122 7.2.1 LEF-Erstlinie 122 7.2.2 Therapieüberleben: Zusätzliche Vergleiche in Abhängigkeit der Therapie 123 7.2.3 Therapieüberleben in Abhängigkeit vom Zeitpunkt der Kombinationstherapie 126 7.2.4 Therapieverlauf im ersten Jahr: Statistische Tests 128 7.2.5 Zusammenhang zwischen CRP bzw. BSG und CDAI für pMTX 133 7.2.6 Nebenwirkungen in Abhängigkeit vom Serostatus 134 7.2.7 pMTX-LM-L-Gruppe 135 7.3 Zusäzliche Analysen zu Kapitel 5 136 7.3.1 LEF und Prednisolon 136 8 Literaturverzeichnis 139

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This simulation study focused on determining the effect of unequal sample sizes on statistical power of SIBTEST and Mantel-Haenszel procedures for detection of DIF of moderate and large magnitudes. Item parameters were estimated by, and generated with the 2PLM using WinGen2 (Han, 2006). MULTISIM was used to simulate ability estimates and to generate response data that were analyzed by SIBTEST. The SIBTEST procedure with regression correction was used to calculate the DIF statistics, namely the DIF effect size and the statistical significance of the bias. The older SIBTEST was used to calculate the DIF statistics for the M-H procedure. SAS provided the environment in which the ability parameters were simulated; response data generated and DIF analyses conducted. Test items were observed to determine if a priori manipulated items demonstrated DIF. The study results indicated that with unequal samples in any ratio, M-H had better Type I error rate control than SIBTEST. The results also indicated that not only the ratios, but also the sample size and the magnitude of DIF influenced the behavior of SIBTEST and M-H with regard to their error rate behavior. With small samples and moderate DIF magnitude, Type II errors were committed by both M-H and SIBTEST when the reference to focal group sample size ratio was 1:.10 due to low observed statistical power and inflated Type I error rates. / Ph. D.

This dissertation details the methods and analysis of extensive physical tests and simulation conducted by the Center for Vehicle Systems and Safety (CVeSS) at Virginia Tech on the maneuverability, roll-stability, and brake type performance of 33-ft double trailers. Little literature exists for 33-ft doubles because they are uncommon on the U.S. roads due to current federal restrictions limiting long-combination vehicles to 28-ft doubles. With the continual rise in e-commerce, however, there is a push by package carriers on legislation to permit carriers to introduce 33-ft doubles into their fleets. Three separate studies detailed herein highlight 33-ft double trailers' off-tracking, roll-stability with stability control systems, and brake type influence on braking performance. The first study compares low-speed off-tracking of a 33-ft double to 28-ft double and 53-ft single configurations via simulation and full-scale tests. Novel numerical tractrix models are introduced and compared to existing models commonly used to evaluate low-speed off-tracking of long combination vehicles (LCVs). Unlike pre-existing models, accuracy of one of the proposed models is largely unaffected by input path resolution and regularity—a significant benefit for reducing computational cost and easing implementation for many applications. Full-scale tests are conducted at Virginia Tech and an extensive uncertainty analysis is detailed for the test procedure and measurements. Field tests compare favorably with simulations for all tested maneuvers and trailer configurations and clearly demonstrate the order from least to most off-tracking as 28-ft double, 33-ft double, and 53-ft single. The 33-ft doubles have slightly larger off-tracking than 28-ft doubles, whereas 53-ft singles have substantially larger off-tracking than 28-ft and 33-ft doubles. The second study evaluates 33-ft double straight-rail trailers rollover propensity with different stability control system implementations: stock (none), tractor electronic stability control (ESC), trailer roll-stability control (RSC), and RSC+ESC. Extensive test vehicle instrumentation and structural reinforcement are detailed for the test preparations. Tests are conducted on a test track with either driver or robot steering. On their own, both ESC and RSC clearly reduce the rollover propensity of the trailers for all maneuvers, and the trailers exhibit the highest roll-stability when both RSC and ESC are active. The tested ESC and RSC modules are off-the-shelf products from industry suppliers chosen by the program sponsor. The third study compares trailer drum and disc brake performance in three conditions: straight-line braking distance, brake type influence on RSC performance, and roll dynamics in a combined braking and turning maneuver. A braking robot is designed, fabricated, and implemented to provide precise and repeatable brake pedal application. Test results suggest that disc brakes tend to provide reduced braking distance and are less susceptible to brake fade than drum brakes. Anti-lock braking system (ABS) and suspension dynamics react differently to the two brake types. Small, noticeable differences in RSC performance are evident between the two brake types. Within the test limitations, rollover dynamics were not clearly different between the two brake types for braking-in-turn maneuvers, performed for a large range of entry speeds and brake activation delay relative to the start of steering. / Doctor of Philosophy / Due to their large size, mass, and high center-of-gravity, heavy vehicles, especially long combination vehicles (LCVs) require a substantial amount of space to negotiate turns, long distances to brake from highway speeds to a stop and are susceptible to rollover. Combination vehicles on the U.S. roads are commonly in 53-ft single trailer or 28-ft double trailer configurations. With the continual rise of e-commerce, package carriers are pursuing 33-ft double trailers to increase each vehicle's cargo volume. Before introducing these trailers into a fleet, there is a need to understand (1) if 33-ft doubles can negotiate existing routes traveled by 28-ft double and 53-ft single configurations, (2) if 33-ft doubles can benefit from existing stability control systems, and (3) how trailer brake types perform on 33-ft doubles. Three separate studies are conducted to address these topics. The first study compares off-tracking for the three mentioned trailer configurations through low-speed, real-world maneuvers via physical full-scale tests and simulation. Off-tracking is a metric illustrative of maneuverability and is defined as the relative distance in paths of the rearmost axle to the lead steer axle. New mathematical models are introduced and used to simulate vehicle motion through low-speed maneuvers. The simulation and field tests determine that, for all tested maneuvers, the order from smallest to largest off-tracking is 28-ft double, 33-ft double, and 53-ft single configurations, with the 33-ft doubles having slightly larger off-tracking than 28-ft doubles. This suggests that 33-ft doubles can travel through routes typically traveled by a 53-ft single but need slightly more space on the road than a 28-ft double. The second study tests 33-ft double trailers with and without stability control systems. Tests, conducted at a test track, are designed to replicate real-world maneuvers that induce trailer rollover. It is found that the 33-ft double trailers are clearly less likely to rollover with the tested stability enhancement systems than without. The tests also illustrate that the different tested control systems' effectiveness in reducing rollover propensity is maneuver dependent. The third study tests the braking distance, brake influence on the stability control systems, and rollover dynamics while braking-in-turn for two different types of brakes, drum brakes and disc brakes. Small but evident differences in the performance of the two brake types suggest disc brakes could provide shorter stopping distance and time at highway speeds, compared with drum brakes. The studies detailed in this dissertation provide valuable information on 33-ft doubles dynamics and provide guidance for their safe introduction on the U.S. roadways.

Natural Language Processing (NLP) is an interdisciplinary research field of Computer Science, Linguistics, and Pattern Recognition that studies, among others, the use of human natural languages in Human-Computer Interaction (HCI). Most of NLP research tasks can be applied for solving real-world problems. This is the case of natural language recognition and natural language translation, that can be used for building automatic systems for document transcription and document translation. Regarding digitalised handwritten text documents, transcription is used to obtain an easy digital access to the contents, since simple image digitalisation only provides, in most cases, search by image and not by linguistic contents (keywords, expressions, syntactic or semantic categories). Transcription is even more important in historical manuscripts, since most of these documents are unique and the preservation of their contents is crucial for cultural and historical reasons. The transcription of historical manuscripts is usually done by paleographers, who are experts on ancient script and vocabulary. Recently, Handwritten Text Recognition (HTR) has become a common tool for assisting paleographers in their task, by providing a draft transcription that they may amend with more or less sophisticated methods. This draft transcription is useful when it presents an error rate low enough to make the amending process more comfortable than a complete transcription from scratch. Thus, obtaining a draft transcription with an acceptable low error rate is crucial to have this NLP technology incorporated into the transcription process. The work described in this thesis is focused on the improvement of the draft transcription offered by an HTR system, with the aim of reducing the effort made by paleographers for obtaining the actual transcription on digitalised historical manuscripts. This problem is faced from three different, but complementary, scenarios: · Multimodality: The use of HTR systems allow paleographers to speed up the manual transcription process, since they are able to correct on a draft transcription. Another alternative is to obtain the draft transcription by dictating the contents to an Automatic Speech Recognition (ASR) system. When both sources (image and speech) are available, a multimodal combination is possible and an iterative process can be used in order to refine the final hypothesis. · Interactivity: The use of assistive technologies in the transcription process allows one to reduce the time and human effort required for obtaining the actual transcription, given that the assistive system and the palaeographer cooperate to generate a perfect transcription. Multimodal feedback can be used to provide the assistive system with additional sources of information by using signals that represent the whole same sequence of words to transcribe (e.g. a text image, and the speech of the dictation of the contents of this text image), or that represent just a word or character to correct (e.g. an on-line handwritten word). · Crowdsourcing: Open distributed collaboration emerges as a powerful tool for massive transcription at a relatively low cost, since the paleographer supervision effort may be dramatically reduced. Multimodal combination allows one to use the speech dictation of handwritten text lines in a multimodal crowdsourcing platform, where collaborators may provide their speech by using their own mobile device instead of using desktop or laptop computers, which makes it possible to recruit more collaborators. / El Procesamiento del Lenguaje Natural (PLN) es un campo de investigación interdisciplinar de las Ciencias de la Computación, Lingüística y Reconocimiento de Patrones que estudia, entre otros, el uso del lenguaje natural humano en la interacción Hombre-Máquina. La mayoría de las tareas de investigación del PLN se pueden aplicar para resolver problemas del mundo real. Este es el caso del reconocimiento y la traducción del lenguaje natural, que se pueden utilizar para construir sistemas automáticos para la transcripción y traducción de documentos. En cuanto a los documentos manuscritos digitalizados, la transcripción se utiliza para facilitar el acceso digital a los contenidos, ya que la simple digitalización de imágenes sólo proporciona, en la mayoría de los casos, la búsqueda por imagen y no por contenidos lingüísticos. La transcripción es aún más importante en el caso de los manuscritos históricos, ya que la mayoría de estos documentos son únicos y la preservación de su contenido es crucial por razones culturales e históricas. La transcripción de manuscritos históricos suele ser realizada por paleógrafos, que son personas expertas en escritura y vocabulario antiguos. Recientemente, los sistemas de Reconocimiento de Escritura (RES) se han convertido en una herramienta común para ayudar a los paleógrafos en su tarea, la cual proporciona un borrador de la transcripción que los paleógrafos pueden corregir con métodos más o menos sofisticados. Este borrador de transcripción es útil cuando presenta una tasa de error suficientemente reducida para que el proceso de corrección sea más cómodo que una completa transcripción desde cero. Por lo tanto, la obtención de un borrador de transcripción con una baja tasa de error es crucial para que esta tecnología de PLN sea incorporada en el proceso de transcripción. El trabajo descrito en esta tesis se centra en la mejora del borrador de transcripción ofrecido por un sistema RES, con el objetivo de reducir el esfuerzo realizado por los paleógrafos para obtener la transcripción de manuscritos históricos digitalizados. Este problema se enfrenta a partir de tres escenarios diferentes, pero complementarios: · Multimodalidad: El uso de sistemas RES permite a los paleógrafos acelerar el proceso de transcripción manual, ya que son capaces de corregir en un borrador de la transcripción. Otra alternativa es obtener el borrador de la transcripción dictando el contenido a un sistema de Reconocimiento Automático de Habla. Cuando ambas fuentes están disponibles, una combinación multimodal de las mismas es posible y se puede realizar un proceso iterativo para refinar la hipótesis final. · Interactividad: El uso de tecnologías asistenciales en el proceso de transcripción permite reducir el tiempo y el esfuerzo humano requeridos para obtener la transcripción correcta, gracias a la cooperación entre el sistema asistencial y el paleógrafo para obtener la transcripción perfecta. La realimentación multimodal se puede utilizar en el sistema asistencial para proporcionar otras fuentes de información adicionales con señales que representen la misma secuencia de palabras a transcribir (por ejemplo, una imagen de texto, o la señal de habla del dictado del contenido de dicha imagen de texto), o señales que representen sólo una palabra o carácter a corregir (por ejemplo, una palabra manuscrita mediante una pantalla táctil). · Crowdsourcing: La colaboración distribuida y abierta surge como una poderosa herramienta para la transcripción masiva a un costo relativamente bajo, ya que el esfuerzo de supervisión de los paleógrafos puede ser drásticamente reducido. La combinación multimodal permite utilizar el dictado del contenido de líneas de texto manuscrito en una plataforma de crowdsourcing multimodal, donde los colaboradores pueden proporcionar las muestras de habla utilizando su propio dispositivo móvil en lugar de usar ordenadores, / El Processament del Llenguatge Natural (PLN) és un camp de recerca interdisciplinar de les Ciències de la Computació, la Lingüística i el Reconeixement de Patrons que estudia, entre d'altres, l'ús del llenguatge natural humà en la interacció Home-Màquina. La majoria de les tasques de recerca del PLN es poden aplicar per resoldre problemes del món real. Aquest és el cas del reconeixement i la traducció del llenguatge natural, que es poden utilitzar per construir sistemes automàtics per a la transcripció i traducció de documents. Quant als documents manuscrits digitalitzats, la transcripció s'utilitza per facilitar l'accés digital als continguts, ja que la simple digitalització d'imatges només proporciona, en la majoria dels casos, la cerca per imatge i no per continguts lingüístics (paraules clau, expressions, categories sintàctiques o semàntiques). La transcripció és encara més important en el cas dels manuscrits històrics, ja que la majoria d'aquests documents són únics i la preservació del seu contingut és crucial per raons culturals i històriques. La transcripció de manuscrits històrics sol ser realitzada per paleògrafs, els quals són persones expertes en escriptura i vocabulari antics. Recentment, els sistemes de Reconeixement d'Escriptura (RES) s'han convertit en una eina comuna per ajudar els paleògrafs en la seua tasca, la qual proporciona un esborrany de la transcripció que els paleògrafs poden esmenar amb mètodes més o menys sofisticats. Aquest esborrany de transcripció és útil quan presenta una taxa d'error prou reduïda perquè el procés de correcció siga més còmode que una completa transcripció des de zero. Per tant, l'obtenció d'un esborrany de transcripció amb un baixa taxa d'error és crucial perquè aquesta tecnologia del PLN siga incorporada en el procés de transcripció. El treball descrit en aquesta tesi se centra en la millora de l'esborrany de la transcripció ofert per un sistema RES, amb l'objectiu de reduir l'esforç realitzat pels paleògrafs per obtenir la transcripció de manuscrits històrics digitalitzats. Aquest problema s'enfronta a partir de tres escenaris diferents, però complementaris: · Multimodalitat: L'ús de sistemes RES permet als paleògrafs accelerar el procés de transcripció manual, ja que són capaços de corregir un esborrany de la transcripció. Una altra alternativa és obtenir l'esborrany de la transcripció dictant el contingut a un sistema de Reconeixement Automàtic de la Parla. Quan les dues fonts (imatge i parla) estan disponibles, una combinació multimodal és possible i es pot realitzar un procés iteratiu per refinar la hipòtesi final. · Interactivitat: L'ús de tecnologies assistencials en el procés de transcripció permet reduir el temps i l'esforç humà requerits per obtenir la transcripció real, gràcies a la cooperació entre el sistema assistencial i el paleògraf per obtenir la transcripció perfecta. La realimentació multimodal es pot utilitzar en el sistema assistencial per proporcionar fonts d'informació addicionals amb senyals que representen la mateixa seqüencia de paraules a transcriure (per exemple, una imatge de text, o el senyal de parla del dictat del contingut d'aquesta imatge de text), o senyals que representen només una paraula o caràcter a corregir (per exemple, una paraula manuscrita mitjançant una pantalla tàctil). · Crowdsourcing: La col·laboració distribuïda i oberta sorgeix com una poderosa eina per a la transcripció massiva a un cost relativament baix, ja que l'esforç de supervisió dels paleògrafs pot ser reduït dràsticament. La combinació multimodal permet utilitzar el dictat del contingut de línies de text manuscrit en una plataforma de crowdsourcing multimodal, on els col·laboradors poden proporcionar les mostres de parla utilitzant el seu propi dispositiu mòbil en lloc d'utilitzar ordinadors d'escriptori o portàtils, la qual cosa permet ampliar el nombr / Granell Romero, E. (2017). Advances on the Transcription of Historical Manuscripts based on Multimodality, Interactivity and Crowdsourcing [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/86137

No / Activation of fibroblast growth factor receptors (FGFR) is a common oncogenic event. Little is known about the determinants of sensitivity to FGFR inhibition and how these may vary between different oncogenic FGFRs. Using parallel RNA interference (RNAi) genetic screens, we show that the EGF receptor (EGFR) limits sensitivity to FGFR inhibition in FGFR3-mutant and -translocated cell lines, but not in other FGFR-driven cell lines. We also identify two distinct mechanisms through which EGFR limits sensitivity. In partially FGFR3-dependent lines, inhibition of FGFR3 results in transient downregulation of mitogen-activated protein kinase signaling that is rescued by rapid upregulation of EGFR signaling. In cell lines that are intrinsically resistant to FGFR inhibition, EGFR dominates signaling via repression of FGFR3, with EGFR inhibition rescued by delayed upregulation of FGFR3 expression. Importantly, combinations of FGFR and EGFR inhibitors overcome these resistance mechanisms in vitro and in vivo. Our results illustrate the power of parallel RNAi screens in identifying common resistance mechanisms to targeted therapies. SIGNIFICANCE: Our data identify a novel therapeutic approach to the treatment of FGFR3-mutant cancer, emphasizing the potential of combination approaches targeting both FGFR3 and EGFR. Our data extend the role of EGFR in mediating resistance to inhibitors targeting a mutant oncogene, showing that EGFR signaling can repress mutant FGFR3 to induce intrinsic resistance to FGFR targeting.