Title Promoter Affiliations Abstract "Football and integrity: a legal enforcement investigation based on three cases (violence, racism and matchfixing)" "Frank Hendrickx" "Institute for Labour Law" "Voetbal en integriteit: een juridisch handhavingsonderzoek aan de hand van drie cases (geweld, racisme en matchfixing)" "Dilemmas behind bars: A realist evaluation of an ethics training program for prison officers in two Belgian prisons" "Jeroen Maesschalck" "Leuven Institute of Criminology" "In this doctoral dissertation, the researcher will carry out an evaluation of an integrity program aimed at improving the ethical behavior of staff involved in the criminal justice system. Integrity programs are increasingly designed and adopted by organizations in various sectors and aim at tackling unethical behavior and stimulating ethical behavior of managers and employees of the organization. Such integrity programs can consist of various components including integrity training sessions, formal mentoring programs and the development of an ethics code. In spite of the widespread enthusiasm about integrity programs, research to evaluate the impact of such programs has been scarce. This doctoral dissertation aims at addressing this research gap by carrying out a thorough evaluation of an integrity program, designed for application within the criminal justice system. This will be done using the promising ‘realistic evaluation’ approach. This approach, first developed by Pawson and Tilley in 1997, emphasizes the importance of contextual factors and of the underlying mechanisms that make an intervention succeed or fail. Rather than ‘what works?’, the question is ‘’What works for whom and why?’ Following a thorough review of the literature on integrity within the criminal justice system as well as on integrity programs, we will first design and then execute an integrity program in a criminal justice organization in Belgium. That program will then be evaluated using the realistic evaluation approach. " "Relevance of an altered epithelial function in gastrointestinal and non-gastrointestinal disorders" "Ricard Farré Marti" "Translational Research in GastroIntestinal Disorders" "The intestinal barrier separates the internal environment from the lumen of the gastrointestinal (GI) tract. To keep the normal epithelial homeostasis (absorption of nutrients and water, water secretion…) a tight epithelial regulation is essential. Luminal components cross the intestinal barrier through the cells (transcellular pathway), or between the cells (paracellular pathway). During this project, we will explore the role of altered epithelial physiology including the barrier function (epithelial permeability) in the pathophysiology of several GI (GERD, functional dyspepsia, irritable bowel syndrome, IBD, intestinal ischemia) and non-GI disorders (chronic kidney disease, liver disease, and rhinitis, cystic fibrosis). For this, we will use cell cultures, animal models, and tissue from humans to study the epithelium functionally and structurally at the molecular level. " . "Jan Tolleneer" "Department of Movement Sciences" "Scientific Integrity in Biomedical Research: a European Perspective" "Kris Dierickx" "Interfaculty Centre for Biomedical Ethics and Law" "The issues of research integrity and misconduct feature regularly in academic journals and the press. Misconduct within biomedical research is harmful because it threatens the excellence and progression of biomedical research. It can lead for example to wrong medication and damages trust, both the public’s trust in biomedical research and the mutual trust of biomedical researchers. Biomedical research is increasingly interdisciplinary and international. Therefore a breach in trust has a huge impact. Throughout this PhD thesis, we focused on three research objectives:  * What is the situation concerning the research integrity guidance documents of the countries of the European Union (EU) and European Free Trade Association (EFTA)?* What is the empirical situation concerning research integrity and misconduct within biomedical research in Belgium, both within universities and industry?* What are the concluding ethical implications concerning the elaboration of aresearch integrity policy? We opted for an empirical ethics approach. Therefore, the project consists of three phases. In the first phase, a review is made of the official guidance documents on research integrity to map the different policies and strategies towards research integrity guidance within the European economic area. Secondly, both a qualitative and a quantitative study are conducted among biomedical researchers and research managers active within academia and industry. These empirical studies aimed to gauge their perspectives, knowledge and attitudes towards the issues of research integrity and misconduct. Finally, we brought the two previous phases together in a reflection about the concluding ethical implications concerning the elaboration of a research integrity policy. Our research provided several novel findings. There was heterogeneity between the research integrity guidance documents in Europe concerning various elements, including how research misconduct ought to be defined. Within Europe, various systems were implemented. In northern Europe, it was common to have a national commission to deal with research misconduct allegations. Whereas in southern Europe, no such national commissions existed. In addition, it was often challenging to access the research integrity guidance documents. Research misconduct occurred to a substantial degree in both universities and industry. Industry and universities upheld different strategies towards research integrity and misconduct. Our analysis revealed several relations with various factors concerning issues of research integrity and misconduct, and the abstract concept of “research integrity” gained a realistic, empirically-based meaning. The ethical evaluation towards research misconduct differed between biomedical research and research managers on the one hand, and research integrity guidance documents in the other hand. The reported frequency of research misconduct related with research integrity training and the ethical evaluation of the listed items of research misconduct. Based on our research findings, we formulated several recommendations in order to stimulate an agreed upon research integrity policy. We aim to achieve an agreed upon research integrity policy by creating and maintaining a continuous and cyclic interaction between empirical data and research integrity guidance documents. When evaluating a research integrity policy, the perspectives and challenges of biomedical researchers and research managers need to be taken into consideration, within the framework of foundational research integrity principles." "The role of mucosal integrity and low-grade inflammation in functional dyspepsia." "Jan Tack" "Translational Research in GastroIntestinal Disorders" "FD is a common functional gastrointestinal disorder encountered in clinical practice and is characterized by a diversity of symptoms localized in the epigastric region. When the gastrointestinal tract of a patient with FD is observed during routine endoscopic examination, no organic abnormalities are found, hence the term functional. The available treatment options for this disorder remain unsatisfactory, which is mostly related to the poorly understood pathophysiology. FD is associated with a high human and healthcare burden, underlining the need to elucidate the cause of dyspeptic symptom generation. There is growing evidence that FD is a heterogeneous disorder; the wide variety of symptoms seen in patients with FD argues for diverse pathophysiological pathways. Studies have demonstrated the presence of several alterations of the stomach and more recently of the duodenum in patients with FD. Whether these abnormalities play a crucial role in the manifestation of dyspeptic symptoms needs to be further elucidated. The general aim of this thesis was therefore to advance the role of duodenal implications in the pathophysiology ofFD.It is well established that food ingestion plays a significant role in dyspeptic symptom generation in the majority of patients with FD. However, whether these postprandial symptoms are generated in the stomach or in the small intestine is unknown. We therefore evaluated the time course of dyspeptic symptoms after a meal and compared the intensityof these symptoms when food is predominantly in the stomach to the symptom severity when food is mainly in the small intestine. We observed that the stomach seems to play a relevant role in the induction of fullness, bloating and belching, while epigastric pain and epigastric burning are suggested to be generated in the small intestine. As these results suggest at least a partial contribution of the small intestine in dyspepticsymptom generation, we aimed to further elucidate the involvement of the duodenum in FD. Several studies have reported the presence of low-grade inflammation in the duodenal mucosa of patients with FD. The origin ofthis low-grade inflammation remains to be identified, but we hypothesized that patients with FD display impaired duodenal barrier function. This will enable luminal antigens to pass through the epithelium, in that way eliciting immune responses in the lamina propria and resulting in low-grade inflammation. Duodenal integrity of routine endoscopic biopsy specimens was therefore assessed and we found functional and structural evidence of increased permeability in patients with FD. We also detected increased numbers of eosinophils and mast cells in the lamina propria of duodenal biopsy samples, and demonstrated an association with the changesin duodenal integrity. We next investigated activation of eosinophils and mast cells in patients with FD and found ultrastructural changes in degranulation of these cells. The cause of increased duodenal permeability and immune activation in FD is unclear, but a likely candidate is an increased duodenal acid exposure since this has been shown to be present in patients with FD. For this reason, we perfused the duodenum of healthy volunteers with acid during 30 min and demonstrated that duodenal acid perfusion disrupts epithelial integrity and activates mast cells.To conclude, we identified a specific set of small intestinal symptoms, thereby underlining the possible pathophysiological role of the duodenum in FD. Our study is of particular interest, as we are the first to demonstrate increased duodenal permeability in patients with FD. We alsoconfirmed the involvement of an inflammatory mechanism in the pathophysiology of FD and reported that this could be associated with altered duodenal barrier function. Moreover, increased duodenal acid exposure was identified as a potential mechanism involved in the generation of decreased duodenal integrity and immune activation. These data challenge the classical paradigm that the structure of the gastrointestinal tract is unaltered in patients with FD and provide evidence that FD is an organic rather than a functional disorder. Our findings suggest that inhibitors of mast cell activation, stabilizers of cell-to-cell adhesion proteins and acid suppressive therapy could be of therapeutic potential for the treatment of FD." "Do we have a choice ? An analysis of judicial review intensity of discretional actions" "Bernard Tilleman" "Centre for Methodology of Law, Faculty of Law and Criminology, Kulak Kortrijk Campus" "Government enacts a flight plan, but it increases noise pollution, or, a company takes an economic risk, but it turns out badly. Can a court say they should have taken another decision? This addresses the problem to which extent courts can intervene with freedom of action. Four types of attitudes can be distinguished: three restrict the scope of review, while the fourth allows the judge to intervene fully. Belgium and the Netherlands apply a content-based limitation of judicial review. It entails that courts can review the content of the decision which has been taken, but can look only at manifest violations. However, this solution has been increasingly attacked, often in opposite directions – some want more scrutiny, some want more discretion. Looking elsewhere, we can see that solutions adopted in the US and Germany might not have this problem. We observe that an empirical observation of how courts apply this content-based test is lacking, and that studies on the topic remain limited to one area of law. This project aims to fill these gaps by conducting a thorough legal analysis, as well as a (descriptive) empirical and (evaluative) analysis in corporate and administrative law. In this way, the research aims to contribute to the (normative) question of how far courts can intervene in our freedom of action. " "Process intensification of industrial O3/UV-reactors: experimental approach and modeling." "Jan Degrève" "Bio- & Chemical Systems Technology, Reactor Engineering and Safety Section" "Eén van de grootste uitdagingen van de 21ste eeuw is het voorzien van drinkwater voor de steeds toenemende populatie op aarde. Een verregaande zuivering van (industrieel) afvalwater gekoppeld aan maximaal hergebruik is dan ook aangewezen. Deze verregaande zuivering kan in een tertiaire zuiveringsstap o.a. met behulp van geavanceerde oxidatietechnieken (AOPs) worden verkregen. De kostprijs van AOPs voor een volledigechemische oxidatie is over het algemeen echter tamelijk hoog. Een alternatief bestaat er dan ook in om deAOPs met partiële doseringen oxidans als voorbehandeling te gebruiken. Het beoogde doel hierbij is hetverhogen van de biodegradeerbaarheid om vervolgens verdere afbraak in de biologische zuivering te latenplaatsgrijpen.In dit doctoraatsproject wordt de nadruk gelegd op O3 en UV. Deze zijn uitermate geschikt voor integratie in een bestaande waterzuivering. Bovendien wordt in sommige gevallen een duidelijke synergie waargenomen bij gecombineerd gebruik van deze technieken.In een eerste fase worden de parameters, karakteristiek voor de reactiesnelheid en de massa-overdracht, experimenteel bepaald. Op basis hiervan kunnen de designvergelijkingen voor reactoren opgesteld worden. Omwille van de sterke koppeling tussen deze vergelijkingen worden deze numeriek via eindige elementen opgelost. Hiertoe worden de vergelijkingen geïmplementeerd in een commercieel Computational Fluid Dynamics softwarepakket.Vervolgens wordt in een tweede fase bestudeerd hoe de principes van procesintensificatie kunnen toegepastworden op een O3/UV-installatie. In het bijzonder zal het gebruik van een fotokatalysator geëvalueerd worden om de UV intensiteit beter te benutten. Daarnaast zal nagegaan worden of het gebruik van een magnetisch veld een invloed heeft op de levensduur van de gebruikte UV-lamp. Tenslotte zal ook het stromingsgedrag in de reactor en de positie van de UV-lampen op basis van de CFD-resultaten worden geoptimaliseerd.In het kader van deze doctoraatsstudie zal er met verschillende onderzoeksgroepen samengewerkt worden:- Afdeling Toegepaste Fysische Scheikunde en Milieutechnologie, Departement Chemische Ingenieurstechnieken, KU Leuven: Professor Tom Van Gerven- Centrum voor Oppervlaktechemie en Katalyse, Departement Microbiële en Moleculaire Systemen, KULeuven: Professor Johan Martens" "Novel HIV inhibitors targeting the interaction between integrase and LEDGF/p75" "Zeger Debyser" "Molecular Virology and Gene Therapy" "Three decades after its discovery, the human immunodeficiency virus (HIV), the etiologic agent of the acquired immunodeficiency syndrome (AIDS), continues to wreak havoc on a global scale. However, thanks to the significant scientific achievements, combination antiretroviral therapy (ART) better known as highly active antiretroviral therapy (HAART) has significantly improved the prognosis of the disease.  There is a continuous search for better drugs targeting alternative steps of the replication cycle with a higher genetic barrier and tolerability aiming at complementing the existing repertoire of drugs and reducing thelatent reservoir, a major obstacle of an HIV cure. Moreover, their application can help us to further understand the knowable unknowns of thebiology of the HIV. Although most clinical anti-HIV drugs target reverse transcriptase and protease, integrase is also a prime target for anti-HIV therapy. Accordingly, several classes of integrase (IN) inhibitors have been discovered including the first IN inhibitor approved for patient treatment, raltegravir.  To efficiently insert the viral DNA, IN is dependent on cellular proteins called cofactors. One such protein is lens epithelium-derived growth factor (LEDGF)/p75. The interaction between LEDGF/p75 and IN is a potential therapeutic target thatcan accommodate small molecule inhibitors. At the start of this doctoral study, through multidisciplinary efforts, our research group identified three novel classes of integration inhibitors: (i) IN catalytic site inhibitors, (ii) LEDGINs and (iii) LEDGF/p75-binding peptides identified by phage display. The present study focuses on the virological characterization and the elucidation of the mechanism of action of these inhibitors. Moreover, using some of these inhibitors we investigated the role ofLEDGF/p75 in late stage HIV replication. The first part of the study aimed at the characterization of the antiviral activityof the IN catalytic site inhibitor MB-76, a lead compound of the 2-hydroxyisoquinoline-1,3(2H, 4H)diones (HQD) series. In a series of experiments, we showed that MB-76 displays a broad-spectrum antiviral activity with low to submicromolar 50% effective concentrations (EC50) with aselectivity index (SI) of >53. MB-76 exhibits no cross-resistance with other classes of antiretrovirals (ARVs) including integrase strand transfer inhibitors (INSTIs). Using quantitative PCR and time-of-addition experiments, we demonstrated that MB-76, similar to raltegravir, solely inhibits the integration step. We could not select resistant variants afterpassaging the virus for 15 months in cell culture, indicating that the HQD compounds have a superior genetic barrier to resistance development compared to the clinical INSTIs supporting their potential for further development. In search of a novel class of allosteric IN inhibitors, we exploited the interaction between LEDGF/p75 and HIV-1 IN. This protein-protein interaction (PPI) displays a distinct key and lock-like interaction, amenable for small molecule PPI inhibitor design. A rational drug design effort has led to the identification of small molecule allosteric IN inhibitors targeting the LEDGF/p75 binding pocket in integrase termed LEDGINs. Here, I characterized the antiviralactivity and pinpointed the mechanism of action of LEDGINs. LEDGINs prevent the interaction between LEDGF/p75 and HIV-1 IN, and indirectly interfere with the catalytic activity of IN. LEDGINs inhibit HIV-1 replication at low micromolar EC50 by blocking the integration step. Furthermore,a resistance selection experiment revealed a single amino acid substitution, A128T, in the IN-coding region confirming the molecular target. LEDGINs lack cross-resistance with other ARVs including INSTIs. Moreover, we observed a significant effect on the infectivity of progeny virions produced in the presence of LEDGINs, suggesting that LEDGINs inhibit bothintegration and late stages of HIV. In conclusion, our work demonstrates the feasibility of rational design of small molecules inhibiting PPI between a viral protein and a cellular factor underscoring their potential for further (clinical) development. While LEDGINs inhibit HIV-1 replication by occupying the LEDGF/p75 pocket in integrase,it remained unknown whether LEDGF/p75 by itself can be targeted. Therefore, using cyclic peptides (CPs) identified by a carefully designed phage display strategy, we demonstrated for the first time that LEDGF/p75-binding ligands can inhibit HIV replication by blocking the interaction between LEDGF/p75 and HIV-1 IN. Here, we showed that the CPs inhibit HIV replication without overt toxicity. In accord with the role of LEDGF/p75 in HIV integration, CP64 and CP65 block HIV replication by inhibiting integration. Moreover, the CPs retained activity against HIV-1 strains resistant to raltegravir or LEDGINs and HIV-2, indicating their differing mechanism of action compared to LEDGINs or INSTIs. We also observed a strong effect on the infectivity of progeny virions generated in CP65 expressing cells, suggesting a yet unidentified role of LEDGF/p75 in late stage HIV replication. Serial passaging of virus in the presence of CPs did not yield resistant strains. Our work provides proof-of-concept for direct targeting of LEDGF/p75 as a novel therapeutic strategy. Moreover,the CPs may serve as a scaffold for future development of new HIV therapeutics. In the final part of this doctoral study,we elucidated the molecular mechanism of the late effect of LEDGINs, which can also explain the late effect of the LEDGF/p75-binding CPs. Through parallel approaches using LEDGINs, LEDGF/p75-depleted cells, and interaction mutants of LEDGF/p75 (D366N) and HIV-1 IN (W131A), we unveil a hitherto unknown role of LEDGF/p75 in HIV biology by demonstrating its requirement for the generation of fully infectious HIV particles. Virions produced in the presence of LEDGINs display a 2- to 4-log reduction in infectivity. Detailed analysis excluded defects in genomic RNA packaging or proteolytic maturation of the virions produced in the presence of LEDGINs; instead, our findings reveal a post-entry defect during early replication steps including reverse transcription, nuclear import, and integration in the target cells. Experiments to explain the mechanism of the late effect of LEDGINs indicated that LEDGF/p75 is incorporated in the viral particles and is inhibited by LEDGINs. We then showed that LEDGF/p75 is recruited through its direct interaction with IN and/or Pol polyprotein into nascent virions. In summary, we have identified an unanticipated role of LEDGF/p75 in HIV-1 replication and corroborated a unique mechanism of action of LEDGINs inhibiting both early and late steps of HIV replication. These novel classes of inhibitors, results of multidisciplinary efforts, represent some of the most attractive ARVs for further pharmacological development to complement the existing drugs. The inhibitors described in this study have proven multimodal anti-HIV activity and a moderate to very high genetic barrier to resistance development. Particularly, LEDGINs - allosteric IN inhibitors in advancedpreclinical development - are highly potent and have compatible pharmacokinetic profiles to advance further. Notwithstanding, their ultimate success will critically depend on further clinical research and development."