Medicine and Health Sciences

Public defences 2021

Attend a phd defence or find the archive of concluded doctoral research

Characterization of pathogen-specific human CD4 T cells after natural infection and vaccination - George Elias (26/04/2021)

George Elias

  • 26 April 2021
  • Time: 1 PM - 3 PM.
  • Online defence
  • Supervisors: Prof. V. Van Tendeloo and prof. B. Ogunjimi


Pancreatic Neuroendocrine Neoplasms: from Genetics to Everolimus Resistance - Timon Vandamme (20/04/2021)

Timon Vandamme

  • 20 April 2021
  • Time: 1 PM - 2 PM.
  • Online defence
  • Supervisors: Prof. L. Hofland, Prof. M. Peeters, Prof. P. Pauwels and prof. K. OP de Beeck


Pancreatic neuroendocrine neoplasms (pNENs) comprise only 1-2% of all pancreatic neoplasms, with an incidence of about 0.48 per 100,000 person years. Recent advances in next-generation sequencing (NGS) has led to a better understanding of the genetic constitution of pNENs, uncovering the role of the phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt)/mTOR signalling in these tumors. Surgical resection is the primary treatment in locoregional pNENs, and the only curative treatment option. However, more than 50% of cases present with unresectable disease at time of diagnosis. For these advanced pNENs, the mTOR-inhibitor everolimus, a so-called rapalog, has demonstrated to improve progression-free survival. However, primary and acquired resistance to everolimus, may limit its efficacy as single treatment modality. In acquired resistance, patients who initially respond to everolimus, later relapse and develop resistance, whereas in primary resistance, patients do not respond at all. To allow in vitro study of pNEN, the BON-1 and QGP-1 human cell lines have been developed. In this thesis, we characterize the genetic make-up of both cell lines and compare it to patient samples. In addition, we establish a model for acquired everolimus resistance and use this to uncover everolimus resistance mechanisms.

Identification of gait deviations in patients with Dravet Syndrome - Lore Wyers (19/04/2021)

Lore Wyers

  • 19 April 2021
  • Time: 5 PM - 7 PM.
  • Online joint PhD defence
  • Supervisors: Prof. A. Hallemans, Prof. P. Van de Walle and prof. K. Desloovere


Dravet Syndrome (DS) is a developmental and epileptic encephalopathy, characterised by severe epilepsy and cognitive and motor impairments. Patients with Dravet syndrome are often confronted with walking problems. As a comorbidity in the broad clinical picture of this syndrome, walking problems form a disabling factor. Studying gait deviations provides insight into the pathological processes that underlie walking problems. Research on gait in patients with DS is, however, still limited. This makes it difficult to formulate clinical advice for the evaluation and treatment of walking problems.

This PhD project aimed to characterise the main gait deviations in patients with DS. First, the state-of-the-art regarding motion analysis and gait deviations in patients with intellectual disabilities (ID) and DS is established. To this end, two review studies are conducted. Thereafter, three empirical studies document biomechanical aspects of gait in children, adolescents and young adults with DS.

Literature often described gait deviations as crouch gait in patients with DS as well as in the general population with ID. The results of the current research project confirmed that increased knee flexion increased the lower limb support moment in stance, reducing the efficiency of the gait pattern. Based on knee extensor moments and trunk lean, three kinetic strategies to maintain stance limb stability were identified. Moreover, foot function seemed impaired, as half of the participants did not consistently perform heel strikes and showed deviations in plantar pressure measures. Even though feasibility of strength measurements was low in this population, indications of dereased muscle strength were observed.

An overall inefficient gait pattern was identified, mainly characterised by increased knee flexion and diverse neurologic, motor and musculoskeletal deviations. Two main hypotheses are formulated to explain the observed gait deviations in patients with DS. First, the musculoskeletalhypothesis suggests that in DS, decreased muscle strength and lever arm dysfunction only partly explain the gait deviations. Second, the motor control hypothesis states that the contribution of impaired neuromotor control and delayed psychomotor development to gait deviations in patients with DS should not be underestimated

Developing experimental therapeutic strategies for impaired gastrointestinal permeability, bacterial translocation, intestinal inflammation, and adhesiogenesis during sepsis - Philip Plaeke (30/03/2021)

Philip Plaeke

  • 30 March 2021
  • Time: 4 PM - 6 PM.
  • Online defence
  • Supervisors: Prof. G. Hubens and prof. B. De Winter


Sepsis is a severe inflammatory disorder that affects the whole body and remains one of the leading causes of mortality worldwide. A highly important mechanism in sepsis is the loss of the intestinal barrier which leads to the influx of proinflammatory and pathogenic molecules and micro‐organisms into the body. As such, intestinal barrier impairment has been recognized as a driving force for sepsis. In this dissertation we discuss the effects of intestinal alkaline phosphatase, protease inhibitors such as nafamostat mesylate and UAMC‐00050, and gelatin tannate on the intestinal barrier during sepsis. Moreover, during sepsis of abdominal origin an intraperitoneal adhesiogenic response is often observed. These adhesions, also often seen in patients that underwent abdominal surgery, can have severe clinical implications frequently leading to urgent surgical interventions. In the second part of this dissertation, we discuss how proteases play a crucial role in several pathways responsible for adhesion formation and how protease inhibitors can interfere with the adhesiogenesis.

Gadolinium Retention And DEposition (GRADE): effects and technical considerations - Carlo Augusto Mallio (11/03/2021)

Carlo Augusto Mallio

  • 11 March 2021
  • Time: 2 PM - 4 PM.
  • Online defence
  • Supervisors: Prof. P. Parizel and prof. C. Quatrocchi


In this project we have investigated current evidence and illustrated future landscapes in the field of gadolinium deposition and safety. Even if what really counts is whether or not retained gadolinium in the brain and body is harmful, and to date no proven causation with permanent severe adverse effects has been reported in patients, we should keep investigating the topic and, if the current standard practice can be outperformed using different strategies, we should definitely go for it.

Urinary extracellular vesicles as source of biomarkers for the diagnosis and follow up of bladder cancer patients - Eline Oeyen (09/03/2021)

Eline Oeyen

  • 9 March 2021
  • Time: 5 PM - 7 PM.
  • Online defence
  • Supervisors: Prof. I. Mertens, prof. S. De Wachter and prof. G. Baggerman


Bladder cancer is the 4th most common cancer in men and the 8th most common in women in the Western world. Approximately 550,000 new cases occur yearly worldwide. The current gold standard methods to diagnose a bladder tumour are cystoscopy and urine cytology. However, limitations exist. Early detection is required to avoid cystectomy. Due to the high risk of relapse, intensive follow-up of bladder cancer patients is recommended. A non-invasive and inexpensive diagnostic method to detect bladder cancer in an early stage and monitor the patient to detect relapse will reduce the costs and is beneficial for the patient.

Urine biomarkers are an attractive alternative for the detection of a bladder cancer tumour. However, no urinary biomarkers are used in daily clinical practice yet due to the lack of sensitivity or specificity or negative predictive value. Recently, it was demonstrated that small extracellular vesicles (<200 nanometres), that are present in different types of liquid biopsies, are a potential source of biomarkers for cancer diagnosis. Tumour-derived vesicles have a role in cancer development and therefore a potential source of biomarkers with high sensitivity and specificity. The ultimate goal of this dissertation was to explore the cargo of urinary small extracellular vesicles to identify biomarker candidates for the initial diagnosis and recurrence diagnosis of bladder cancer patients.

Optimisation of the separation of small extracellular vesicles from urine was performed. Next, a variation analysis was performed on the isolated proteins to obtain insights into the interbiological variation and a sample size calculation was performed. Mass spectrometry was used to identify protein biomarker candidates in the urinary sEV isolates for (1) the diagnosis of an initial bladder cancer tumour and (2) the follow-up of patients to detect a bladder cancer relapse. Protein biomarkers allow the easy and fast diagnosis of biomarkers in antibody-based assays.This resulted in a list of 1,226 identified and quantified proteins and respectively 69 and 2 proteins were differentially detected based on high quality raw data. Although this study was promising, extra training cohorts are required. Ultimately, further verification and validation steps of the biomarker candidates are required to investigate the sensitivity, specificity and predictive values of the final biomarker panel and compare them with the current diagnostic standards to develop inexpensive and non-invasive tests.

The development and validation of tools to improve the efficacy of sacral neuromodulation and understanding of its action - Donald Vaganée (02/03/2021)

Donald Vaganée

  • 2 March 2021
  • Time: 5 PM - 7 PM.
  • Online defence
  • Supervisor: Prof. S. De Wachter


Sacral neuromodulation is a longstanding, minimally invasive treatment for patients with overactive bladder syndrome, non-obstructive urinary retention and fecal incontinence, refractory to conservative treatments. The treatment consists of placement of a tined lead with four stimulation electrodes through the third or fourth sacral foramen in order to stimulate in the vicinity of the sacral spinal nerves. Lead placement can occur under general or local anaesthesia. Correct lead position with respect to the sacral spinal nerves is determined guided by adequate pelvic floor motor and/or genital/peri-anal sensory responses after electrical stimulation. With the lead positioned, the electrodes are “programmed”, meaning that one or more electrode(s) are chosen as stimulation point(s) and an electrode as reference point. The current measurement techniques to record the motor and sensory responses during lead placement and electrode programming, are highly subject to subjectivity (visual inspection of contraction of the pelvic floor and verbal inquiry, respectively). For the motor and sensory response are considered the best indicators of optimal nerve stimulation, good tools to objectively record these responses are paramount (i.e. to improve the efficacy of sacral neuromodulation). In this thesis a multiple array electromyography probe and a pelvic chart are presented as tools to record the motor and sensory response. The validity, reliability and feasibility of these tools are assessed. Subsequently, their usefulness in clinical practice is investigated.

A listening ear. Psychotherapeutic interventions in the treatment of chronic, subjective tinnitus - Tine Luyten (15/01/2021)

Tine Luyten

  • 15 January 2021
  • Time: 5 PM - 7 PM
  • Supervisors: Em.Prof P. Van de Heyning, Em.Prof M. De Bodt and Prof A. Gilles
  • Language: Dutch


The perception of tinnitus, known as an internal sound in the absence of external auditory input, can be extremely bothersome and debilitating. Worldwide, tinnitus sounds raise awareness in 8 – 20% of the population and become chronic. For about 1 – 3 %, tinnitus is distressing and therapeutic intervention is needed.

Currently, psychotherapeutic tinnitus interventions commonly consist of psychoeducation, Tinnitus Retraining Therapy (TRT) and / or Cognitive Behavioral Therapy (CBT). The tinnitus population is frequently represented with comorbid complaints such as insomnia, anxiety and depression. For this reason, there is no treatment-fits-all and thus personalized treatment options are recommended, however, to date effective treatment options are scarce. Tinnitus is known as phantom percept and recent research on Eye Movement Desensitization Reprocessing (EMDR) and phantom pain has shown promising results.

This doctoral thesis was performed in order to gain insight in the value of EMDR as treatment for chronic subjective tinnitus, to examine whether this psychotherapeutic intervention can be applied as effective tinnitus treatment, and to explore the influence of personality traits on treatment outcome.

The first part of this dissertation investigated the existence of relevant EMDR - studies. This was the first systematic review on EMDR as treatment for tinnitus resulting in an overview of the currently existing scientifically proven studies assessed by the Platinum Standard, giving support to the effectiveness of EMDR.

Consequently, in the second part of the thesis the study protocol for a prospective, randomized controlled trial with blind evaluator was represented. A total of 166 patients with chronic, subjective, non-pulsatile tinnitus were screened and 91 patients were randomized in two treatment groups: TRT/CBT versus TRT/EMDR. Data from 89 patients were assessed at three time-points i.e. before treatment, after treatment, and at three month follow up. The focus was on analyzing the Tinnitus Functional Index (TFI) as primary outcome measurement, and the Tinnitus Questionnaire (TQ), Hyperacusis Questionnaire (HQ), Hospital Anxiety and Depression Scale (HADS), Visual Analogue Scale for tinnitus loudness (VASLoudness), and Global Perceived Effect (GPE) as secondary outcomes, after psychotherapeutic treatment.

Both bimodal therapies resulted in significant reduction of tinnitus distress, tinnitus related complaints, tinnitus loudness, hypersensitivity to sound, anxiety, and depressive symptoms and led to significant increase of quality of life. Assessments indicated a stable effect of these improvements after three months. The present study provides evidence for the effectiveness of both treatment protocols showing no superiority of TRT/EMDR over TRT/CBT.

In the third part, the influence of specific personality traits in therapeutic outcome was investigated. Data from the RCT were employed to identify correlations between self-report outcome measures and Big Five Inventory (BFI) personality traits. K-means cluster analysis revealed four distinct personality clusters containing a specific combination of traits.

In conclusion, these empirical findings highlight the effectiveness of both bimodal therapies showing no different efficacy and underline the significant influence of personality traits in psychotherapeutic treatments.

New insights in connective tissue and growth disorders - Silke Peeters (14/01/2021)

Silke Peeters

  • 14 January 2021
  • Time: 3 PM - 5 PM.
  • Online defence
  • Supervisors: Prof. G. Mortier and prof. W. Van Hul


The primary purpose of this thesis was to gain more insights in the genetic architecture and disease mechanisms underlying connective tissue and growth disorders. The first and main project focused on carpal tunnel syndrome (CTS). Although CTS is common and widely recognized, its precise etiology still remains largely unknown. In this project, we were able to delineate a new fibrillino-2-pathy by studying a family in whom CTS occurred in three subsequent generations at an unusually young age. Additional clinical features included brachydactyly and short Achilles tendons. Using exome sequencing, we identified a heterozygous pathogenic variant (p.Phe1670Cys) in the fibrillin-2 (FBN2) gene that co‐segregated with the phenotype in the family. We found evidence that the mutant protein affects normal integrin-mediated cell adhesion in the ECM and observed increased TGF-β signaling, resulting in fibrosis of the carpal tissues with entrapment of the median nerve as a consequence. A variant burden test in a large cohort of sporadic CTS patients revealed a significantly increased frequency of rare (6.7% versus 2.5-3.4%, p<0.001) and high-impact (6.9% versus 2.7%, p<0.001) FBN2 variants in patient alleles compared to controls. These findings strongly suggest a role of FBN2 in the pathogenesis of CTS.

The second project of this thesis focused on children born small-for-gestational age (SGA) with persisting growth failure. In a significant proportion of SGA children, the etiology of the growth failure remains unclear after routine diagnostic work-up. In this project, we investigated whether an extensive analysis of the (epi)genome can unravel the (epi)genetic cause of growth failure in a well-defined group of 20 SGA children.

We identified (likely) pathogenic variants in two siblings and two additional probands using exome sequencing. Furthermore,

SNP array analysis in all children and their parents revealed a rare, pathogenic de novo copy number variation (CNV) in two other unrelated probands. In almost all children with a genetic diagnosis, we observed an “above average” response to growth hormone treatment. These results question the relevance of the exclusion of syndromic SGA patients from growth hormone treatment. In a subgroup of 10 children, we performed a genome-wide DNA methylation assay. This analysis revealed multi-locus imprinting disturbances in two additional children. Furthermore, in the child harboring the NSD1-containing microduplication, we identified a novel DNA methylation signature. The conclusion of this second project is that a more advanced approach with deep genotyping can unravel unexpected (epi)genomic alterations in SGA children with persistent growth failure.