Despite the interest and success in immunotherapy, our current understanding of how the immune activation balance – on the macro level – and the expression of receptors and their ligands – on the... Show moreDespite the interest and success in immunotherapy, our current understanding of how the immune activation balance – on the macro level – and the expression of receptors and their ligands – on the micro level – shape health and disease is still limited. By identifying novel regulatory networks that dictate immune cell activity in physiologically relevant settings, well-designed pooled genetic screens could offer a relevant approach to address this knowledge gap. Genetic screens have become a powerful tool to identifygenes that affect the response and phenotype of a cell in an unbiased manner.In this thesis, I aimed to identify regulators of immune cell activation in the context of cancer through a combination of in vitro and in vivo genetic screens and genetically modified mouse models. Specifically, this was achieved by both 1) using genetic screening technologies to identify novel cancer cell-expressed inhibitory ligands or regulatorsof immune-modulating ligands in an unbiased manner, and 2) investigating the effect of these regulators on the cellular components and signaling pathways that constitute the local tumor microenvironment and potentially dictate anti-tumor efficacy. Show less
Hebbrecht, K.; Morrens, M.; Giltay, E.J.; Nuijs, A.L.N. van; Sabbe, B.; Ameele, S. van den 2021
Introduction: Chronic low-grade inflammation is suggested to play a pathophysiological role in bipolar disorder (BD) and its related cognitive dysfunctions. Although kynurenine (KYN) pathway... Show moreIntroduction: Chronic low-grade inflammation is suggested to play a pathophysiological role in bipolar disorder (BD) and its related cognitive dysfunctions. Although kynurenine (KYN) pathway metabolites are key inflammatory mediators, studies investigating the association between KYN metabolism and cognition in BD are scarce. We aimed to explore the relationship between KYN metabolism and cognitive functioning across different mood states in BD. Methods: Sixty-seven patients with BD (35 depressed and 32 [hypo] manic) and 29 healthy controls were included. Cognitive functioning was assessed at 3 time intervals (baseline, 4, and 8 months) assessing processing speed, sustained attention, verbal memory, working memory, and response inhibition. Plasma samples for quantification of 3-hydroxykynurenine, quinolinic acid, and kynurenic acid (KYNA) were concurrently provided. Linear mixed models were used for statistical analysis. Results: The manic group showed deficits in all assessed cognitive domains with the exception of verbal memory at all test moments. The bipolar depression group showed deficits in the processing speed at all test moments. Throughout the whole follow-up period, KYNA was significantly lower in both patient groups than in controls. Only in the bipolar depression group, low KYNA was associated with worse global cognitive functioning (B = 0.114, p = 0.02) and slower processing speed in particular (B = 0.139, p = 0.03). Conclusion: Only in the bipolar depression group, lower KYNA was associated with worse cognitive functioning. Future large-scale longitudinal studies are warranted to confirm the role of KYN metabolites in cognitive impairment in patients with BD and the possible therapeutic implications of this relationship. Show less
Our research group recently published a positive association between early postoperative pain and 30-day postoperative complications in a broad surgical population. To investigate whether... Show moreOur research group recently published a positive association between early postoperative pain and 30-day postoperative complications in a broad surgical population. To investigate whether heterogeneity of the population and surgical procedures influenced these results, we explored this association in a homogenous surgical population. A secondary analysis of the LEOPARD-2 (NCT02146417) and RELAX-1 study (NCT02838134) in laparoscopic donor nephrectomy patients (n = 160) was performed. Pain scores on the postanesthesia care unit and postoperative day (POD) 1 and 2 were compared between patients with infectious, noninfectious, and no complications 30 days after surgery. Patients who developed infectious complications had significantly higher pain scores on POD1 and 2 (6.7 +/- 2.1 and 6.4 +/- 2.8) than patients without complications (4.9 +/- 2.2 and 4.1 +/- 1.9), respectively (P= 0.006 andP= 0.000). Unacceptable pain (numeric rating scale [NRS] >= 6) on POD1 was reported by 72% of patients who developed infectious complications, compared to 38% with noninfectious complications and 30% without complications (P= 0.018). This difference was still present on POD2 at 67% with infectious complications, 21% with noninfectious, and 40% without complications (P= 0.000). Multiple regression analysis identified unacceptable pain (numeric rating scale >= 6) on POD2 as a significant predictor for 30-day infectious complications (odds ratio 6.09,P= 0.001). Results confirm the association between early postoperative pain and 30-day infectious complications in a separate, homogenous surgical population. Further clinical trials should focus on finetuning of postoperative analgesia to elucidate the effects on the endocrine and immune response, preserve immune homeostasis, and prevent postoperative infectious complications. Show less
The immune system is quite remarkable having both the ability to tolerate innocuous and self-antigens while possessing a robust capacity to recognize and eradicate infectious pathogens and foreign... Show moreThe immune system is quite remarkable having both the ability to tolerate innocuous and self-antigens while possessing a robust capacity to recognize and eradicate infectious pathogens and foreign entities. The genetics that encode this delicate balancing act include multiple genes and specialized cell types. Over the past several years, whole exome and whole genome sequencing has uncovered the genetics driving many human immune-mediated diseases including monogenic disorders and hematological malignancies. With the advent of genome editing technologies, the ability to correct genetic immune defects in autologous cells holds great promise for a number of conditions. Since assessment of novel therapeutic strategies have been difficult in mice, in recent years, immunodeficient mice capable of engrafting human cells and tissue have been developed and utilized for a variety of research applications. In this review, we discuss immune-humanized mice as a research tool to study human immunobiology and genetic immune disorders in vivo and the promise of future applications. Show less
In modern society, circadian rhythms and sleep are often disturbed, which may negatively affect health. This thesis examines these associations and focuses on the basic functioning of sleep and the... Show moreIn modern society, circadian rhythms and sleep are often disturbed, which may negatively affect health. This thesis examines these associations and focuses on the basic functioning of sleep and the circadian system in mice and in humans. Circadian rhythms are orchestrated by ~20,000 neurons in the central clock in the suprachiasmatic nuclei (SCN) in the brain. In mice, a complete abolishment of central clock-driven rhythms resulted in obesity and severe hepatic insulin resistance. An attenuation of rhythms resulted in decreased muscle strength, osteoporosis-like bone changes and transient changes in the immune system. In humans, short sleeping obese individuals with a preference for evening activities ("evening chronotypes") had increased cardiovascular risk factors. Their neurocognitive function was often impaired and could be improved with sleep extension. Insufficient sleep was also associated with an increased risk for osteopenia and sarcopenia. Taken together, disrupted circadian rhythms and insufficient sleep associate with a spectrum of unfavorable health outcomes. Studies described in the thesis provide insight in potential strategies to improve rhythms and sleep: by appropriately timed behavior (active behavior during the active phase; rest during the rest phase), light exposure (light during the subjective day; darkness at night) as well as caffeine intake. Show less
