Joining forces in endocrine cancer genetics: molecular testing, surveillance and treatment decision making in clinical practice

This thesis, describes investigations of the genetic background of a wide variety of rare endocrine tumors, including those of the thyroid, parathyroid, adrenal and paraganglia. In the first part, our studies focus on the role of molecular testing in diagnostics and treatment decision making in patients with DICER1 syndrome or advanced radioactive iodine refractory thyroid cancer. In the second part, we investigated the of genetic background of pediatric non-medullary thyroid carcinoma. In the third part we focused on genetic counseling in the following endocrine tumor predisposition syndromes: CDC73-related disorder, SDHA-associated paraganglioma and MEN2a syndrome. Our studies contributed to the debate on accurate estimation of disease penetrance. In order to provide answers to the questions - “Why do I have cancer? Are other relatives at risk? And if so, can we prevent cancer?” - patient- and family centered endocrine cancer care encourages active collaboration between the departments of endocrinology, oncology, surgery, pathology, chemistry, radiology, nuclear medicine and clinical genetics.The research presented in this thesis was (partly) financially supported by the Children Cancer-free Foundation (KiKa, project number 265) and the Archer® International Research Challenge GrantLUMC / Geneeskunde Repositoriu

The added value of daily diary data in 1- and 3-year prediction of psychopathology and psychotic experiences in individuals at risk for psychosis

This study aimed to assess whether adding information on psychological experiences derived from a daily diary to baseline cross-sectional data could improve short- (1-year) and long-term (3-years) prediction of psychopathology and positive psychotic experiences (PEs). We used 90-day daily diary data from 96 individuals in early subclinical risk stages for psychosis. Stepwise linear regression models were built for psychopathology and PEs at 1- and 3-years follow-up, adding: (1) baseline questionnaires, (2) the mean and variance of daily psychological experiences, and (3) individual symptom network density. We assessed whether similar results could be achieved with a subset of the data (7-14- and 30-days). The mean and variance of the diary improved model prediction of short- and long-term psychopathology and PEs, compared to prediction based on baseline questionnaires solely. Similar results were achieved with 7-14- and 30-day subsets. Symptom network density did not improve model prediction except for short-term prediction of PEs. Simple metrics, i.e., the mean and variance from 7 to 14 days of daily psychological experiences assessments, can improve short- and long-term prediction of both psychopathology and PEs in individuals in early subclinical stages for psychosis. Diary data could be a valuable addition to clinical risk prediction models for psychopathology development.</p

A unique case of two somatic APC mutations in an early onset cribriform-morular variant of papillary thyroid carcinoma and overview of the literature

We report a case of a 22-year-old female patient who was diagnosed with a cribriform-morular variant of papillary thyroid carcinoma (CMV-PTC). While at early ages this thyroid cancer variant is highly suggestive for familial adenomatous polyposis (FAP), there was no family history of FAP. In the tumor biallelic, inactivating APC variants were identified. The patient tested negative for germline variants based on analysis of genomic DNA from peripheral blood leukocytes. Somatic mosaicism was excluded by subsequent deep sequencing of leukocyte and normal thyroid DNA using next generation sequencing (NGS). This report presents a rare sporadic case of CMV-PTC, and to the best of our knowledge the first featuring two somatic APC mutations underlying the disease, with an overview of CMV-PTC cases with detected APC and CTNNB1 pathogenic variants from the literature

Re-vitalizing the American Feminist-Philosophical Classroom: Transformative Academic Experimentations with Diffractive Pedagogies

This chapter touches upon the damaging impact of neoliberal reason on institutions of higher education, and my efforts as a teacher to help turn things around by re-vitalizing the classroom. After a critique of current neoliberal ‘borderline times’, the chapter takes the reader on a journey of diffractive re-imaginings in which I share some of my experiences of co-learning with undergraduates in an American feminist-philosophical classroom. My central argument is that the neoliberalism-induced crisis in education can be affirmatively counteracted through experimentations with various posthuman and new materialist theories, and the Harawayan-Baradian methodology of diffraction in particular. Furthermore, informed by the impression that theory and pedagogical praxis go hand in hand in many contemporary feminist new materialisms, I zoom in on daily acts of resistance against the neoliberal corporatization of the American university, acts that actualized themselves as feminist new materialist pedagogies. Three examples of diffractive pedagogical strategies are then discussed in detail

Lipopolysaccharide Lowers Cholesteryl Ester Transfer Protein by Activating F4/80Clec4fVsig4Ly6C Kupffer Cell Subsets

BACKGROUND: Lipopolysaccharide (LPS) decreases hepatic CETP (cholesteryl ester transfer protein) expression albeit that the underlying mechanism is disputed. We recently showed that plasma CETP is mainly derived from Kupffer cells (KCs). In this study, we investigated the role of KC subsets in the mechanism by which LPS reduces CETP expression. METHODS AND RESULTS: In CETP-transgenic mice, LPS markedly decreased hepatic CETP expression and plasma CETP concentration without affecting hepatic macrophage number. This was paralleled by decreased expression of the resting KC markers C-type lectin domain family 4, member f (Clec4f) and V-set and immunoglobulin domain containing 4 (Vsig4), while expression of the infiltrating monocyte marker lymphocyte antigen 6 complex locus C (Ly6C) was increased. Simultaneously, the ratio of plasma high-density lipoprotein-cholesterol over non-high-density lipoprotein-cholesterol transiently increased. After ablation hepatic macrophages via injection with liposomal clodronate, the reappearance of hepatic gene and protein expression of CETP coincided with Clec4f and Vsig4, but not Ly6C. Double-immunofluorescence staining showed that CETP co-localized with Clec4f+ KCs and not Ly6C+ monocytes. In humans, microarray gene-expression analysis of liver biopsies revealed that hepatic expression and plasma level of CETP both correlated with hepatic VSIG4 expression. LPS administration decreased the plasma CETP concentration in humans. In vitro experiments showed that LPS reduced liver X receptor-mediated CETP expression. CONCLUSIONS: Hepatic expression of CETP is exclusively confined to the resting KC subset (ie, F4/80+Clec4f+Vsig4+Ly6C-). LPS activated resting KCs, leading to reduction of Clec4f and Vsig4 expression and reduction of hepatic CETP expression, consequently decreasing plasma CETP and raising high-density lipoprotein (HDL)-cholesterol. This sequence of events is consistent with the anti-inflammatory role of HDL in the response to LPS and may be relevant as a defense mechanism against bacterial infections

M2 Macrophages Activate WNT Signaling Pathway in Epithelial Cells: Relevance in Ulcerative Colitis

Macrophages, which exhibit great plasticity, are important components of the inflamed tissue and constitute an essential element of regenerative responses. Epithelial Wnt signalling is involved in mechanisms of proliferation and differentiation and expression of Wnt ligands by macrophages has been reported. We aim to determine whether the macrophage phenotype determines the expression of Wnt ligands, the influence of the macrophage phenotype in epithelial activation of Wnt signalling and the relevance of this pathway in ulcerative colitis. Human monocyte-derived macrophages and U937-derived macrophages were polarized towards M1 or M2 phenotypes and the expression of Wnt1 and Wnt3a was analyzed by qPCR. The effects of macrophages and the role of Wnt1 were analyzed on the expression of β-catenin, Tcf-4, c-Myc and markers of cell differentiation in a co-culture system with Caco-2 cells. Immunohistochemical staining of CD68, CD206, CD86, Wnt1, β-catenin and c-Myc were evaluated in the damaged and non-damaged mucosa of patients with UC. We also determined the mRNA expression of Lgr5 and c-Myc by qPCR and protein levels of β-catenin by western blot. Results show that M2, and no M1, activated the Wnt signaling pathway in co-culture epithelial cells through Wnt1 which impaired enterocyte differentiation. A significant increase in the number of CD206+ macrophages was observed in the damaged mucosa of chronic vs newly diagnosed patients. CD206 immunostaining co-localized with Wnt1 in the mucosa and these cells were associated with activation of canonical Wnt signalling pathway in epithelial cells and diminution of alkaline phosphatase activity. Our results show that M2 macrophages, and not M1, activate Wnt signalling pathways and decrease enterocyte differentiation in co-cultured epithelial cells. In the mucosa of UC patients, M2 macrophages increase with chronicity and are associated with activation of epithelial Wnt signalling and diminution in enterocyte differentiation

Duodenal Adenomas and Cancer in MUTYH-associated Polyposis: An International Cohort Study

Although duodenal adenomas and cancer appear to occur significantly less frequently in autosomal recessive MUTYH-associated polyposis (MAP) than in autosomal dominant familial adenomatous polyposis (FAP),1 current guidelines recommend similar endoscopic surveillance for both disorders.2-4 This involves gastro-duodenoscopy starting at 25 to 35 years of age and repeated at intervals determined by Spigelman staging based on the number, size, histological type and degree of dysplasia of adenomas, and by ampullary staging. Case reports of duodenal cancers in MAP suggest that they may develop in the absence of advanced Spigelman stage benign disease and even without coexisting adenomas.1 Recent molecular analyses suggest thatMAPduodenal adenomashave a higher mutational burden than FAP adenomas and are more likely to harbor oncogenic drivermutations, such as those in KRAS.5 These apparent differences in the biology and natural history of duodenal polyposis in FAP and MAP challenge the assumption that the same surveillance should be applied in both conditions

Correction to: Putting genome-wide sequencing in neonates into perspective

The original version of this Article contained an error in the spelling of the author Pleuntje J. van der Sluijs, which was incorrectly given as Eline (P. J.) van der Sluijs. This has now been corrected in both the PDF and HTML versions of the Article