57 research outputs found
The importance of thyroid hormone sulfation during fetal development
Normal fetal development requires the presence of thyroid hormone. Disruption of any of the
processes regulating the bioavailability of thyroid hormone may contribute to congenital
anomalies. This thesis is focussed a) on the importance of thyroid hormone sulfation during fetal
development, and b) on the potential sulfation-disrupting effects of environmental chemicals such
as hydroxylated polychlorinated biphenyls (PCBs), because of potential pathogenetic
consequences of disturbed thyroid hormone sulfation for the development of organs, such as
lungs and brain.
In this general introduction, first some information is given on the development of fetal thyroid
status, and the importance of thyroid hormone for the development of organs such as the brain is
discussed. Secondly, Ihyroid hormone synthesis, transport and metabolism, which are all
processes regulating thyroid hormone bioavailability, are reviewed. Additionally, the role of
sulfation in thyroid hormone metabOlism, especially during fetal development, is addressed.
Furthermore, some general information on PCBs and other polyhalogenated aromatic
hydrocarbons is given, and their potential estrogen and thyroid hormone-disrupting effects are
discussed. Finally, the outline of this thesis is presented
Characterization of iodothyronine sulfatase activities in human and rat liver and placenta
In conditions associated with high serum iodothyronine sulfate
concentrations, e.g. during fetal development, desulfation of these
conjugates may be important in the regulation of thyroid hormone
homeostasis. However, little is known about which sulfatases are involved
in this process. Therefore, we investigated the hydrolysis of
iodothyronine sulfates by homogenates of V79 cells expressing the human
arylsulfatases A (ARSA), B (ARSB), or C (ARSC; steroid sulfatase), as well
as tissue fractions of human and rat liver and placenta. We found that
only the microsomal fraction from liver and placenta hydrolyzed
iodothyronine sulfates. Among the recombinant enzymes only the endoplasmic
reticulum-associated ARSC showed activity toward iodothyronine sulfates;
the soluble lysosomal ARSA and ARSB were inactive. Recombinant ARSC as
well as human placenta microsomes hydrolyzed iodothyronine sulfates with a
substrate preference for 3,3'-diiodothyronine sulfate (3,3'-T(2)S)
approximately T(3) sulfate (T(3)S) >> rT(3)S approximately T(4)S, whereas
human and rat liver microsomes showed a preference for 3,3'-T(2)S > T(3)S
>> rT(3)S approximately T(4)S. ARSC and the tissue microsomal sulfatases
were all characterized by high apparent K(m) values (>50 microM) for
3,3'-T(2)S and T(3)S. Iodothyronine sulfatase activity determined using
3,3'-T(2)S as a substrate was much higher in human liver microsomes than
in human placenta microsomes, although ARSC is expressed at higher levels
in human placenta than in human liver. The ratio of estrone sulfate to
T(2)S hydrolysis in human liver microsomes (0.2) differed largely from
that in ARSC homogenate (80) and human placenta microsomes (150). These
results suggest that ARSC accounts for the relatively low iodothyronine
sulfatase activity of human placenta, and that additional arylsulfatase(s)
contributes to the high iodothyronine sulfatase activity in human liver.
Further research is needed to identify these iodothyronine sulfatases, and
to study the physiological importance of the reversible sulfation of
iodothyronines in thyroid hormone metabolism
Characterization of human iodothyronine sulfotransferases
Sulfation is an important pathway of thyroid hormone metabolism that
facilitates the degradation of the hormone by the type I iodothyronine
deiodinase, but little is known about which human sulfotransferase
isoenzymes are involved. We have investigated the sulfation of the
prohormone T4, the active hormone T3, and the metabolites rT3 and
3,3'-diiodothyronine (3,3'-T2) by human liver and kidney cytosol as well
as by recombinant human SULT1A1 and SULT1A3, previously known as
phenol-preferring and monoamine-preferring phenol sulfotransferase,
respectively. In all cases, the substrate preference was 3,3'-T2 >> rT3 >
T3 > T4. The apparent Km values of 3,3'-T2 and T3 [at 50 micromol/L
3'-phosphoadenosine-5'-phosphosulfate (PAPS)] were 1.02 and 54.9
micromol/L for liver cytosol, 0.64 and 27.8 micromol/L for kidney cytosol,
0.14 and 29.1 micromol/L for SULT1A1, and 33 and 112 micromol/L for
SULT1A3, respectively. The apparent Km of PAPS (at 0.1 micromol/L 3,3'-T2)
was 6.0 micromol/L for liver cytosol, 9.0 micromol/L for kidney cytosol,
0.65 micromol/L for SULT1A1, and 2.7 micromol/L for SULT1A3. The sulfation
of 3,3'-T2 was inhibited by the other iodothyronines in a
concentration-dependent manner. The inhibition profiles of the 3,3'-T2
sulfotransferase activities of liver and kidney cytosol obtained by
addition of 10 micromol/L of the various analogs were better correlated
with the inhibition profile of SULT1A1 than with that of SULT1A3. These
results indicate similar substrate specificities for iodothyronine
sulfation by native human liver and kidney sulfotransferases and
recombinant SULT1A1 and SULT1A3. Of the latter, SULT1A1 clearly shows the
highest affinity for both iodothyronines and PAPS, but it remains to be
established whether it is the prominent isoenzyme for sulfation of thyroid
hormone in human liver and kidney
Implementation of paediatric precision oncology into clinical practice: The Individualized Therapies for Children with cancer program ‘iTHER’
iTHER is a Dutch prospective national precision oncology program aiming to define tumour molecular profiles in children and adolescents with primary very high-risk, relapsed, or refractory paediatric tumours. Between April 2017 and April 2021, 302 samples from 253 patients were included. Comprehensive molecular profiling including low-coverage whole genome sequencing (lcWGS), whole exome sequencing (WES), RNA sequencing (RNA-seq), Affymetrix, and/or 850k methylation profiling was successfully performed for 226 samples with at least 20% tumour content. Germline pathogenic variants were identified in 16% of patients (35/219), of which 22 variants were judged causative for a cancer predisposition syndrome. At least one somatic alteration was detected in 204 (90.3%), and 185 (81.9%) were considered druggable, with clinical priority very high (6.1%), high (21.3%), moderate (26.0%), intermediate (36.1%), and borderline (10.5%) priority. iTHER led to revision or refinement of diagnosis in 8 patients (3.5%). Temporal heterogeneity was observed in paired samples of 15 patients, indicating the value of sequential analyses. Of 137 patients with follow-up beyond twelve months, 21 molecularly matched treatments were applied in 19 patients (13.9%), with clinical benefit in few. Most relevant barriers to not applying targeted therapies included poor performance status, as well as limited access to drugs within clinical trial. iTHER demonstrates the feasibility of comprehensive molecular profiling across all ages, tumour types and stages in paediatric cancers, informing of diagnostic, prognostic, and targetable alterations as well as reportable germline variants. Therefore, WES and RNA-seq is nowadays standard clinical care at the Princess Máxima Center for all children with cancer, including patients at primary diagnosis. Improved access to innovative treatments within biology-driven combination trials is required to ultimately improve survival
Implementation of paediatric precision oncology into clinical practice: The Individualized Therapies for Children with cancer program ‘iTHER’
iTHER is a Dutch prospective national precision oncology program aiming to define tumour molecular profiles in children and adolescents with primary very high-risk, relapsed, or refractory paediatric tumours. Between April 2017 and April 2021, 302 samples from 253 patients were included. Comprehensive molecular profiling including low-coverage whole genome sequencing (lcWGS), whole exome sequencing (WES), RNA sequencing (RNA-seq), Affymetrix, and/or 850k methylation profiling was successfully performed for 226 samples with at least 20% tumour content. Germline pathogenic variants were identified in 16% of patients (35/219), of which 22 variants were judged causative for a cancer predisposition syndrome. At least one somatic alteration was detected in 204 (90.3%), and 185 (81.9%) were considered druggable, with clinical priority very high (6.1%), high (21.3%), moderate (26.0%), intermediate (36.1%), and borderline (10.5%) priority. iTHER led to revision or refinement of diagnosis in 8 patients (3.5%). Temporal heterogeneity was observed in paired samples of 15 patients, indicating the value of sequential analyses. Of 137 patients with follow-up beyond twelve months, 21 molecularly matched treatments were applied in 19 patients (13.9%), with clinical benefit in few. Most relevant barriers to not applying targeted therapies included poor performance status, as well as limited access to drugs within clinical trial. iTHER demonstrates the feasibility of comprehensive molecular profiling across all ages, tumour types and stages in paediatric cancers, informing of diagnostic, prognostic, and targetable alterations as well as reportable germline variants. Therefore, WES and RNA-seq is nowadays standard clinical care at the Princess Máxima Center for all children with cancer, including patients at primary diagnosis. Improved access to innovative treatments within biology-driven combination trials is required to ultimately improve survival
Creating space for agency: a conceptual framework to understand and study adolescents’ school engagement from a Funds of Identity perspective
A conceptual framework is presented to understand and study the role of students’ agency in their school (dis-)engagement from a Funds of Identity (FoI) perspective. The framework includes the notion of agency combined with Funds of Learner Identity (FoLI): learning preferences that can be considered part of people’s Funds of Identity. The framework holds that students manifest agency to negotiate engaging learning experiences when the school’s affordances and constraints are considerably relatable to their FoLI and allow them to define themselves in desired ways. However, adolescents who feel that possibilities to engage their FoLI are rather limited in school are expected to turn to other contexts to learn, such as home, peer groups and workplaces. An exemplary case study is presented to illustrate the framework and implications are discussed
- …