Synthesis and Evaluation of New Fluorine-18 Labeled Verapamil Analogs To Investigate the Function of P-Glycoprotein in the Blood-Brain Barrier

P-glycoprotein is an efflux transporter located in the blood brain barrier. (R)-[C-11]Verapamil is widely used as a PET tracer to investigate its function in patients with epilepsy, Alzheimer's disease, and other neurodegenerative diseases. Currently it is not possible to use this successful tracer in clinics without a cyclotron, because of the short half-life of carbon-11. We developed two new fluorine-18 labeled (R)-verapamil analogs, with the benefit of a longer half-life. The synthesis of (R)-N[F-18]fluoroethylverapamil ([F-18]1) and (R)-O-[F-18]fluoroethylnorverapamil ([F-18]2) has been described. [F-18]1 was obtained in reaction of (R)-norverapamil with the volatile [F-18]fluoroethyltriflate acquired from bromoethyltosylate and a silver trilate column with a radiochemical yield of 2.7% +/- 1.2%. [F-18]2 was radiolabeled by direct fluorination of precursor 13 and required final Boc-deprotection with TFA resulting in a radiochemical yield of 17.2% 9.9%. Both tracers, [F-18]1 and [F-18]2, were administered to Wistar rats, and blood plasma and brain samples were analyzed for metabolic stability. Using [F-18] 1 and [F-18]2, PET scans were performed in Wistar rats at baseline and after blocking with tariquidar, showing a 3.6-and 2.4-fold increase in brain uptake in the blocked rats, respectively. In addition, for both [F-18]1 and [F-18]2, PET scans in Mdri1a/b((-1-)), Bcrpl((-1-)), and WT mice were acquired, in which [F-18]2 showed a more specific brain uptake in MdrIa/b((-1-)) mice and no increased signal in Bcrpl((-/-)) mice. [F-18]2 was selected as the best performing tracer and should be evaluated further in clinical studies

High Fat Diet Increases Circulating Endocannabinoids Accompanied by Increased Synthesis Enzymes in Adipose Tissue

The endocannabinoid system (ECS) controls energy balance by regulating both energy intake and energy expenditure. Endocannabinoid levels are elevated in obesity suggesting a potential causal relationship. This study aimed to elucidate the rate of dysregulation of the ECS, and the metabolic organs involved, in diet-induced obesity. Eight groups of age-matched male C57Bl/6J mice were randomized to receive a chow diet (control) or receive a high fat diet (HFD, 45% of calories derived from fat) ranging from 1 day up to 18 weeks before euthanasia. Plasma levels of the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (N-arachidonoylethanolamine, AEA), and related N-acylethanolamines, were quantified by UPLC-MS/MS and gene expression of components of the ECS was determined in liver, muscle, white adipose tissue (WAT) and brown adipose tissue (BAT) during the course of diet-induced obesity development. HFD feeding gradually increased 2-AG (+132% within 4 weeks, P < 0.05), accompanied by upregulated expression of its synthesizing enzymes Daglα and β in WAT and BAT. HFD also rapidly increased AEA (+81% within 1 week, P < 0.01), accompanied by increased expression of its synthesizing enzyme Nape-pld, specifically in BAT. Interestingly, Nape-pld expression in BAT correlated with plasma AEA levels (R2 = 0.171, β = 0.276, P < 0.001). We conclude that a HFD rapidly activates adipose tissue depots to increase the synthesis pathways of endocannabinoids that may aggravate the development of HFD-induced obesity

Afstudeerwerk

Preface In nummer 2 van 2022 introduceerde het Bulletin KNOB een tweejaarlijkse rubriek ‘afstudeerwerk’, waarin de studenten die hadden meegedongen naar de KNOB Stimuleringsprijs 2021 hun onderzoek presenteerden. In dit nummer vindt u de tweede editie van die rubriek. Het bevat samenvattingen van scripties ingezonden voor de KNOB Stimuleringsprijs 2023. De zestien scripties zijn geschreven aan twee Belgische universiteiten (Katholieke Universiteit Leuven en Vrije Universiteit Brussel), vier Nederlandse (Rijksuniversiteit Groningen, Technische Universiteit Delft, Universiteit Utrecht, Universiteit van Amsterdam) en een hogeschool (Inholland Delft). Ze behandelen herkenbare architectuurhistorische thema’s als de negentiendeeeuwse arbeiderswoning, plafondontwerpen van Daniel Marot en historisch glas-in-lood, maar ook aanverwante onderwerpen als de ‘soundscape’ van de kerken van Christopher Wren, archeologisch erfgoed als herinneringsplaats, en – op het snijvlak van de architectuurhistorie en de sociale geschiedenis – de speeltuin tussen 1878 en 1978. De KNOB Stimuleringsprijs leidt tot meer. Het afstudeeronderzoek van Sara Duisters over kunststof gevels resulteerde al in een publicatie in het recente themanummer Post 65. Winnaar van de Stimuleringsprijs 2023 Lara Reyniers schreef voortbouwend op haar afstudeeronderzoek voor het huidige nummer samen met Stephanie Van de Voorde en Ine Wouters een artikel over de omgang met afbraakmaterialen in Brussel in de periode 1860-1940. Daarmee is dit nummer bijna volledig gevuld met het werk van jonge vakgenoten. In de bijdrage van Reyniers et al staan nu eens niet de creatie en bouw van architectuur centraal, maar de afbraak ervan, en dan met name het beleid ten aanzien van het sloopafval. De behandelde periode was er een van grootschalige stedelijke vernieuwing die veel afval opleverde, waaronder puin, bijzondere bouwfragmenten en van alles daar tussenin. Hoe de Brusselse overheid hiermee omging is interessant, zeker ook in het huidige tijdsgewricht, waarin sloop en sloopafval – nu vanuit een duurzaamheidsoogpunt – opnieuw in de aandacht staan. De redactieVoorwoord In nummer 2 van 2022 introduceerde het Bulletin KNOB een tweejaarlijkse rubriek ‘afstudeerwerk’, waarin de studenten die hadden meegedongen naar de KNOB Stimuleringsprijs 2021 hun onderzoek presenteerden. In dit nummer vindt u de tweede editie van die rubriek. Het bevat samenvattingen van scripties ingezonden voor de KNOB Stimuleringsprijs 2023. De zestien scripties zijn geschreven aan twee Belgische universiteiten (Katholieke Universiteit Leuven en Vrije Universiteit Brussel), vier Nederlandse (Rijksuniversiteit Groningen, Technische Universiteit Delft, Universiteit Utrecht, Universiteit van Amsterdam) en een hogeschool (Inholland Delft). Ze behandelen herkenbare architectuurhistorische thema’s als de negentiendeeeuwse arbeiderswoning, plafondontwerpen van Daniel Marot en historisch glas-in-lood, maar ook aanverwante onderwerpen als de ‘soundscape’ van de kerken van Christopher Wren, archeologisch erfgoed als herinneringsplaats, en – op het snijvlak van de architectuurhistorie en de sociale geschiedenis – de speeltuin tussen 1878 en 1978. De KNOB Stimuleringsprijs leidt tot meer. Het afstudeeronderzoek van Sara Duisters over kunststof gevels resulteerde al in een publicatie in het recente themanummer Post 65. Winnaar van de Stimuleringsprijs 2023 Lara Reyniers schreef voortbouwend op haar afstudeeronderzoek voor het huidige nummer samen met Stephanie Van de Voorde en Ine Wouters een artikel over de omgang met afbraakmaterialen in Brussel in de periode 1860-1940. Daarmee is dit nummer bijna volledig gevuld met het werk van jonge vakgenoten. In de bijdrage van Reyniers et al staan nu eens niet de creatie en bouw van architectuur centraal, maar de afbraak ervan, en dan met name het beleid ten aanzien van het sloopafval. De behandelde periode was er een van grootschalige stedelijke vernieuwing die veel afval opleverde, waaronder puin, bijzondere bouwfragmenten en van alles daar tussenin. Hoe de Brusselse overheid hiermee omging is interessant, zeker ook in het huidige tijdsgewricht, waarin sloop en sloopafval – nu vanuit een duurzaamheidsoogpunt – opnieuw in de aandacht staan. De redacti

Folate Receptor-Beta Has Limited Value for Fluorescent Imaging in Ovarian, Breast and Colorectal Cancer

Aims Tumor-specific targeted imaging is rapidly evolving in cancer diagnosis. The folate receptor alpha (FR-alpha) has already been identified as a suitable target for cancer therapy and imaging. FR-alpha is present on similar to 40% of human cancers. FR-beta is known to be expressed on several hematologic malignancies and on activated macrophages, but little is known about FR-beta expression in solid tumors. Additional or simultaneous expression of FR-beta could help extend the indications for folate-based drugs and imaging agents. In this study, the expression pattern of FR-beta is evaluated in ovarian, breast and colorectal cancer. Methods FR-beta expression was analyzed by semi-quantitative scoring of immunohistochemical staining on tissue microarrays (TMAs) of 339 ovarian cancer patients, 418 breast cancer patients, on 20 slides of colorectal cancer samples and on 25 samples of diverticulitis. Results FR-beta expression was seen in 21% of ovarian cancer samples, 9% of breast cancer samples, and 55% of colorectal cancer samples. Expression was weak or moderate. Of the diverticulitis samples, 80% were positive for FR-beta expression in macrophages. FR-beta status neither correlated to known disease-related variables, nor showed association with overall survival and progression free survival in ovarian and breast cancer. In breast cancer, negative axillary status was significantly correlated to FR-beta expression (p=0.022). Conclusions FR-beta expression was low or absent in the majority of ovarian, breast and colorectal tumor samples. From the present study we conclude that the low FR-beta expression in ovarian and breast tumor tissue indicates limited practical use of this receptor in diagnostic imaging and therapeutic purposes. Due to weak expression, FR-beta is not regarded as a suitable target in colorectal cancer

multicentre analysis, I-MOVE-COVID-19 and ECDC networks, July to August 2021

Funding Information: This project received funding from the European Centre for Disease Prevention and Control (ECDC) under the contract ECD.11486. Funding Information: This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 101003673. Publisher Copyright: © 2022 European Centre for Disease Prevention and Control (ECDC). All rights reserved.Introduction: In July and August 2021, the SARS-CoV-2 Delta variant dominated in Europe. Aim: Using a multicentre test-negative study, we measured COVID-19 vaccine effectiveness (VE) against symptomatic infection. Methods: Individuals with COVID-19 or acute respiratory symptoms at primary care/community level in 10 European countries were tested for SARS-CoV-2. We measured complete primary course overall VE by vaccine brand and by time since vaccination. Results: Overall VE was 74% (95% CI: 69-79), 76% (95% CI: 71-80), 63% (95% CI: 48-75) and 63% (95% CI: 16-83) among those aged 30-44, 45-59, 60-74 and ≥ 75 years, respectively. VE among those aged 30-59 years was 78% (95% CI: 75-81), 66% (95% CI: 58-73), 91% (95% CI: 87-94) and 52% (95% CI: 40-61), for Comirnaty, Vaxzevria, Spikevax and COVID-19 Vaccine Janssen, respectively. VE among people 60 years and older was 67% (95% CI: 52-77), 65% (95% CI: 48-76) and 83% (95% CI: 64-92) for Comirnaty, Vaxzevria and Spikevax, respectively. Comirnaty VE among those aged 30-59 years was 87% (95% CI: 83-89) at 14-29 days and 65% (95% CI: 56-71%) at ≥ 90 days between vaccination and onset of symptoms. Conclusions: VE against symptomatic infection with the SARS-CoV-2 Delta variant varied among brands, ranging from 52% to 91%. While some waning of the vaccine effect may be present (sample size limited this analysis to only Comirnaty), protection was 65% at 90 days or more between vaccination and onset.publishersversionpublishe

Correction:How the COVID-19 pandemic highlights the necessity of animal research (vol 30, pg R1014, 2020)

(Current Biology 30, R1014–R1018; September 21, 2020) As a result of an author oversight in the originally published version of this article, a number of errors were introduced in the author list and affiliations. First, the middle initials were omitted from the names of several authors. Second, the surname of Dr. van Dam was mistakenly written as “Dam.” Third, the first name of author Bernhard Englitz was misspelled as “Bernard” and the surname of author B.J.A. Pollux was misspelled as “Pullox.” Finally, Dr. Keijer's first name was abbreviated rather than written in full. These errors, as well as various errors in the author affiliations, have now been corrected online

The LifeCycle Project-EU Child Cohort Network : a federated analysis infrastructure and harmonized data of more than 250,000 children and parents

Early life is an important window of opportunity to improve health across the full lifecycle. An accumulating body of evidence suggests that exposure to adverse stressors during early life leads to developmental adaptations, which subsequently affect disease risk in later life. Also, geographical, socio-economic, and ethnic differences are related to health inequalities from early life onwards. To address these important public health challenges, many European pregnancy and childhood cohorts have been established over the last 30 years. The enormous wealth of data of these cohorts has led to important new biological insights and important impact for health from early life onwards. The impact of these cohorts and their data could be further increased by combining data from different cohorts. Combining data will lead to the possibility of identifying smaller effect estimates, and the opportunity to better identify risk groups and risk factors leading to disease across the lifecycle across countries. Also, it enables research on better causal understanding and modelling of life course health trajectories. The EU Child Cohort Network, established by the Horizon2020-funded LifeCycle Project, brings together nineteen pregnancy and childhood cohorts, together including more than 250,000 children and their parents. A large set of variables has been harmonised and standardized across these cohorts. The harmonized data are kept within each institution and can be accessed by external researchers through a shared federated data analysis platform using the R-based platform DataSHIELD, which takes relevant national and international data regulations into account. The EU Child Cohort Network has an open character. All protocols for data harmonization and setting up the data analysis platform are available online. The EU Child Cohort Network creates great opportunities for researchers to use data from different cohorts, during and beyond the LifeCycle Project duration. It also provides a novel model for collaborative research in large research infrastructures with individual-level data. The LifeCycle Project will translate results from research using the EU Child Cohort Network into recommendations for targeted prevention strategies to improve health trajectories for current and future generations by optimizing their earliest phases of life.Peer reviewe

Samen werken aan feitenonderzoek: Een studie naar verbeterpunten voor participatie, kwaliteit van feitenonderzoek en rapportage

Het Nederlands Jeugdinstituut is gevraagd goede en minder goede voorbeelden van feitenonderzoek te beschrijven, naar aanleiding van het Actieplan Verbetering Feitenonderzoek in de Jeugdbeschermingsketen, dat de gecertificeerde instellingen, de Raad voor de Kinderbescherming en Veilig Thuis in 2018 opstelden. De onderzoekers spraken daarvoor met professionals, cliënten en beleidsmakers van organisaties uit de jeugdbeschermingsketen. Het feitenonderzoek in de jeugdbescherming vraagt om verbeteringen en daar zijn mogelijkheden voor, blijkt uit de studie. Daarbij is het belangrijk dat professionals en cliënten samenwerken op basis van zo veel mogelijk gelijkwaardigheid, ondanks het gedwongen karakter van die samenwerking

Efficient Synthesis and Molecular Structure of 2-Hydroxyisophthaldehyde

A new highly effective procedure has been developed for the preparation of 2-hydroxyisophthaldehyde from 2,6-dimethylphenol. The X-ray crystal structure shows infinite chains of molecules joined by hydrogen bonds.