Sphingosine Kinases in B-lineage Acute Lymphoblastic Leukaemia

The work presented in this thesis examines firstly, the effects of the sphingosine like immunomodulatory drug FTY720 on B-lineage acute lymphoblastic leukaemia (ALL) cells. Secondly, the research focuses on a related area, namely, the intra-cellular enzymes called sphingosine kinases (SphKs). FTY720 resulted in cytotoxic effects and the induction of autophagy, in vitro in ALL cells. However, disparate in vivo effects were seen in Ph+ and Ph- ALL with a reduction in disease burden seen only in the former, highlighting the importance of pharmacological testing in both in vitro and in vivo settings. Sphingosine kinase 1 (SphK1) and sphingosine kinase 2 (SphK2) are over-expressed in ALL with inhibition producing cytotoxic effects, autophagy and predominantly caspase-independent cell death. SphK1 and SphK2 gene deletion resulted in reduced leukaemia penetrance in a murine Ph+ ALL disease model and SphK2 inhibition reduced the growth of human ALL xenografts. SphK2 inhibition resulted in lower MYC gene and protein expression through reduced association of acetylated histone H3 with the MYC promoter. This establishes a completely novel insight into the interactions of SphK2 in ALL and signifies the importance of sphingolipid signalling in this aggressive malignancy

Is eenvoudig beter? : Twee essays over natuur en landschap in het nieuwe omgevingsbeleid

This report includes two essays on the foundations of planning and environmental policy, focusing on natureand landscape. At a time when policy is changing, it is important to reflect on the foundations of thesepolicies, specifically on the question ‘What wisdom in caring for the environment?’ To reflect on this questionthe thinking of pioneers of regional planning, nature conservation and landscape management is linked withthat of a number of contemporary philosophers. The resulting proposal to consider environmental care as an‘anhropo-technique’, for which societal learning is crucial, implies a curbing of the standard thinking and aclear definition of the public interest, also at the national level. The second essay argues for a better use ofspatial planning policy to support objectives for nature and the landscape. Besides the Environment andPlanning Act, this should include the development and deployment of ‘policy arrangements’ that reflectvarious perspectives on nature and landscape---Dit rapport bevat twee essays over de grondslagen voor het omgevingsbeleid toegespitst op natuur enlandschap. In een periode waarin het beleid voor de omgeving sterk verandert, is het belangrijk om tereflecteren op de grondslagen van dit beleid. Wat is wijsheid in de zorg voor de omgeving? Daartoe wordt inhet eerste essay het denken van pioniers van de ruimtelijke ordening, het natuurbeheer en hetlandschapsonderhoud gerelateerd aan een aantal hedendaagse filosofen. Dit leidt tot het voorstel om deomgevingszorg te zien als een antropotechniek waarin maatschappelijke oefening centraal staat. Ditimpliceert onder meer een beperking van het norm-denken en een heldere definitie van het publieke belang,ook op nationaal niveau. Het tweede essay bepleit om het ruimtelijk beleid beter in te zetten voor natuur- enlandschapsopgaven. Het gaat daarbij naast de Omgevingswet om het ontwikkelen en benutten vanruimtelijke beleidsarrangementen die aansluiten bij verschillende kijkrichtingen naar natuur en landscha

Evaluatie landinrichtingsinstrumentarium Wet inrichting landelijk gebied

Deze beleids- en wetsevaluatie van de landinrichtingsregels uit de Wet inrichting landelijk gebied toont dat inzet van het landinrichtingsinstrumentarium voor doorzettingsmacht zorgt bij de aanpak van meervoudige inrichtingsopgaven in het landelijk gebied. Doorzettingsmacht alleen is hiervoor echter niet voldoende. Om succes te hebben moeten gebiedspartijen ervan overtuigd zijn dat landinrichting nodig is en zich mede-eigenaar voelen van het proces. De meerwaarde van landinrichting ten opzichte van integrale vrijwillige gebiedsprocessen bestaat uit meer zekerheid over doelbereik voor de overheid, realisatie van een optimale verkaveling, meer rechtszekerheid voor belanghebbenden en de mogelijkheid om meerdere verwervingsinstrumenten in te zetten. Ondanks deze voordelen is het aantal landinrichtingsprojecten de afgelopen decennia gestaag afgenomen. Veel provincies associëren landinrichting met langdurige en ingewikkelde processen en/of vinden het instrumentarium niet passen bij de aard van de huidige opgaven. Verder schrikken zij vaak terug voor het dwingende karakter van landinrichting. Wijzigingen in de Wilg en recente procesvernieuwingen hebben aan deze beeldvorming weinig veranderd

Variation in the management of benign liver tumors: a European survey and case vignette study

Background: Management of focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA), is multidisciplinary and subject to practice variation. We aimed to evaluate variation in clinical management of FNH and HCA in Europe.Methods: We distributed an online survey (November 2021-March 2022) among 294 European experts. The survey included questions on local practice and included eight clinical vignettes. The clinical vignettes focused on FNH or HCA management in the setting of sex, lifestyle modifi-cation, and pregnancy.Results: The response rate was 32% and respondents included surgeons (38%), gastroenterolo-gists/hepatologists (25%), radiologists (32%), and pathologists (1.6%) from ten European coun-tries. We observed practice variation with regard to lifestyle modification and imaging follow-up in patients with FNH, and with regard to the management of HCA >5 cm before and during pregnancy. Finally, the management of HCA >5 cm after lifestyle modification deviated from EASL guideline recommendations.Conclusion: Our survey illustrates variability in FNH and HCA management in Europe. Several areas were identified for future research and guideline recommendations, including FNH follow-up and the management of HCA >5 cm. We propose the organization of Delphi consensus meet-ings to prioritize areas of research and update current guidelines to optimize management for all patients with benign liver tumors.(c) 2023 Published by Elsevier Masson SAS.Radiolog

Protocol for a randomized controlled multicenter trial assessing the efficacy of leuprorelin for severe polycystic liver disease : the AGAINST-PLD study

Altres ajuts: Dutch Government (ZonMW grant 10140261910001); Abbvie (SA-003047 (ACA-NETH-20-01)).Background: In patients with severe polycystic liver disease (PLD), there is a need for new treatments. Estrogens and possibly other female sex hormones stimulate growth in PLD. In some patients, liver volume decreases after menopause. Female sex hormones could therefore be a target for therapy. The AGAINST-PLD study will examine the efficacy of the GnRH agonist leuprorelin, which blocks the production of estrogen and other sex hormones, to reduce liver growth in PLD. Methods: The AGAINST-PLD study is an investigator-driven, multicenter, randomized controlled trial. Institutional review board (IRB) approval was received at the University Medical Center of Groningen and will be collected in other sites before opening these sites. Thirty-six female, pre-menopausal patients, with a very large liver volume for age (upper 10% of the PLD population) and ongoing liver growth despite current treatment options will be randomized to direct start of leuprorelin or to 18 months standard of care and delayed start of leuprorelin. Leuprorelin is given as 3.75 mg subcutaneously (s.c.) monthly for the first 3 months followed by 3-monthly depots of 11.25 mg s.c. The trial duration is 36 months. MRI scans to measure liver volume will be performed at screening, 6 months, 18 months, 24 months and 36 months. In addition, blood will be drawn, DEXA-scans will be performed and questionnaires will be collected. This design enables comparison between patients on study treatment and standard of care (first 18 months) and within patients before and during treatment (whole trial). Main outcome is annualized liver growth rate compared between standard of care and study treatment. Secondary outcomes are PLD disease severity, change in liver growth within individuals and (serious) adverse events. The study is designed as a prospective open-label study with blinded endpoint assessment (PROBE). Discussion: In this trial, we combined the expertise of hepatologist, nephrologists and gynecologists to study the effect of leuprorelin on liver growth in PLD. In this way, we hope to stop liver growth, reduce symptoms and reduce the need for liver transplantation in severe PLD. Trial registration Eudra CT number 2020-005949-16, registered at 15 Dec 2020. https://www.clinicaltrialsregister.eu/ctr-search/search?query=2020-005949-16

Incident gallstones during somatostatin analog treatment are associated with acute biliary complications especially after discontinuation

Introduction Gallstones are a known adverse effect of somatostatin analogs, but the exact incidence and clinical implications are unknown.Objectives The aim of this study was to investigate the incidence of gallstones on imaging and related complications in unbiased trial data.Methods Data from the DIPAK 1 trial, in which 305 polycystic kidney disease patients were randomized to standard of care (SoC) or lanreotide for 120 weeks, were used. Magnetic resonance imaging (MRI) was performed at baseline and end of treatment and was assessed for the presence, number, and size of gallstones. For all patients who had gallstones at the end of the trial, we obtained follow-up after the trial.Results Of 249 patients with data available, 11 patients randomized to lanreotide and four randomized to SoC had gallstones at baseline. During the study, new gallstones were formed in 19/124 patients using lanreotide (15%) and 1/125 patients receiving SoC (1%). The odds ratio for gallstone formation with lanreotide use was 25.9 (95% confidence interval 3.37-198.8; p 20 stones in 69% of patients) and small (<= 3 mm in 63% of patients). Of the 19 patients with incident gallstones during lanreotide treatment, 9 experienced gallstone-associated complications, 8 of whom experienced gallstone-associated complications after discontinuation of treatment (median time after discontinuation 2.5 years). In patients with gallstones at baseline and in patients receiving SoC, no complications occurred.Conclusions Treatment with a somatostatin analog leads to the formation of multiple, small gallstones that are associated with severe complications, especially after discontinuation of therapy.Functional Genomics of Systemic Disorder

The oncological outcomes of isolated limb perfusion and neo-adjuvant radiotherapy in soft tissue sarcoma patients: a nationwide multicenter study

Introduction: Patients with locally extensive high-grade extremity soft tissue sarcomas (eSTS) are often presented in multidisciplinary teams to decide between ablative surgery (amputation) or limb-salvage surgery supplemented with either neo-adjuvant radiotherapy (RT) or induction isolated limb perfu-sion (ILP).In The Netherlands, ILP typically aims to reduce the size of tumors that would otherwise be considered irresectable, whereas neo-adjuvant RT aims mainly at improving local control and reducing morbidity of required marginal margins. This study presents a 15-year nationwide cohort to describe the oncological outcomes of both pre-operative treatment strategies.Methods: All consecutive patients with locally extensive primary high-grade eSTS surgically treated between 2000 and 2015 at five tertiary sarcoma centers that received neo-adjuvant ILP or RT were included. 169 patients met the inclusion criteria (89 ILP, 80 RT). Median follow-up was 7.3 years. Results: Limb salvage was achieved in 84% of cases in the ILP group (80% for patients with amputation indication) and 96% of cases in the RT group. 5-Year overall survival was 47% in the ILP group, 69% in the RT group. 5-Year local recurrence rate was 14% in the ILP group, 10% in the RT group. Distant metastasis rate was 55% in the ILP group, 36% in the RT group.Conclusion: We find oncological outcomes and limb salvage rates in line with existing literature for both treatment modalities. Whether the tumor was locally advanced with an indication for induction therapy to prevent amputation or morbid surgery appeared to be the main determinant in choosing between neo-adjuvant ILP or RT.(c) 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Orthopaedics, Trauma Surgery and Rehabilitatio

Strange particle production in 158 and 40 AA GeV/cc Pb-Pb and p-Be collisions

Results on strange particle production in Pb-Pb collisions at 158 and 40 $A$ GeV/$c$ beam momentum from the NA57 experiment at CERN SPS are presented. Particle yields and ratios are compared with those measured at RHIC. Strangeness enhancements with respect to p-Be reactions at the same beam momenta have been also measured: results about their dependence on centrality and collision energy are reported and discussed.Comment: Contribution to the proceedings of the "Hot Quarks 2004" Conference, July 18-24 2004, New Mexico, USA, submitted to Journal of Physics G 7 pages, 5 figure

Highly deformed 40^{40}Ca configurations in 28^{28}Si + 12^{12}C

The possible occurrence of highly deformed configurations in the $^{40}$Ca di-nuclear system formed in the $^{28}$Si + $^{12}$C reaction is investigated by analyzing the spectra of emitted light charged particles. Both inclusive and exclusive measurements of the heavy fragments (A $\geq$ 10) and their associated light charged particles (protons and $\alpha$ particles) have been made at the IReS Strasbourg {\sc VIVITRON} Tandem facility at bombarding energies of $E_{lab} (^{28}$Si) = 112 MeV and 180 MeV by using the {\sc ICARE} charged particle multidetector array. The energy spectra, velocity distributions, and both in-plane and out-of-plane angular correlations of light charged particles are compared to statistical-model calculations using a consistent set of parameters with spin-dependent level densities. The analysis suggests the onset of large nuclear deformation in $^{40}$Ca at high spin.Comment: 33 pages, 11 figure

Hypothermic machine perfusion in liver transplantation: a randomized trial

BACKGROUNDTransplantation of livers obtained from donors after circulatory death is associated with an increased risk of nonanastomotic biliary strictures. Hypothermic oxygenated machine perfusion of livers may reduce the incidence of biliary complications, but data from prospective, controlled studies are limited.METHODSIn this multicenter, controlled trial, we randomly assigned patients who were undergoing transplantation of a liver obtained from a donor after circulatory death to receive that liver either after hypothermic oxygenated machine perfusion (machine-perfusion group) or after conventional static cold storage alone (control group). The primary end point was the incidence of nonanastomotic biliary strictures within 6 months after transplantation. Secondary end points included other graft-related and general complications.RESULTSA total of 160 patients were enrolled, of whom 78 received a machine-perfused liver and 78 received a liver after static cold storage only (4 patients did not receive a liver in this trial). Nonanastomotic biliary strictures occurred in 6% of the patients in the machine-perfusion group and in 18% of those in the control group (risk ratio, 0.36; 95% confidence interval [CI], 0.14 to 0.94; P=0.03). Postreperfusion syndrome occurred in 12% of the recipients of a machine-perfused liver and in 27% of those in the control group (risk ratio, 0.43; 95% CI, 0.20 to 0.91). Early allograft dysfunction occurred in 26% of the machine-perfused livers, as compared with 40% of control livers (risk ratio, 0.61; 95% CI, 0.39 to 0.96). The cumulative number of treatments for nonanastomotic biliary strictures was lower by a factor of almost 4 after machine perfusion, as compared with control. The incidence of adverse events was similar in the two groups.CONCLUSIONSHypothermic oxygenated machine perfusion led to a lower risk of nonanastomotic biliary strictures following the transplantation of livers obtained from donors after circulatory death than conventional static cold storage.Cellular mechanisms in basic and clinical gastroenterology and hepatolog