Living in times of war: waste of c. 1600 from two garderobe chutes from the Castle of Middelburg-in-Flanders (Belgium)

The material remains and environmental data recovered during a rescue excavation in 2002-03 in the castle of the new town of Middelburg-in-Flanders throw light on the site, region and landscape in wartime. The paper discusses the historical context at the turn of the 16th century, the excavation of the castle, the taphonomy of the chutes, the analysis of the artefacts and ecological data recovered from two garderobe chutes in the upper court, and concludes with a synthesis focussing on the interpretation of the excavated record in the historically attested natural and socio-economic disruption caused by the Spanish-Dutch War

Preclinical studies performed in appropriate models could help identify optimal timing of combined chemotherapy and immunotherapy

Immune checkpoint inhibitors (ICI) have been revolutionary in the field of cancer therapy. However, their success is limited to specific indications and cancer types. Recently, the combination treatment of ICI and chemotherapy has gained more attention to overcome this limitation. Unfortunately, many clinical trials testing these combinations have provided limited success. This can partly be attributed to an inadequate choice of preclinical models and the lack of scientific rationale to select the most effective immune-oncological combination. In this review, we have analyzed the existing preclinical evidence on this topic, which is only limitedly available. Furthermore, this preclinical data indicates that besides the selection of a specific drug and dose, also the sequence or order of the combination treatment influences the study outcome. Therefore, we conclude that the success of clinical combination trials could be enhanced by improving the preclinical set up, in order to identify the optimal treatment combination and schedule to enhance the anti-tumor immunity

M & L Jaargang 11/6

GeneriekEloy Koldeweij Het goude leer. [Gold leather.]Historische binnenaankledingen blijven een nog nauwelijks ontgonnen onderzoeksterrein waar M&L graag met enige regelmaat plaats voor ruimt. Ooit fel gegeerd en met eigen Zuidnederlandse productiecentra, verdient goudleder in dit opzicht meer dan de gewone aandacht. Ontstaan en bloei - met de nadruk op de 17de en 18de eeuw - van dit merkwaardig ambachtelijk product worden door Eloy Koldeweij met een vanzelfsprekende eruditie meteen ook een Europese dimensie aangemeten.Ann Bergmans en Eloy Koldeweij Inventaris van het 17de- en 18de-eeuwse goudleder in Vlaanderen. [Inventory of the 17th and 18th century gold leather in Flanders.]Aansluitend op het totstandkomingsverhaal gingen Ann Bergmans en Eloy Koldeweij gezamenlijk op zoek naar wàt van deze kostbare goudledervellen in Vlaanderen bewaard bleef. Tegelijk, zo blijkt, verrassend veel maar ook bedroevend weinig.Of vormt deze inventaris slechts een eerste aanzet?Jan Wouters Opbouw en analyse van leder: een uiteenzetting voor een beter begrip van conservatorische problemen en ingrepen. [Structure and analysis of leather: fundamentals for a better understandig of conservation problems and treatments.]Meer nog dan reeds gebruikelijk veronderstelt de conserverende behandeling van goudleder een grondige kennis van het materiaal en aanmaakproces dan wel de afbraakmechanismen.Huid en looistoffen in het bijzonder maken voor Jan Wouters elk bereid vel immers vrijwel uniek. Meteen brengt hij de elementen aan voor een verantwoorde diagnose.An Peckstadt, Lieve Watteeuw en Jan Wouters Conservering van het goudlederbehang van de dekenij van Zele. [Conservation of the gold leather hangings from the deanery of Zele.]Van vele aftakelingsverschijnselen die de restauratieve aanpak van goudlederbehang onontkoombaar maken bood het ensemble in de dekenij van Zele een uitgelezen staalkaart. Redenen te over dus om de ingreep zelf te laten voorafgaan door een intensief vooronderzoek. An Peckstadt, Lieve Watteeuw en Jan Wouters illustreren met het relaas van deze opdracht nogmaals het belang van een interdisciplinaire benadering.Beter voorkomen dan genezen. Richtlijnen voor de bewaring van goudleder.SummaryM&L Binnenkran

Impact of critical illness and withholding of early parenteral nutrition in the pediatric intensive care unit on long-term physical performance of children:a 4-year follow-up of the PEPaNIC randomized controlled trial

Background: Many critically ill children face long-term developmental impairments. The PEPaNIC trial attributed part of the problems at the level of neurocognitive and emotional/behavioral development to early use of parenteral nutrition (early-PN) in the PICU, as compared with withholding it for 1 week (late-PN). Insight in long-term daily life physical functional capacity after critical illness is limited. Also, whether timing of initiating PN affects long-term physical function of these children remained unknown. Methods: This preplanned follow-up study of the multicenter PEPaNIC randomized controlled trial subjected 521 former critically ill children (253 early-PN, 268 late-PN) to quantitative physical function tests 4 years after PICU admission in Leuven or Rotterdam, in comparison with 346 age- and sex-matched healthy children. Tests included handgrip strength measurement, timed up-and-go test, 6-min walk test, and evaluation of everyday overall physical activity with an accelerometer. We compared these functional measures for the former critically ill and healthy children and for former critically ill children randomized to late-PN versus early-PN, with multivariable linear or logistic regression analyses adjusting for risk factors. Results: As compared with healthy children, former critically ill children showed less handgrip strength (p &lt; 0.0001), completed the timed up-and-go test more slowly (p &lt; 0.0001), walked a shorter distance in 6 min (p &lt; 0.0001) during which they experienced a larger drop in peripheral oxygen saturation (p ≤ 0.026), showed a lower energy expenditure (p ≤ 0.024), performed more light and less moderate physical activity (p ≤ 0.047), and walked fewer steps per day (p = 0.0074). Late-PN as compared with early-PN did not significantly affect these outcomes. Conclusions: Four years after PICU admission, former critically ill children showed worse physical performance as compared with healthy children, without impact of timing of supplemental PN in the PICU. This study provides further support for de-implementing the early use of PN in the PICU. Trial registration ClinicalTrials.gov, NCT01536275; registered on February 22, 2012.</p

The MDM2-inhibitor Nutlin-3 synergizes with cisplatin to induce p53 dependent tumor cell apoptosis in non-small cell lung cancer

The p53/MDM2 interaction has been a well-studied target for new drug design leading to the development of the small molecule inhibitor Nutlin-3. Our objectives were to combine Nutlin-3 with cisplatin (CDDP), a well-known activator of the p53 pathway, in a series of non-small cell lung cancer cell lines in order to increase the cytotoxic response to CDDP. We report that sequential treatment (CDDP followed by Nutlin-3), but not simultaneous treatment, resulted in strong synergism. Combination treatment induced p53's transcriptional activity, resulting in increased mRNA and protein levels of MDM2, p21, PUMA and BAX. In addition we report the induction of a strong p53 dependent apoptotic response and induction of G2/M cell cycle arrest. The strongest synergistic effect was observed at low doses of both CDDP and Nutlin-3, which could result in fewer (off-target) side effects while maintaining a strong cytotoxic effect. Our results indicate a promising preclinical potential, emphasizing the importance of the applied treatment scheme and the presence of wild type p53 for the combination of CDDP and Nutlin-3

The association of hypoglycemia with outcome of critically ill children in relation to nutritional and blood glucose control strategies

Abstract Background Withholding parenteral nutrition (PN) until one week after PICU admission facilitated recovery from critical illness and protected against emotional and behavioral problems 4 years later. However, the intervention increased the risk of hypoglycemia, which may have counteracted part of the benefit. Previously, hypoglycemia occurring under tight glucose control in critically ill children receiving early PN did not associate with long-term harm. We investigated whether hypoglycemia in PICU differentially associates with outcome in the context of withholding early PN, and whether any potential association with outcome may depend on the applied glucose control protocol. Methods In this secondary analysis of the multicenter PEPaNIC RCT, we studied whether hypoglycemia in PICU associated with mortality (N = 1440) and 4-years neurodevelopmental outcome (N = 674) through univariable comparison and multivariable regression analyses adjusting for potential confounders. In patients with available blood samples (N = 556), multivariable models were additionally adjusted for baseline serum NSE and S100B concentrations as biomarkers of neuronal, respectively, astrocytic damage. To study whether an association of hypoglycemia with outcome may be affected by the nutritional strategy or center-specific glucose control protocol, we further adjusted the models for the interaction between hypoglycemia and the randomized nutritional strategy, respectively, treatment center. In sensitivity analyses, we studied whether any association with outcome was different in patients with iatrogenic or spontaneous/recurrent hypoglycemia. Results Hypoglycemia univariably associated with higher mortality in PICU, at 90 days and 4 years after randomization, but not when adjusted for risk factors. After 4 years, critically ill children with hypoglycemia scored significantly worse for certain parent/caregiver-reported executive functions (working memory, planning and organization, metacognition) than patients without hypoglycemia, also when adjusted for risk factors including baseline NSE and S100B. Further adjustment for the interaction of hypoglycemia with the randomized intervention or treatment center revealed a potential interaction, whereby tight glucose control and withholding early PN may be protective. Impaired executive functions were most pronounced in patients with spontaneous or recurrent hypoglycemia. Conclusion Critically ill children exposed to hypoglycemia in PICU were at higher risk of impaired executive functions after 4 years, especially in cases of spontaneous/recurrent hypoglycemia

Laat- en postmiddeleeuwse sporen aan de Klapstraat te Aalst (Oost-Vlaanderen) Eindverslag van een toevalsvondst

Bij graafwerken voor de uitbreiding van het Sint-Jozefscollege werden verschillende archeologische sporen en vondsten opgemerkt. Een evaluatie op het terrein door de verantwoordelijke archeoloog van het agentschap maakte duidelijk dat het om een grote hoeveelheid waardevolle sporen en vondsten ging, die een registratie noodzakelijk maakte. De doorgedreven analyse van de verschillende materiaalcategorieën heeft tot meer en nieuwe inzichten geleid en zal op termijn toelaten om verfijningen door te voeren wat betreft de bewoningsgeschiedenis van dit specifiek stadsdeel en de kennis van de laatmiddeleeuwse stad in het algemeen

The radiosensitising effect of gemcitabine and its main metabolite dFdU under low oxygen conditions is in vitro not dependent on functional HIF-1 protein.

BACKGROUND: Regions within solid tumours often experience oxygen deprivation, which is associated with resistance to chemotherapy and irradiation. The aim of this study was to evaluate the radiosensitising effect of gemcitabine and its main metabolite dFdU under normoxia versus hypoxia and to determine whether hypoxia-inducible factor 1 (HIF-1) is involved in the radiosensitising mechanism. METHODS: Stable expression of dominant negative HIF-1α (dnHIF) in MDA-MB-231 breast cancer cells, that ablated endogenous HIF-1 transcriptional activity, was validated by western blot and functionality was assessed by HIF-1α activity assay. Cells were exposed to varying oxygen environments and treated with gemcitabine or dFdU for 24 h, followed by irradiation. Clonogenicity was then assessed. Using radiosensitising conditions, cells were collected for cell cycle analysis. RESULTS: HIF-1 activity was significantly inhibited in cells stably expressing dnHIF. A clear radiosensitising effect under normoxia and hypoxia was observed for both gemcitabine and dFdU. No significant difference in radiobiological parameters between HIF-1 proficient and HIF-1 deficient MDA-MB-231 cells was demonstrated. CONCLUSIONS: For the first time, radiosensitisation by dFdU, the main metabolite of gemcitabine, was demonstrated under low oxygen conditions. No major role for functional HIF-1 protein in radiosensitisation by gemcitabine or dFdU could be shown