Retrospective studies in mesenchymal tumours: clinical implications for the future

This thesis describes several retrospective studies in mesenchymal tumours. Sarcomas are the malignant variant and are very rare with an incidence of approximately 1000 patients per year in the Netherlands divided over more than 50 subtypes. It is essential to use the available patient data as much as possible.Due to its rarity, all stages of sarcomas are usually grouped in one study. This thesis shows that patients with distant metastatic disease have a worse prognosis compared to patients with locally advanced disease. To improve the prognosis of sarcoma patients, maintenance treatment after first line doxorubicin treatment is currently considered. However, we show that only 33% of the patients qualifies for maintenance treatment. Patients that qualify for maintenance treatment have a significantly better prognosis than all doxorubicin treated sarcoma patients.Further, this thesis describes several rare side effects and treatment for this side effect of treatment in mesenchymal tumours and it reports the incidences of giant cell tumours of bone and gastro-intestinal stromal tumours . It also studies the outcomes of non-surgical treatment options for desmoid-type fibromatosis. Last, the outcomes of ifosfamide treatment as second line treatment for osteosarcoma are reported.LUMC / Geneeskund

Voortzetting van een traditie. Kerkeraadsacta gereformeerd Leiden januari-april 1650

Wetensch. publicatieFaculty of Theolog

Application of the Benthic Ecosystem Quality Index 2 to benthos in Dutch transitional and coastal waters

The Benthic Ecosystem Quality Index 2 (BEQI2) is the Dutch multi-metric index (MMI) for assessing the status and trend of benthic invertebrates in transitional and coastal waters for the Water Framework Directive (WFD). It contains the same indicators, i.e. species richness, Shannon index and AMBI, as in the multivariate m-AMBI. The latter MMI has been adopted by several European countries in the context of WFD implementation. In contrast to m-AMBI, the BEQI2 calculation procedure has been strongly simplified and consists of two steps, i.e. the separate indicator values are normalized using their long-term reference values resulting in three Ecological Quality Ratios (EQRs), which are subsequently averaged to give one BEQI2 value. Using this method only small numbers of samples need to be analysed by Dutch benthos laboratories annually, without the necessity to co-analyse a larger historical dataset. BEQI2 EQR values appeared to correlate quantitatively very well with m-AMBI EQR values. In addition, a data pooling procedure has been added to the BEQI2 tool which enables the pooling of small core samples (0.01–0.025 m²) into larger standardized data pools of 0.1 m² in order to meet the data requirements of the AMBI indicator and to obtain comparable reference values. Furthermore, the BEQI2 tool automatically and efficiently converts species synonym names into standardized species names. The BEQI2 tool has been applied to all Dutch benthos data monitored by Rijkswaterstaat in the period of 1991–2010 in the transitional and coastal waters and salt lakes and these results are reported here for the first time. Reference values for species richness and Shannon index (99 percentile values) and AMBI reference values (1 percentile values) were estimated for all water body–ecotopes and are discussed. BEQI2 results for all these water bodies are discussed in view of natural and human pressures. The pressure sensitivity of the BEQI2 for sewage and dredging/dumping, via the state variables oxygen and suspended matter respectively, was demonstrated

A remarkable response to pazopanib, despite recurrent liver toxicity, in a patient with a high grade endometrial stromal sarcoma, a case report

Experimentele farmacotherapi

Perforin proteostasis is regulated through its C2 domain: supra-physiological cell death mediated by T431D-perforin

The pore forming, Ca2+-dependent protein, perforin, is essential for the function of cytotoxic lymphocytes, which are at the frontline of immune defence against pathogens and cancer. Perforin is a glycoprotein stored in the secretory granules prior to release into the immune synapse. Congenital perforin deficiency causes fatal immune dysregulation, and is associated with various haematological malignancies. At least 50% of pathological missense mutations in perforin result in protein misfolding and retention in the endoplasmic reticulum. However, the regulation of perforin proteostasis remains unexplored. Using a variety of biochemical assays that assess protein stability and acquisition of complex glycosylation, we demonstrated that the binding of Ca2+ to the C2 domain stabilises perforin and regulates its export from the endoplasmic reticulum to the secretory granules. As perforin is a thermo-labile protein, we hypothesised that by altering its C2 domain it may be possible to improve protein stability. On the basis of the X-ray crystal structure of the perforin C2 domain, we designed a mutation (T431D) in the Ca2+ binding loop. Mutant perforin displayed markedly enhanced thermal stability and lytic function, despite its trafficking from the endoplasmic reticulum remaining unchanged. Furthermore, by introducing the T431D mutation into A90V perforin, a pathogenic mutation, which results in protein misfolding, we corrected the A90V folding defect and completely restored perforin’s cytotoxic function. These results revealed an unexpected role for the Ca2+-dependent C2 domain in maintaining perforin proteostasis and demonstrated the possibility of designing perforin with supra-physiological cytotoxic function through stabilisation of the C2 domain

Higher incidence rates than previously known in tenosynovial giant cell tumors A nationwide study in The Netherlands

Molecular tumour pathology - and tumour geneticsMTG

Infeasibility in automatic test assembly models: a comparison study of different methods

Several techniques exist to automatically put together a test meeting a number of specifications. In an item bank, the items are stored with their characteristics. A test is constructed by selecting a set of items that fulfills the specifications set by the test assembler. Test assembly problems are often formulated in terms of a model consisting of restrictions and an objective to be maximized or minimized. A problem arises when it is impossible to construct a test from the item pool that meets all specifications, that is, when the model is not feasible. Several methods exist to handle these infeasibility problems. In this article, test assembly models resulting from two practical testing programs were reconstructed to be infeasible. These models were analyzed using methods that forced a solution (Goal Programming, Multiple-Goal Programming, Greedy Heuristic), that analyzed the causes (Relaxed and Ordered Deletion Algorithm (RODA), Integer Randomized Deletion Algorithm (IRDA), Set Covering (SC), and Item Sampling), or that analyzed the causes and used this information to force a solution (Irreducible Infeasible Set-Solver). Specialized methods such as the IRDA and the Irreducible Infeasible Set-Solver performed best. Recommendations about the use of different methods are given

Refinement and cross-validation of nickel bioavailability in pnec-pro, a regulatory tool for site-specific risk assessment of metals in surface water

Conservation Biolog