762 research outputs found
Metrology of Nail Clippings as Trace Element Biomarkers
No full textRST/Radiation, Science and TechnologyApplied Science
Somatostatin-Receptors-Targeted Liposomes for MRI / SPEeT Dual Imaging Probes
No full textRRR/Radiation, Radionuclides and ReactorsApplied Science
A tracer aided study on silicon chemistry in biological systems
No full textSilicon (Si) is omnipresent in nature, and it is involved in important but diverse roles in a broad range of organisms, including diatoms, higher plants and humans. Some organisms, like the diatoms, need high amounts of silicon, and master silicon chemistry to a high extend using several enzymes. Other organisms which need silicon as an essential trace element apparently do not have the capability to handle silicon by any biochemical means and it was hypothesized that silicon chemistry as such plays a major role. The aim of the research described in this thesis was to gain more insight in the mechanisms behind the role of silicon in several organisms and to investigate to what extend silicon chemistry can play a role in biological processes. This study focused on the chemical or biological role of silicon in metal metabolism, on the risks that are connected to silicon polymerization, and on a possible application in biotechnology. For this a study was performed on Baker’s yeast Saccharomyces cerevisiae which often serves as a model organism for the eukaryotic cell (chapters 3 and 4), diatoms (chapter 5) and biofilms (bacterial communities attached to a surface, chapter 6). A silicon tracer was developed (chapter 2) to aid the studies described in this thesis. No-carrier added 31Si was produced by a 31P(n,p)31Si reaction by fast neutrons in the nuclear reactor of the Delft University of Technology. Several methods were investigated to remove the side product 32P. Anion exchange with Dowex resin gave the best results in total activity yield and specific activity, but precipitation with BaCO3 appeared to be the fastest and cheapest purification method, and sufficiently high yields were obtained as well. It was determined that the 31Si tracer was in the desired chemical form of silicic acid (Si(OH)4), and suitable to apply in biological systems. Since yeasts and biofilms do not possess any biochemical means to handle silicon, it is likely that any influence of silicon on these organisms has a chemical origin. This was investigated by studying the interaction of silicon and metals in these organisms. In chapter 3, the influence of silicon (as silicic acid Si(OH)4) on the growth rate and intracellular accumulation of a number of metals was investigated in Baker's yeast Saccharomyces cerevisiae, a model organism for the eukaryotic cell. It was found that the growth rate was not influenced by silicic acid up to concentrations of 10 mmol per liter growth medium and a slight growth inhibition was observed when silicate was present in an extremely high concentration of 100 mM. Intracellular metal concentrations were investigated in yeast cultures grown in normal culture medium without added silicate (-Si) or with the addition of 10 mmol/L silicate (+Si). Decreased amounts of Co, Mn and Fe were found within +Si grown yeast cultures as compared to -Si grown ones, while increased amounts of Mo and Mg were found. Zn and K were apparently unaffected by the presence of silicon. +Si enhanced yeast growth rate under low Zn2+ conditions, but decreased growth rate under low Mg2+ conditions. +Si did not alter the growth rates in high Zn2+ and Co2+ media. +Si doubled the uptake rate of Co2+, but did not influence that of Zn2+. It was proposed that these results could be explained by the formation of a polysilicate layer on the cell wall which changes the cell wall binding capacity for metal ions. The toxicity of silicic acid was compared to germanium (Ge, as GeO2), a member of the same group of elements as Si (group 14) and sometimes used in literature as a silicon analogue. Ge proved to be far more toxic to yeast than Si and no influence was found of Si on Ge toxicity. It was proposed that these results relate to differences in cellular uptake and that is not always possible to use Ge as a Si analogue. These results also indicated that a chemical mechanism, rather than a biological one, is important. This was further investigated by studying the influence of zinc and magnesium on Si-accumulation at several silicate concentrations in the medium by use of 31Si(OH)4 (chapter 4). Si-accumulation fitted well with Freundlich adsorption. Si-release followed depolymerization kinetics, indicating that silicate adsorbs to the surface of the cell rather than being transported over the cell membrane. Subsequently, adsorbed silicate interacts with metal ions and, therefore, alters the cell’s affinity for these ions. Since several metals are nutritional, these Si interactions can significantly change the growth and viability of organisms. In conclusion, the results show that chemistry is important in Si and metal accumulation in Baker’s yeast, and suggest that similar mechanisms should be studied in detail in other organisms to unravel essential roles of Si. The capability of silicon to adsorb on organic substances was also investigated in biofilms, bacterial communities linked together by extracellular polymeric substances (EPS) to study a possible application of silicon chemistry in a biological system. Biofilms have developed mechanisms to accumulate nutrients and organic substrates in their EPS matrix, probably to increase the substrate availability. It may be expected that the binding of ions by the EPS can result in interaction with silicon in the biofilm. Probably this interaction can be used for applications in civil engineering (e.g. biogrouting of soil). To study this the spatial distribution of silicate and phosphate binding in biofilms under different metal conditions was investigated (chapter 6). For this a new autoradiography method using 31Si (as silicic acid) accompanied by 32P (as phosphate) was developed. The equilibrium in silicon uptake was reached within minutes, so it was possible to quantify the 31Si signal, but for 32P this was not possible. Using this method it was shown that both silicon and phosphate bound heterogeneously to the biofilm. In addition, the metal concentrations in the growth medium affected the biofilm structure as well as the silicate and phosphate binding characteristics of the biofilm. In contrast to yeast and biofilms, diatoms master silicon chemistry to a high extend. Here it was investigated how diatoms cope with high amounts of silicon during valve formation as polymerization at/in vital structures should be avoided (chapter 5). Silicic acid uptake using 31Si(OH)4 was studied during valve formation in synchroneously dividing cells of the diatom Pleurosira laevis and other diatoms. Valve formation in diatoms requires bulk uptake and transport of silicic acid to the silica deposition vesicle (SDV). Two earlier proposed mechanisms for silicic acid uptake and transport were investigated: 1) uptake of silicon via silicon transporters (SITs) with subsequent intracellular transport, and 2) (macro)pinocytosis-mediated uptake. The SITs mechanism requires a controlled mechanism to stabilize the high amounts of reactive silicon species to prevent autopolymerization and simultaneously direct these species towards the SDV, whereas this problem does not play a role in the (macro)pinocytosis-mediated mechanism. Experimental data were correlated to systematically derived mathematical models for a compartmental analysis of the possible uptake/transport pathways, including those for both SITs- and (macro)pinocytosis-mediated uptake and transport. This study indicates that the experimental data on silicon uptake during valve formation match best with the model that describes (macro)pinocytosis-mediated uptake. This process not only explains observed surge uptake at high demands for silicon, but also suggests that another pathway exists in which SITs apparently are not involved. The study showed that the pinocytosis mechanism gave a good description of the uptake kinetics that were found in this study. This result offers a simple explanation for how the diatomic cell is able to fulfill its silicon needs without exposing the inner part of the cell to high silicic acid concentrations and the problems related to spontaneous polymerization. Further molecular and (bio)physical-chemical research is needed on diatom biosilicification. The results described in this thesis shed new light on the role of silicon chemistry in several bioprocesses. The influence of silicon on bioprocesses in yeast is probably from chemical origin, resulting from interactions with organic compounds and metals. These interactions, which also occur in biofilms, could also take place in higher organisms as well, and could probably explain at least part of the influence of silicon in biological processes in higher organisms. This may explain why despite many years of research biological binding sites or bioorganical compounds containing silicon have never been found (yet) except for some plants and for bulk consumers like the diatoms and some sponges. But when silicon chemistry itself is taken into account, enzymes and binding sites are probably not needed for silicon to do its job as an essential element. Further research is required on this subject to get clear-cut answers on this matter.Radiation, Radionuclides & ReactorsApplied Science
Whole Body Activity Retentions in the Peptide Receptor Radionuclide Therapy with Lu-177
No full textThe patients with the neuroendocrine tumours (liver, spleen, etc.) often need treatment by the Peptide Receptor Radionuclide Therapy with 177Lu. The amount of 177Lu activity in the body of patients has to be known accurately for assessment of the dosimetry and for evaluation of the effectiveness of the therapy. Whole-body activities at the given time after administration can be derived from measurements of the activity of a sub-sample from the excreted urine, collected by the patient him/herself. This approach has to be abandoned because it increases the radiation dose of analysts and nurses involved. Moreover, the collection is patient unfriendly; there is a high risk of contamination by spills, and therefore, a risk of incomplete collection. As such, it is not unlikely that the urine collection method results in an underestimated indication of the total amount of activity actually excreted. As a consequence, the urine collection method may render an overestimated value of the whole-body activity. On the other hand, it is an intrinsic problem that the measurement uncertainty of the whole-body activity derived from the urine collection method increases when the whole-body activity decreases with time. As an example, the expanded uncertainties of the whole-body activity were about ±4% (the coverage factor k=2) shortly after administration and up to >±20% at 24 h; however all expanded uncertainties of the activity of the collected urine were about ±3.4%. The objective of the research described in this thesis was to develop a patient friendly technique for an accurate estimate of the whole-body activity of 177Lu as an alternative for the collection of the excreted urine by patient themselves. Two methods, (i) direct measurement of the activity of the excreted urine in the toilet pot and (ii) paired whole-body measurements, have been developed to overcome the concerns. In the first method, the activity of the excreted urine was measured in the toilet pot itself. A small CeBr3 detector is positioned on the side wall of the toilet room, aligned to centre of the water in the toilet pot. The patient uses the toilet as normal but does not need to flush it. The only modification for the current toilet system is to replace the mechanical flushing by a delayed flushing. The activity of the excreted urine is measured directly in the toilet pot after the patient has left the room. This approach is friendly and comfortable for patients and does not lead to an enhanced radiation dose to the staff that otherwise need handling the collected urine. The effects of urine volume and the voiding flow rate were investigated with 177Lu mock-up urine solutions. The expanded uncertainty varied from ±5 to ±10 %, dependent on the occurrence of diarrhea or extreme voiding styles. Therefore measurement uncertainties of the derived whole-body activity were equivalent to the values derived from the urine collection method or even a little bit worse. As an alternative, a radiation measurement system was designed by which the activity in the patient’s body can be measured directly by positioning the patient between two CeBr3 detectors for simultaneous measurements. Whole-body activities during subsequent measurements are commonly normalized to the administered activity before the first voiding. The detector responses of the measurement system are affected by the fully filled bladder during this measurement before the first voiding and by activity redistributions in between subsequent measurements. This was confirmed by measurements with patients, in which the geometric mean value of the count rates of the two detectors after voiding differed from that before the next voiding and by comparison with the results from the urine collection method. This problem could be largely overcome by a series of paired measurements before and after each voiding consecutively, from which time-dependent detector responses were derived. The whole-body activities were then determined accurately using these time-dependent responses, with measurement uncertainties of about ±7%. The results around 1 h after administration have been validated by measurements of the collected first excreted urine from 5 patients. The uncertainty of the whole-body dose is an essential quantity in the individual dosimetry of radionuclide therapy and is mainly dependent on the time-integrated activity coefficient, which is calculated by the bi-exponential regression of the time-activity curve. Using the trapezoidal area under the measurement curve as a reference, the uncertainty of the time-integrated activity coefficient was estimated from the three components, e.g. the uncertainty of the trapezoidal area under the measurement curve, the sum of squares of fitting residuals and the bias between the fitting and trapezoidal areas. The expanded uncertainty in measurement is about ±4% for the new paired measurements method. The toilet measurement set-up is in principle ready for implementation but requires additional modifications of the logistics in the use of the toilet, such as a delayed flushing and blocking of the access during the measurements. The whole-body measurement system is ready for implementation. Handling of radioactive urine is not needed any more. The approaches meet the objective: a reduction of the burden to radiotherapy patients and analysts in the assays of the amount of activity in the patient body.Radiation, Radionuclides & ReactorsApplied Science
Environment-friendly inland shipping: Dynamic modeling of propulsion systems for inland ships using different fuels and fuel cells
No full textTo meet possible future emission regulations for inland ships alternative propulsion systems with fuel cell technology and batteries are researched. A rather simple, yet efficient dynamic model is being developed to simulate four different propulsion system configurations with different fuel cells and different fuels. The system configurations and sub models are discussed in this paper, as well as the design considerations and lay-out of the energy control system and results of the first simulations.Accepted Author ManuscriptShip Design, Production and Operation
The use of simulation models in education: the affordable engineer
No full textAccepted Author ManuscriptShip Design, Production and Operation
New biomarkers of exposure to metals using exhaled breath condensate (EBC)
No full textRadiation, Science and TechnologyApplied Science
An in vitro approach to evaluate and develop potential Sn-117m based bone-seeking radiopharmaceuticals
No full textIt has become standard practice in the development of radiopharmaceuticals to evaluate/assess the efficacy of prospective therapeutic or diagnostic agents by animal models, which generally calls for subjecting a substantial number of animals to intensive test and retest measurements for obtaining representative and conclusive results/data. This work communicates the advantage of combining various analytical modalities with mathematical and computational modeling as a multifaceted tool, for pre-vivo screening of prospective radiopharmaceuticals intended for the treatment of metastases in bone. Ultimately, the methods applied here could help curtail the number of futile tests, and in so doing reduce the number of animals used in the typical trial-and error approach of developing radiopharmaceuticals, in particular metal-chelate type drugs. The benefits being that of an ethical nature as well as cost minimization - in terms of time, facilities and professional consultation hours (vets, radiographers, etc) required. The Sn-117m radionuclide was identified as an ideal radiopharmaceutical component for the treatment of bone pain, owing to its favourable radiation properties – with a half life of 13.6 days and decay emission of conversion (Auger) electrons. The short emission range of the Auger electrons lends itself to minimizing radioxicity/radiation dose to the sensitive bone marrow. In order to best exploit the radiation characteristics of Sn-117m for therapy various methods were considered for the preparation of the isotope with high specific activity. The quintessence of the production techniques attempted employed the Szilard-Chalmers effect, whereby the product atoms or ions are separable from the original target matrix due to chemical and/or structural differences incurred during nuclear bombardment, or as a result of recoil of the atoms from the target lattice due to extreme activation/excitation energy acquired. The nuclear reactions considered were that of neutron capture, Sn-116(n,gamma)Sn-117m, and photonuclear, Sn(IV)-118(gamma,n)Sn(II)-117m. Chemical separation and isolation methods were unique for each reaction, namely recoil capture of Sn-117m in the (n,gamma) reaction followed by chemical extraction – yielding a specific activity of 2.53 MBq/mmol (0.07 % yield); and anion exchange chromatography for (gamma,n) reaction, which produced Sn-117m with a yield of 60% and specific activity of 2.94 GBq/mA/h/mg (349.01 GBq/mA/h/mmol). Two tin-bisphosphonate complexes were studied in this thesis, namely Sn(II)-APDDMP and Sn(IV)-PEI-MP, where the bisphosphonate ligands are N,N-dimethylenephosphonate-1-hydroxy-4-aminopropylidenediphosphonate and N,N’,N’-trimethylenephosphonate-polyethyleneimine, respectively. Using glass electrode potentiometry, the complexes of the former were studied for divalent tin (Sn(II)) and compared against those of the most prominent physiological metal ions, namely Ca(II), Mg(II), Zn(II), which revealed that Ca(II) formed more stable with APDDMP and was therefore prone to displacing the Sn(II). As a result of the dissociation the Sn(II) could then be taken up by amino acids in the plasma thus negating the tumour targeting. The biodistribution of [Sn-117m]Sn(II)-APDDMP was tested in a rodent model, which showed fairly rapid renal clearance of the [Sn-117m]Sn(II). With the aid of blood plasma modeling software, ECCLES, various postulates were tested to explain the observed biodistribution. This confirmed that the complexes did in fact dissociate as a result of Ca(II) competition, resulting in the formation of Sn(II)-complexes with histidine and cysteine, which were then excreted via the kidneys. In an attempt to improve the tumour selectivity and uptake, the water soluble phosphonate polymer PEI-MP was studied, exploiting a phenomenon known as the Enhanced Permeation and Retention effect (EPR), whereby macromolecules, e.g. polymers, selectively accumulate within tumours due to irregularities in the vasculature and poor lymphatic clearance. PEI-MP was complexed with Sn(IV), and in similar fashion as had been performed for Sn(II)-APDDMP, the susceptibility was tested by ECCLES blood plasma modeling. The simulation suggested that the complexes would dissociate within blood plasma, resulting the formation of Sn(IV)-glutamine complexes and Ca-PEI-MP. The stability of Sn(IV)-PEI-MP was lower than that of its Sn(II) counterpart. Therefore, biodistribution studies were averted, given the validity of previous modeling predictions – i.e. Sn(II)-APDDMP and Sn(II)-PEI-MP. When working with tin, and especially Sn(II), an argument ensues as to valence stability of the metal ion(s), that when preparing or injecting a complex of tin with a particular oxidation state, is it certain to remain in that form and not be oxidized (Sn(II)) or reduced (Sn(IV)) within the environment of blood plasma – given the inherent reducing nature of Sn(II) and the oxygen abundance of blood. A study of the tin-phosphonate complexes by P-31 NMR was successful in addressing this question. The coordination of the ligands to Sn(II) and Sn(IV) were distinguishable by the chemical shift of the phosphorous signal. In so doing any interconversion of oxidation states could be easily monitored by changes in intensity of the respective P-31 peaks. The complexes were put through their paces by observing their P-31 spectra in time, and applying oxidative pressure in the form of hydrogen peroxide, and inversely, using glutathione (GSH) to reverse the oxidation. The extreme conditions required to achieve complete conversion was considerably beyond that which can be expected in blood plasma, therefore it was concluded that the tin within the complexes would essentially remain unchanged for the duration of treatment. Concurrently with the blood plasma modeling assessment, the prospective “bone seeking” agents Sn(IV)-PEI-MP and Sn(II)-PEI-MP were tested for their adsorption characteristics with hydroxyapatite, which served as an in vitro model for bone mineral. The adsorption of the complexes as well as the free ligand was adequately described by Langmuir adsorption isotherms – deriving information about the adsorption affinity and the maximum adsorption capacity of each for hydroxyapatite. The ideal combination for optimum complex adsorption was determined, taking into account the polymer, with size fractions of 10-30kDA or 30-50kDa, and the particular valence form of tin. The Sn(II)-PEI-MP complex, with a polymer size of 10-30kDa, was best. This complemented the blood plasma modeling findings, and the adsorption speciation substantiated speciation results obtained by the potentiometry, with M2L complexes forming for Sn(II)-PEI-MP and ML species for Sn(IV)-PEI-MP. Furthermore, the presence of tin favourably enhanced the adsorption of the complex(es), which was evident by: (i) the superior adsorption data/figures of the tin complexes over that of the free ligand; and (ii) dinuclear complexes (M2L) of Sn(II)-PEI-MP. In general this thesis provides a holistic approach to investigating some of the fundamental issues in the development of radiopharmaceuticals – intended particularly for the treatment of bone metastases. The combination of the methods used in this study made it possible to better understand and predict the behaviour of novel drug concepts without the conventional and elaborate animal models – save for the rodent biodistribution study of [Sn-117m]Sn(II)-APDDMP, which, in retrospect, validated the adequacy of the thermodynamic blood plasma model. The study leaves room for adaptation and inclusion of additional techniques – depending on the expected activity of, or hypotheses surrounding the drug being considered, which could help resolve many of the underlying factors influencing efficacy. These could include: cell assays; and dissociation kinetic measurements by free-ion selective radiotracer extraction (FISRE), for example.Department of Radiation, Radionuclides & Reactors (TUDelft), and the Department of Radiochemistry (Necsa)Applied Science
Different approaches to enhancing selenium levels in wheat cultivars
No full textRadiation, Science and TechnologyApplied Science
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