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  • 301.
    Tamburro, Davide
    et al.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Fredolini, Claudia
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Espina, Virginia
    Douglas, Temple A.
    Ranganathan, Adarsh
    Ilag, Leopold
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Zhou, Weidong
    Russo, Paul
    Espina, Benjamin H.
    Muto, Giovanni
    Petricoin, Emanuel F., III
    Liotta, Lance A.
    Luchini, Alessandra
    Multifunctional Core-Shell Nanoparticles: Discovery of Previously Invisible Biomarkers2011In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 133, no 47, p. 19178-19188Article in journal (Refereed)
    Abstract [en]

    Many low-abundance biomarkers for early detection of cancer and other diseases are invisible to mass spectrometry because they exist in body fluids in very low concentrations, are masked by high-abundance proteins such as albumin and immunoglobulins, and are very labile. To overcome these barriers, we created porous, buoyant, core-shell hydrogel nanoparticles containing novel high affinity reactive chemical baits for protein and peptide harvesting, concentration, and preservation in body fluids. Poly(N-isopropylacrylamide-co-acrylic acid) nanoparticles were functionalized with amino-containing dyes via zero-length cross-linking amidation reactions. Nanoparticles functionalized in the core with 17 different (12 chemically novel) molecular baits showed preferential high affinities (K(D) < 10(-11) M) for specific low-abundance protein analytes. A poly(N-isopropylacrylamide-co-vinylsulfonic acid) shell was added to the core particles. This shell chemistry selectively prevented unwanted entry of all size peptides derived from albumin without hindering the penetration of non-albumin small proteins and peptides. Proteins and peptides entered the core to be captured with high affinity by baits immobilized in the core. Nanoparticles effectively protected interleukin-6 from enzymatic degradation in sweat and increased the effective detection sensitivity of human growth hormone in human urine using multiple reaction monitoring analysis. Used in whole blood as a one-step, in-solution preprocessing step, the nanoparticles greatly enriched the concentration of low-molecular weight proteins and peptides while excluding albumin and other proteins above 30 kDa; this achieved a 10,000-fold effective amplification of the analyte concentration, enabling mass spectrometry (MS) discovery of candidate biomarkers that were previously undetectable.

  • 302.
    Tengstrand, Erik
    et al.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Lindberg, Johan
    Åberg, K. Magnus
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    TracMass 2-A Modular Suite of Tools for Processing Chromatography-Full Scan Mass Spectrometry Data2014In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 86, no 7, p. 3435-3442Article in journal (Refereed)
    Abstract [en]

    In untargeted proteomics and metabolomics, raw data obtained with an LC/MS instrument are processed into a format that can be used for statistical analysis. Full scan MS data from chromatographic separation of biological samples are complex and analyte concentrations need to be extracted and aligned so that they can be compared across the samples. Several computer programs and methods have been developed for this purpose. There is still a need to improve the ease of use and feedback to the user because of the advanced multi-parametric algorithms used. Here, we present and make publicly available, TracMass 2, a suite of computer programs that gives immediate graphical feedback to the data analyst on parameter settings and processing results, as well as producing state-of-the-art results. The main advantage of TracMass 2 is that the feedback and transparency of the processing steps generate confidence in the end result, which is a table of peak intensities. The data analyst can easily validate every step of the processing pipeline. Because the user receives feedback on how all parameter values affect the result before starting a lengthy computation, the user's learning curve is enhanced and the total time used for data processing can be reduced. TracMass 2 has been released as open source and is included in the Supporting Information. We anticipate that TracMass 2 will set a new standard for how chemometrical algorithms are implemented in computer programs.

  • 303.
    Tengstrand, Erik
    et al.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Rosén, Johan
    Hellenäs, Karl-Erik
    Åberg, K. Magnus
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    A concept study on non-targeted screening for chemical contaminants in food using liquid chromatography–mass spectrometry in combination with a metabolomics approach2013In: Analytical and Bioanalytical Chemistry, ISSN 1618-2642, E-ISSN 1618-2650, Vol. 405, no 4, p. 1237-1243Article in journal (Refereed)
    Abstract [en]

    A generic method to screen for new or unexpected contaminants at ppm levels in food has been developed. The method comprises an acidic acetonitrile extraction, detection with ultra-high-pressure liquid chromatography coupled to electrospray ionisation time-of-flight mass spectrometry and statistical evaluation using a metabolomics approach comparing suspected contaminated food with uncontaminated foods. The method was tested for 26 model contaminants from 100 μg/g down to 0.4 μg/g in three brands of fresh orange juice. Blinded statistical evaluation revealed signals from all added contaminants detectable by liquid chromatography –electrospray ionisation using positive ionisation mode, while only two false-positive signals were reported. The method is primarily intended to be used  for investigation of food samples suspected to be contaminated with unknown substances. Additionally it could be used to continuously monitor for appearance of new food contaminants as a complement to the specific targeted analysis that is today’s foundation of food safety analysis.

  • 304.
    Thewalim, Yasar
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Retention time predictions in Gas Chromatography2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In gas chromatography, analytes are separated by differences in their partition between a mobile phase and a stationary phase. Temperature-program, column dimensions, stationary and mobile phases, and flow rate are all parameters that can affect the quality of the separation in gas chromatography. To achieve a good separation (in a short amount of time) it is necessary to optimize these parameters. This can often be quite a tedious task.

    Using computer simulations, it is possible to both gain a better understanding of how the different parameters govern retention and separation of a given set of analytes, and to optimize the parameters within minutes. In the research presented here, this was achieved by taking a thermodynamic approach that used the two parameters ΔH (enthalpy change) and ΔS (entropy change) to predict retention times for gas chromatography. By determining these compound partition parameters, it was possible to predict retention times for analytes in temperature-programmed runs. This was achieved through the measurement of the retention times of n-alkanes, PAHs, alcohols, amines and compounds in the Grob calibration mixture in isothermal runs. The isothermally obtained partition coefficients, together with the column dimensions and specifications, were then used for computer simulation using in-house software.

    The two-parameter model was found to be both robust and precise and could be a useful tool for the prediction of retention times. It was shown that it is possible to calculate retention times with good precision and accuracy using this model. The relative differences between the predicted and experimental retention times for different compound groups were generally less than 1%.

    The scientific studies (Papers I-IV) are summarized and discussed in the main text of this thesis. 

  • 305.
    Thewalim, Yasar
    et al.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Aldaeus, Fredrik
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Colmsjö, Anders
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Retention time prediction of compounds in Grob standard mixture for apolar capillary columns in temperature-programmed gas chromatography2009In: Analytical and Bioanalytical Chemistry, ISSN 1618-2642, E-ISSN 1618-2650, Vol. 393, no 1, p. 327-334Article in journal (Refereed)
    Abstract [en]

    This paper presents an extension of a previous investigation in which the behavior of nonpolar compounds in temperature-programmed gas chromatographic runs was predicted using thermodynamic (entropy and enthalpy) parameters derived from isothermal runs. In a similar manner, entropy and enthalpy parameters were determined for a Grob standard mixture of compounds with widely varying chemical characteristics. These parameters were used to predict the retention times and chromatographic behaviors of the compounds on four gas chromatography capillary columns: three that had phenyl-based stationary phases (with degrees of substitution of 0%, 5% and 50%) and one with (50%) cyanopropyl substitution. The predictions matched data empirically obtained from temperature-programmed chromatographic runs for all of the compounds extremely well, despite the wide variations in polarity of both the compounds and stationary phases. Thus, the results indicate that such simulations could greatly reduce the time and material costs of chromatographic optimizations.

  • 306.
    Thewalim, Yasar
    et al.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Bruno, Oscar
    Colmsjö, Anders
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Study of the chromatographic behaviour of selected alcohols and amines2011In: Analytical and Bioanalytical Chemistry, ISSN 1618-2642, E-ISSN 1618-2650, Vol. 399, no 3, p. 1335-1345Article in journal (Refereed)
    Abstract [en]

    The gas chromatographic behavior of selected linear and non-linear alcohols and amines was investigated using four capillary columns containing phenyl substitution levels of 0%, 5%, and 50% and 50% cyanopropyl substitution. In a previous study, the positions of specific compounds inside the capillary column were iteratively modeled using only two thermodynamic parameters (ΔH and ΔS). The present study addresses the validation of the two-parameter model for retention time prediction for selected alcohols and amines using thermodynamic data obtained from as few as two data points. The difference between predicted and observed retention times under different temperature conditions was generally less than 1% of the experimental value and the predicted order of elution was correct in the used model.

  • 307.
    Thewalim, Yasar
    et al.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Sadiktsis, Ioannis
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Colmsjö, Anders
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Comparing columns for gas chromatography with the two-parameter model for retention prediction2011In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1218, no 31, p. 5305-5310Article in journal (Refereed)
    Abstract [en]

    The retention times of selected compounds in temperature programmed gas chromatography were predicted using a two-parameter model, on the basis of thermodynamic data obtained from isothermal runs on seven capillary columns, primarily substituted with 5% diphenylsiloxane. The scope for using thermodynamic data obtained from isothermal runs on one column to optimize separation on a different column or a different instrument setup was investigated. Additionally, the predictive utility of thermodynamic data obtained using a DB-5 column that had been in use for three years was compared to that of a new column of the same model. It was found that satisfactory separation could be achieved on one capillary column or instrument setup on the basis of thermodynamic data obtained using a different column or instrument set-up.

  • 308.
    Thorsén, Gunnar
    et al.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Ericson, Hanna
    Kumblad, Linda
    Stockholm University, Faculty of Science, Department of Systems Ecology.
    Quantification of human pharmaceuticals in Baltic Sea blue mussels2009In: Abstracts / 12th EuCheMS International conference on chemistry and the environment: 14-17 June 2009, Stockholm university, Stockholm, Sweden, 2009, p. Ana P62-Conference paper (Other academic)
  • 309.
    Thuy, Tran Thi
    et al.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Inganas, Mats
    Ekstrand, Gunnar
    Thorsén, Gunnar
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Parallel sample preparation of proteins, from crude samples to crystals ready for MALDI-MS, in an integrated microfluidic system2010In: Journal of chromatography. B, ISSN 1570-0232, E-ISSN 1873-376X, Vol. 878, no 28, p. 2803-2810Article in journal (Refereed)
    Abstract [en]

    A microfluidic structure is presented where selective capture of proteins in complex samples, followed by clean-up, enzymatic processing, and MALDI-MS sample preparation of peptides generated, can be performed. The structure uses an affinity column to capture the protein while all other components in the sample are disposed of. The protein of interest is then eluted from the affinity column and captured on a second column on which the enzymatic processing is performed. Salts and hydrophilic contaminants are then removed before the products from the enzymatic reaction are eluted together with a suitable MALDI matrix and the solvent evaporated in a designated MALDI target structure. All steps can be performed automatically in 54 parallel microstructures on a microfluidic compact disc. The process is demonstrated by the selective capture and tryptic digest of recombinant IgG molecules from samples containing other proteins: an excess of bovine serum albumin or spent cell culture media.

  • 310.
    Thuy, Tran Thi
    et al.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Tengstrand, Erik
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Åberg, Magnus
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Thorsen, Gunnar
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Discrimination between glycosylation patterns of therapeutic antibodies using a microfluidic platform, MALDI-MS and multivariate statistics2012In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 70, p. 47-52Article in journal (Refereed)
    Abstract [en]

    Optimal glycosylation with respect to the efficacy, serum half-life time, and immunogenic properties is essential in the generation of therapeutic antibodies. The glycosylation pattern can be affected by several different parameters during the manufacture of antibodies and may change significantly over cultivation time. Fast and robust methods for determination of the glycosylation patterns of therapeutic antibodies are therefore needed. We have recently presented an efficient method for the determination of glycans on therapeutic antibodies using a microfluidic CD platform for sample preparation prior to matrix-assisted laser-desorption mass spectrometry analysis. In the present work, this method is applied to analyse the glycosylation patterns of three commercially available therapeutic antibodies and one intended for therapeutic use. Two of the antibodies produced in mouse myeloma cell line (SP2/0) and one produced in Chinese hamster ovary (CHO) cells exhibited similar glycosylation patterns but could still be readily differentiated from each other using multivariate statistical methods. The two antibodies with most similar glycosylation patterns were also studied in an assessment of the method's applicability for quality control of therapeutic antibodies. The method presented in this paper is highly automated and rapid. It can therefore efficiently generate data that helps to keep a production process within the desired design space or assess that an identical product is being produced after changes to the process.

  • 311. Thuy, Tran Thi
    et al.
    Thorsen, Gunnar
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Glycosylation Profiling of Therapeutic Antibodies in Serum Samples Using a Microfluidic CD Platform and MALDI-MS2013In: Journal of the American Society for Mass Spectrometry, ISSN 1044-0305, E-ISSN 1879-1123, Vol. 24, no 7, p. 1053-1063Article in journal (Refereed)
    Abstract [en]

    The serum clearance rate of therapeutic antibodies is important as it affects the clinical efficacy, required dose, and dose frequency. The glycosylation of antibodies has in some studies been shown to have an impact on the elimination rates in vivo. Monitoring changes to the glycan profiles in pharmacokinetics studies can reveal whether the clearance rates of the therapeutic antibodies depend on the different glycoforms, thereby providing useful information for improvement of the drugs. In this paper, a novel method for glycosylation analysis of therapeutic antibodies in serum samples is presented. A microfluidic compact-disc (CD) platform in combination with MALDI-MS was used to monitor changes to the glycosylation profiles of samples incubated in vitro. Antibodies were selectively purified from serum using immunoaffinity capture on immobilized target antigens. The glycans were enzymatically released, purified, and finally analyzed by MALDI-TOF-MS. To simulate changes to glycan profiles after administration in vivo, a therapeutic antibody was incubated in serum with the enzyme alpha 1-2,3 mannosidase to artificially reduce the amount of the high mannose glycoforms. Glycan profiles were monitored at specific intervals during the incubation. The relative abundance of the high mannose 5 glycoform was clearly found to decrease and, simultaneously, that of high mannose 4 increased over the incubation period. The method can be performed in a rapid, parallel, and automated fashion for glycosylation profiling consuming low amounts of samples and reagents. This can contribute to less labor work and reduced cost of the studies of therapeutic antibodies glycosylation in vitro and in vivo.

  • 312.
    Tollbäck, J
    et al.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Bigata, M B
    Crescenzi, C
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Strom, J
    Feasibility of Analyzing Fine Particulate Matter in Air Using Solid-Phase Extraction Membranes and Dynamic Subcritical Water Extraction2008In: Analytical Chemistry, Vol. 80, p. 3159-3167Article in journal (Refereed)
  • 313.
    Tollbäck, Johanna
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    New methods for determination of airborne pollutants: Focus on tetrabromobisphenol A, organophosphate triesters and polycyclic aromatic hydrocarbons2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The work presented in this thesis concerns the development and evaluation of new methods of sampling and analysis of organic pollutants in the indoor and outdoor environment.

    In Paper I, the development of a new method was reported for the determination of the brominated flame retardant tetrabromobisphenol A (TBBPA) in air using sampling with glass fiber filter and polyurethane foam (PUF), ultrasonic solvent extraction and liquid chromatography coupled to electrospray ionisation mass spectrometry (LC-ESI/MS). The MS fragmentation mechanism of TBBPA was thoroughly investigated and different acquisition modes were evaluated to achieve the most sensitive and selective detection.

    In Papers II and III, the potential use of Empore SPE membranes was evaluated for air sampling of volatile, semi-volatile and particle-associated organic compounds. Breakthrough studies conducted for 24h at air flows of 10- 20 L/min showed that the SPE membranes efficiently retains volatile and semi-volatile organophosphate esters and particles >10 nm. Effort was invested in the development of fast and environmental friendly methods, with low cost, for sample clean up and analysis.

    In Paper II, the sample preparation technique was dynamic solvent extraction with methanol coupled to LC-ESI/MS. The total run time per sample, including both extraction and separation, was less than 34 min, consuming only 1.6mL methanol. In Paper III, efficiency of selective extraction of polycyclic aromatic hydrocarbons from particulate matter sampled with Empore SPE membranes, using dynamic subcritical water extraction (DSWE) was investigated. Acceptable recoveries of the investigated compounds from reference material (SRM 1649a) were achieved. In Paper IV, the application of dynamic solid phase micro-extraction (SPME) air sampling was evaluated using, gas chromatography/positive ion chemical ionisation (GC/PICI) and tandem-MS detection for the determination of organophosphate esters in work environment.

  • 314.
    Tollbäck, Johanna
    et al.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Bigatá, María Blasco
    Crescenzi, Carlo
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Ström, Johan
    Stockholm University, Faculty of Science, Department of Applied Environmental Science (ITM).
    Feasibility of analyzing fine particulate matter in air using solid-phase extraction membranes and dynamic subcritical water extraction2008In: Analytical chemistry, ISSN 1520-6882, Vol. 80, no 9, p. 3159-67Article in journal (Refereed)
    Abstract [en]

    We have evaluated the feasibility of using Empore solid-phase extraction (SPE) membranes as an alternative to conventional techniques for sampling fine airborne particulate matter (PM), including nanoparticles, utilizing a scanning mobility particle sizer (SMPS) and a condensation particle counter to evaluate their efficiency for trapping fine particles in the 10-800 nm size range. The results demonstrate that the membranes can efficiently trap these particles and can then be conveniently packed into an extraction cell and extracted under matrix solid-phase dispersion (MSPD) conditions. The potential utility of sampling PM using Empore membranes followed by dynamic subcritical water extraction (DSWE) for fast, efficient, class-selective extraction of polycyclic aromatic hydrocarbons (PAHs) associated with the particles, prior to changing the solvent and analysis by GC/MS, was then explored. The performance of the method was tested using National Institute of Standards and Technology (NIST)-certified "urban dust" reference material (SRM 1649a) and real samples collected at a site in central Rome with heavy road traffic. The method appears to provide comparable extraction efficiency to that of conventional techniques and with using GC/MS, detection limits ranged in the few picograms per cubic meter level. Sampling PM by Empore membranes may reduce the risks of losses of semivolatile compounds, while allowing relatively high sampling flow rates and safe sample storage. Moreover, the combination of MSPD with DSWE permits specific fractions of the PM components to be eluted, thereby generating clean extracts and reducing both analysis time and sample manipulation.

  • 315.
    Tollbäck, Johanna
    et al.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Crescenzi, Carlo
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Dyremark, Eva
    Determination of the flame retardant tetrabromobisphenol A in air samples by liquid chromatography-mass spectrometry.2006In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1104, no 1-2, p. 106-12Article in journal (Refereed)
    Abstract [en]

    An original method based on LC-MS for determination of the flame retardant tetrabromobisphenol A (TBBPA) in air is presented, as an alternative to the traditionally used GC-MS. The soft ionization in LC-MS makes it possible to monitor the intact molecule and to use 13C-labelled TBBPA as an internal surrogate standard, two features that improve both accuracy and precision of the analyses. Comparison of different acquisition modes in electrospray ionization showed that the lowest detections limit, 3.1 pg TBBPA injected, was obtained in SIM monitoring the molecular ions 542.7/544.7. A fragmentation pathway of TBBPA in LC-ESI-MS is suggested. The only sample clean-up steps required are solvent reduction and filtration of the sample extract. Recoveries were 93% at a 30 ng level and 75% at 3 ng. The new method was tested by analyses of air samples collected at a recycling plant for electronic equipment. The amount of TBBPA found was 13.8 ng/m3 with an RSD of 5.9%. Furthermore, it was found that TBBPA in a standard solution could be partially debrominated, if not carefully protected from light during storage.

  • 316.
    Tollbäck, Johanna
    et al.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Isetun, Sindra
    Colmsjö, Anders
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Nilsson, Ulrika
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Dynamic non-equilibrium SPME combined with GC, PICI, and ion trap MS for determination of organophosphate esters in air2010In: Analytical and Bioanalytical Chemistry, ISSN 1618-2642, E-ISSN 1618-2650, Vol. 396, no 2, p. 839-844Article in journal (Refereed)
    Abstract [en]

    Methodology for time-weighted average (TWA) air measurements of semivolatile organophosphate triesters, widely used flame-retardants and plasticizers, and common indoor pollutants is presented. Dynamic non-equilibrium solid-phase microextraction (SPME) for air sampling, in combination with GC/PICI and ion trap tandem MS, yields a fast, almost solvent-free method with low detection limits. Methanol was used as reagent gas for PICI, yielding stable protonated molecules and few fragments. A field sampler, in which a pumped airflow over three polydimethylsiloxane (PDMS) 100-μm fibers in series was applied, was constructed, evaluated, and used for the measurements. The method LODs were in the range 2–26 ng m−3 for a sampling period of 2 h. The uptake on the SPME fibers was shown to be about five times faster for triphenyl phosphate compared to the other investigated organophosphate esters, most likely due to more lipophilic properties of the aromatic compound. The boundary layer for triphenyl phosphate when using a 100-µm PDMS sorbent was determined to 0.08 mm at a linear air velocity of 34 cm s−1. Five different organophosphate triesters were detected in air from a laboratory and a lecture hall, at concentrations ranging from 7 ng m−3 up to 2.8 μg m−3.

  • 317.
    Tollbäck, Johanna
    et al.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Tamburro, Davide
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Crescenzi, Carlo
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Carlsson, Håkan
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Air sampling with Empore solid phase extraction membranes and online single-channel desorption/liquid chromatography/mass spectrometry analysis: Determination of volatile and semi-volatile organophosphate esters2006In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1129, no 1, p. 1-8Article in journal (Refereed)
    Abstract [en]

    A method for determining organophosphate esters in air samples using C8 Empore solid phase extraction (SPE) membranes has been developed. After the sampling the analytes trapped in the membrane are completely desorbed with methanol, using an extraction cell connected online to the organic modifier channel of a HPLC gradient pump. The addition of water to the mobile phase prior to analytical chromatography ensures that the analytes are refocused and efficiently separated. Sampling with Empore SPE membranes enables the collection of analytes in both the vapour phase and particulate matter. During the air sampling procedure no losses were observed after 24 h of sampling, yielding a total volume of 14.4 m3, even for the most volatile compound used in this investigation (trimethylphosphate). Complete desorption was observed for all the organophosphate esters and recoveries were greater than 95%, with a relative standard deviation of less than 8%. The limits of detection ranged between 0.4 and 19 pg/m3. The effect of particulate matter on the extraction efficiency was investigated in detail by spiking the membranes with reference standard material. It was also found that the SPE membranes could be stored for at least 5 days at room temperature without any evidence of loss. The efficacy of the method was verified using real samples from different common indoor environments. Interestingly, significant quantities of several phosphate esters were found in a NIST standard reference material (urban dust, SRM 1649a).

  • 318.
    Tollbäck, Petter
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Large Volume Injection and Hyphenated Techniques for Gas Chromatographic Determination of PBDEs and Carbazoles in Air2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis is based on studies in which the suitability of various gas chromatography (GC) injection techniques was examined for the determination of polybrominated diphenyl ethers (PBDEs) and carbazoles, two groups of compounds that are thermally labile and/or have high boiling-points. For such substances, it is essential to introduce the samples into the GC system in an appropriate way to avoid degradation and other potential problems. In addition, different types of gas chromatographic column system and mass spectrometric detectors were evaluated for the determination of PBDEs.

    Conventional injectors, such as splitless, on-column and programmed temperature vaporizing (PTV) injectors were evaluated and optimized for determination of PBDEs. The results show on-column injection to be the best option, providing low discrimination and high precision. The splitless injector is commonly used for “dirty” samples. However, it is not suitable for determination of the high molecular weight congeners, since it tends to discriminate against them and promote their degradation, leading to poor precision and accuracy. The PTV injector appears to be a more suitable alternative. The use of liners reduces problems associated with potential interferents such as polar compounds and lipids and compared to the hot splitless injector, it provides gentler solvent evaporation, due to its temperature programming feature, leading to low discrimination and variance.

    Increasing the injection volume from the conventional 1-3 µL to >50 µL offers two main benefits. Firstly, the overall detection and quantification limits are decreased, since the entire sample extract can be injected into the GC system. Secondly, large volume injections enable hyphenation of preceding techniques such as liquid chromatography (LC), solid phase extraction and other kinds of extraction. Large-volume injections were utilized and optimized in the studies included in this thesis.

    With a loop-type injector/interface large sample volumes can be injected on-column providing low risk of discrimination against compounds with low volatility. This injector was used for the determination of PBDEs in air and as an interface for the determination of carbazoles by LC-GC. Peak distortion is a frequently encountered problem associated with this type of injector that was addressed and solved during the work underlying this thesis.

    The PTV can be used as a large volume injector, in so-called solvent vent mode. This technique was evaluated for the determination of PBDEs and as an interface for coupling dynamic sonication-assisted solvent extraction online to GC. The results show that careful optimization of the injection parameters is required, but also that the PTV is robust and yields reproducible results.

    PBDEs are commonly detected using mass spectrometry in electron capture negative ionization (ECNI) mode, monitoring bromine ions (m/z 79 and 81). The mass spectrometric properties of the fully brominated diphenyl ether, BDE-209, have been investigated. A high molecular weight fragment at m/z 486/488 enables the use of 13C-labeled BDE-209 as an internal surrogate standard.

  • 319.
    Tollbäck, Petter
    et al.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Björklund, Jonas
    Östman, Conny
    Large-volume programmed-temperature vaporizer injection for fast gas chromatography with electron capture and mass spectrometric detection of polybrominated diphenyl ethers2003In: Journal of Chromatography A, ISSN 0021-9673, Vol. 991, no 2, p. 241-253Article in journal (Refereed)
  • 320.
    Tollbäck, Petter
    et al.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Carlsson, Håkan
    Östman, Conny
    Coupled LC-GC-NPD for Determination of Carbazole-Type PANH and its Application to Personal Exposure Measurement2000In: Journal of High Resolution Chromatography, ISSN 0935-6304, Vol. 23, no 2, p. 131-137Article in journal (Refereed)
  • 321.
    Tollbäck, Petter
    et al.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Östman, Conny
    Dynamic Sonication-assisted Solvent Extraction coupled on-line to GC-MS for the determination of PBDEs in AirManuscript (Other academic)
  • 322.
    Torgrip, Ralf
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Metabonomics - the hypothesis, the method and what to expect from the data2009Conference paper (Other academic)
  • 323. Torgrip, Ralf
    et al.
    Alm, Erik
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Åberg, Magnus
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Warping and alignment technologies for inter-sample feature correspondence in 1D H-NMR, chromatography-, and capillary electrophoresis-mass spectrometry data2010In: Bioanalytical Reviews, Vol. 1, p. 105-116Article in journal (Refereed)
  • 324.
    Torgrip, Ralf J. O.
    et al.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Åberg, Magnus
    Karlberg, Bo
    Jacobsson, Sven P.
    Peak alignment using reduced set mapping2003In: Journal of Chemometrics, ISSN 0886-9383, Vol. 17, no 11, p. 573-582Article in journal (Refereed)
  • 325. Torgrip, Ralf
    et al.
    Åberg, Magnus
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Alm, Erik
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    An improved data processing pipe-line for comprehensive H-NMR and X/MS -omics data2009Conference paper (Other academic)
  • 326.
    Tran, Thi Thuy
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Compact-disc microfluidic methods for characterization of therapeutic antibodies: Analysis of post-translational modifications2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Characterization of post-translational modifications (PTMs) of therapeutic proteins is very important during the bioprocess development to maintain desired product quality and during the submission process to regulatory authorities for product approval. Monitoring glycosylation in pharmacokinetic studies can be useful to evaluate the dependence of clearance rates on different glycoforms. The cost and efficiency of characterization affect the speed to market of biopharmaceutical proteins. A reduction in the number of manual processing steps, cost of reagents and consumption of sample, as well as the time required for chemical analysis, is therefore necessary.

    The research presented in this thesis is focused on the potential of using microfluidic discs for automated, miniaturized, parallel and rapid sample preparation for PTM characterization of therapeutic monoclonal antibodies. Paper I describes the method development for N-linked glycosylation profiling. Several sample preparation steps have been performed in an integrated process in the microfluidic compact disc (CD). Paper II demonstrates the use of the method presented in paper I in combination with multivariate statistics for discrimination of glycosylation profiles of different therapeutic antibodies and simulation of a real case of quality control. Paper III is focused on a method for monitoring changes in glycosylation profiles of therapeutic antibodies in serum over time by incubation with an exoglycosidase enzyme. Paper IV describes the method for peptide mapping of therapeutic antibodies. In addition, recent work (unpublished results) assesses the potential of this method for methionine oxidation detection.

    The developed methods were fast, robust with low sample/reagent consumption. Generation of glycosylation profile data for one sample was established in approximately 2 h. The amount of samples and antigens loaded into the CD platform for one replicate was less than 0.3 μg and approximately 0.06 μg, respectively. Furthermore, considering the parallel function of the CD, conducting the analysis for 54 samples can be completed within a day.

  • 327.
    Tran, Thi Thuy
    et al.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Inganas, Mats
    Thorsen, Gunnar
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    High-throughput profiling of N-linked oligosaccharides in therapeutic antibodies using a microfluidic CD platform and MALDI-MS2011In: Analytical and Bioanalytical Chemistry, ISSN 1618-2642, E-ISSN 1618-2650, Vol. 399, no 4, p. 1601-1611Article in journal (Refereed)
    Abstract [en]

    Recombinant therapeutic antibodies have shown a great potential in the treatment of several severe medical conditions such as cancer and autoimmune diseases. Glycosylation plays a critical role in biological activity and immunogenic properties of these compounds. The analysis of glycan profiles is therefore necessary in many steps of the development and manufacturing process from early development to quality control of the final product. In this paper, a fast, parallel, and robust sample preparation platform for glycosylation profiling using a microfluidic compact disc (CD) is presented. A sequential process including selective capture of antibody from a crude cell supernatant using protein A beads, enzymatic release of glycans, purification with a graphitized carbon black column, and crystallisation for MALDI-TOF analysis were performed on the CD. Glycosylation profiles of an antibody intended for therapeutic use produced in two different cell lines were compared.

  • 328.
    Tran, Thuy
    et al.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Thorsén, Gunnar
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Glycosylation profiling of therapeutic antibodies in serum samples using a microfluidic CD platform and MALDI-MSManuscript (preprint) (Other academic)
    Abstract [en]

    The serum clearance rate of therapeutic antibodies is important as it affects the clinical efficacy, required dose and dose frequency. The glycosylation of antibodies has in some studies been shown to have an impact on the elimination rates in vivo. Monitoring changes to the glycan profiles in pharmacokinetics studies can reveal whether the clearance rates of the therapeutic antibodies depend on the different glycoforms, thereby providing useful information for improvement of the drugs. In this paper a novel method for glycosylation analysis of therapeutic antibodies in serum samples is presented. A microfluidic CD platform in combination with MALDI-MS was used to monitor changes to the glycosylation profiles of samples incubated in vitro. Antibodies were selectively purified from serum using immunoaffinity capture on immobilized target antigens. The glycans were enzymatically released, purified and finally analyzed by MALDI-TOF-MS. To simulate changes to glycan profiles after administration in vivo, a therapeutic antibody was incubated in serum with the enzyme α1-2,3 mannosidase to artificially reduce the amount of the high mannose glycoforms. Glycan profiles were monitored at specific intervals during the incubation. The relative abundance of the high mannose 5 glycoform was clearly found to decrease and simultaneously, that of high mannose 4 increased over the incubation period. The method can be performed in a rapid, parallel and automated fashion for glycosylation profiling consuming low amounts of samples and reagents. This can contribute to less labor work and reduced cost of the studies of therapeutic antibodies glycosylation in vitro and in vivo.Keywords:

  • 329.
    Tryzell, Robert
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Multidetection and chemometrics in flow injection analysis1997Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    An ideal method for the determination of ions in aqueous solutions should be fast, inexpensive, simple, reliable and require small sample volumes. Flow Injection Analysis (FIA) is in many respects such an ideal method but it is too often limited to the determination of one analyte at a time. In this thesis some system design aspects have been addressed. A new system for multianalyte determination has been developed which is based on the hyphenation of FIA with capillary electrophoresis (CE). Chemometrics have been used to optimise the design of this new system and further to optimise the design of a typical single analyte FIA manifold namely a gas diffusion manifold for the determination of ammonia.

    The second major theme in this work is the development of new signal evaluation methods for FIA and FIA-CE systems. By using a multivariate approach the simultaneous determination of ammonium and excess acid (sulphuric acid) in one single run has been made possible. For conventional two line or gas diffusion applications in FIA, peak area by triangulation was found to be the evaluation method of choice both for "normal" and extended analyte concentration ranges. For the FIA-CE system, which is based on electrokinetic injection, various evaluation methods, both univariate and multivariate, were critically examined and compared. The conductivity corrected peak area method is superior to the traditionally used evaluation principles such as peak height, peak area, standard addition and internal standard methods.

  • 330. Tyrefors, Niklas
    et al.
    Michelsen, Peter
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Grubb, Anders
    Two new types of assays to determine protein concentrations in biological fluids using mass spectrometry of intact proteins with cystatin C in spinal fluid as an example2014In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 74, no 6, p. 546-554Article in journal (Refereed)
    Abstract [en]

    There is no reference method that is generally acknowledged to be unbiased for the determination of the concentration of any protein in biological fluids. This is probably because mass spectrometry (MS) methods acknowledged as reference methods for determination of low molecular mass substances in biological fluids, e.g. creatinine, have been difficult to adapt for proteins. Here we suggest two tentative MS methods, which might be used as reference methods for the determination of protein concentrations in biological fluids. One is based upon the addition to the fluid of a non-proteome reference protein, very similar to the one to be measured, and analyzing the ratio between the corresponding peaks in a selected ion monitoring (SIM) chromatogram. We call this method LC-MS-NPRP (NPRP, Non-Proteome Reference Protein). The other method is based upon the classical standard addition assay for low molecular mass substances. The results of these assays for cystatin C in spinal fluid were compared to those obtained by an immunoassay. Both methods indicated lower concentration than the immunoassay. This was found to be due to the presence of a significant fraction of monohydroxylated cystatin C in spinal fluid. It turned out that the sum of the unhydroxylated and hydroxylated cystatin C concentrations, determined by either of the two MS methods, were close to the results obtained by the immunoassay. These MS-based methods analyze intact proteins and therefore seem more suitable for the determination of protein concentrations in biological fluids than other MS-based methods requiring proteolytic degradation with its inherent lack of precision.

  • 331. Tzanavaras, P D
    et al.
    Themelis, D G
    Zotou, A
    Stratis, J
    Karlberg, B
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Optimization and validation of a dissolution test for selegiline hydrochloride tablets by a novel rapid HPLC assay using a monolithic stationary phase2008In: Journal of Pharmaceutical and Biomedical Analysis, Vol. 46, p. 670-675Article in journal (Refereed)
  • 332. Umbuzeiro, Gisela A.
    et al.
    Kummrow, Fábio
    Morales, Daniel Alexandre
    Alves, Debora Kristina M.
    Lim, Hwanmi
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Jarvis, Ian W. H.
    Bergvall, Christoffer
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Westerholm, Roger
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Stenius, Ulla
    Dreij, Kristian
    Sensitivity of salmonella YG5161 for detecting PAH-associated mutagenicity in air particulate matter2014In: Environmental and Molecular Mutagenesis, ISSN 0893-6692, E-ISSN 1098-2280, Vol. 55, no 6, p. 510-517Article in journal (Refereed)
    Abstract [en]

    The Salmonella/microsome assay is the most used assay for the evaluation of air particulate matter (PM) mutagenicity and a positive correlation between strain TA98 responses and benzo[a]pyrene (B[a]P) levels in PM has been found. However, it seems that the major causes of PM mutagenicity in this assay are the nitro and oxy-PAHs. Salmonella YG5161, a 30-times more responsive strain to B[a]P has been developed. To verify if YG5161 strain was sufficiently sensitive to detect mutagenicity associated with B[a]P mutagenicity, PM samples were collected in Brazil and Sweden, extracted with toluene and tested in the Salmonella/microsome microsuspension assay. PAHs and B[a]P were determined and the extracts were tested with YG5161 and its parental strain TA1538. The extracts were also tested with YG1041 and its parental strain TA98. For sensitivity comparisons, we tested B[a]P and 1-nitropyrene (1-NP) using the same conditions. The minimal effective dose of B[a]P was 155 ng/plate for TA1538 and 7 ng/plate for YG5161. Although the maximum tested dose, 10 m3/plate containing 9 ng of B[a]P in the case of Brazilian sample, was sufficient to elicit a response in YG5161, mutagenicity was detected at a dose as low as 1 m3/plate (0.9 ng). This is probably caused by nitro-compounds that have been shown to be even more potent than B[a]P for YG5161. It seems that the mutagenicity of B[a]P present in PM is not detectable even with the use of YG5161 unless more efficient separation to remove the nitro-compounds from the PAH extract is performed.

  • 333. Unosson, Jon
    et al.
    Blomberg, Anders
    Sandström, Thomas
    Muala, Ala
    Boman, Christoffer
    Nyström, Robin
    Westerholm, Roger
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Mills, Nicholas L.
    Newby, David E.
    Langrish, Jeremy P.
    Bosson, Jenny A.
    Exposure to wood smoke increases arterial stiffness and decreases heart rate variability in humans2013In: Particle and Fibre Toxicology, ISSN 1743-8977, E-ISSN 1743-8977, Vol. 10, p. 20-Article in journal (Refereed)
    Abstract [en]

    Background: Emissions from biomass combustion are a major source of indoor and outdoor air pollution, and are estimated to cause millions of premature deaths worldwide annually. Whilst adverse respiratory health effects of biomass exposure are well established, less is known about its effects on the cardiovascular system. In this study we assessed the effect of exposure to wood smoke on heart rate, blood pressure, central arterial stiffness and heart rate variability in otherwise healthy persons. Methods: Fourteen healthy non-smoking subjects participated in a randomized, double-blind crossover study. Subjects were exposed to dilute wood smoke (mean particle concentration of 314 +/- 38 mu g/m(3)) or filtered air for three hours during intermittent exercise. Heart rate, blood pressure, central arterial stiffness and heart rate variability were measured at baseline and for one hour post-exposure. Results: Central arterial stiffness, measured as augmentation index, augmentation pressure and pulse wave velocity, was higher after wood smoke exposure as compared to filtered air (p < 0.01 for all), and heart rate was increased (p < 0.01) although there was no effect on blood pressure. Heart rate variability (SDNN, RMSSD and pNN50; p = 0.003, p < 0.001 and p < 0.001 respectively) was decreased one hour following exposure to wood smoke compared to filtered air. Conclusions: Acute exposure to wood smoke as a model of exposure to biomass combustion is associated with an immediate increase in central arterial stiffness and a simultaneous reduction in heart rate variability. As biomass is used for cooking and heating by a large fraction of the global population and is currently advocated as a sustainable alternative energy source, further studies are required to establish its likely impact on cardiovascular disease.

  • 334. Vlčková, Hana
    et al.
    El-Beqqali, Aziza
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Nováková, Lucie
    Solich, Petr
    Abdel-Rehim, Mohamed
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Determination of amphetamine and methadone in human urine by microextraction by packed sorbent coupled directly to mass spectrometry: An alternative for rapid clinical and forensic analysis2014In: Journal of Separation Science, ISSN 1615-9306, E-ISSN 1615-9314, Vol. 37, no 22, p. 3306-3313Article in journal (Refereed)
    Abstract [en]

    Speed and low cost, together with regulatory approval, are the most important requirements of clinical assays. Therefore, a fast and automated on-line sample preparation method is essential for the routine analysis of biological samples. Microextraction by packed sorbent is an option for optimal sample preparation due to its easy automation, minimal requirements for the sample and elution solvent volumes, elimination of evaporation and reconstitution steps, and ability to integrate sample preparation and injection into one step. The use of effective sample preparation steps circumvents the need for chromatographic separation and therefore allows more rapid and less expensive sample analysis in clinical and forensic practice. Two biologically active compounds, amphetamine and methadone, were chosen as representative drugs of abuse for the application of microextraction by packed sorbent coupled directly to mass spectrometry. The developed method was validated, with the results confirming the suitability of the combination of these techniques for the analysis of biological samples. The approach was confirmed to be appropriate for use in clinical and forensic practice with regard to cost and time requirements for analysis.

  • 335. Waermlaender, Sebastian K. T. S
    et al.
    Sholts, Sabrina B
    Erlandson, Jon M.
    Gjerdrum, Thor
    Westerholm, Roger
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Could the health decline of prehistoric California Indians be related to exposure to polycyclic aromatic hydrocarbons (PAHs) from naturalbitumen?2011In: Energy & Fuels, ISSN 0887-0624, E-ISSN 1520-5029, Vol. 25, no 1, p. 315-323Article in journal (Refereed)
  • 336.
    Westerholm, R
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Testresultat från FFV fordon körda på etanol- inblandad bensin: Svenska Luftvårdsföreningens höstseminarium2008Report (Other academic)
  • 337.
    Westerholm, Roger
    et al.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Ahlvik, P
    An exhaust characterisation study based on regulated and unregulated tailpipe and evaporative emissions from bi-fuel and flexi-fuel light-duty passenger cars fuelled by petrol (E5), bioethanol (E70, E85) and biogas tested at ambient temperatures of +22°C and -7°C: Report to Swedish Road Administration2008Report (Other academic)
  • 338.
    Westerholm, Roger
    et al.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Ahlvik, P
    Lu-Karlsson, H
    An exhaust characterisation study based on regulated and un-regulated tailpipe and evaporative emissions from bi-fuel and flexi-fuel light-duty passenger cars fuelled by petrol (E5), bio-ethanol (E85) and biogas tested at ambient temperatures of +22°C and -7°C.: Report to Swedish Road Administration2007Report (Other academic)
  • 339.
    Westerholm, Roger
    et al.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Bergvall, Christoffer
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Sadiktsis, Ioannis
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Johansson, Christer
    Stockholm University, Faculty of Science, Department of Applied Environmental Science (ITM).
    Stenius, Ulla
    Karolinska Institutet, Institutet för miljömedicin (IMM), Biokemisk toxikologi.
    Mätning av starkt carcinogena dibensopyrener i jämförelse med humancarcinogenenbens(a)pyren [B(a)P] i Stockholmsluft från vägtrafik2012Report (Other academic)
  • 340.
    Westerholm, Roger
    et al.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Karlsson, Hans
    Stockholm University, Faculty of Science, Department of Applied Environmental Science (ITM).
    Ahlvik, P
    Åsman, P
    Exhaust emissions from flexi-fuel light-duty passenger cars fuelled by petrol (E5) and bioethanol (E70, E85) tested at ambient temperatures of +22°C and -7°C: Part 2:Unregulated emissions and cancer potency.2008In: Proceedings of the 17:th International Symposium on Alcohol Fuels, 2008Conference paper (Other academic)
  • 341.
    Wiberg, Kent
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Multivariate spectroscopic methods for the analysis of solutions2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In this thesis some multivariate spectroscopic methods for the analysis of solutions are proposed. Spectroscopy and multivariate data analysis form a powerful combination for obtaining both quantitative and qualitative information and it is shown how spectroscopic techniques in combination with chemometric data evaluation can be used to obtain rapid, simple and efficient analytical methods. These spectroscopic methods consisting of spectroscopic analysis, a high level of automation and chemometric data evaluation can lead to analytical methods with a high analytical capacity, and for these methods, the term high-capacity analysis (HCA) is suggested. It is further shown how chemometric evaluation of the multivariate data in chromatographic analyses decreases the need for baseline separation.

    The thesis is based on six papers and the chemometric tools used are experimental design, principal component analysis (PCA), soft independent modelling of class analogy (SIMCA), partial least squares regression (PLS) and parallel factor analysis (PARAFAC). The analytical techniques utilised are scanning ultraviolet-visible (UV-Vis) spectroscopy, diode array detection (DAD) used in non-column chromatographic diode array UV spectroscopy, high-performance liquid chromatography with diode array detection (HPLC-DAD) and fluorescence spectroscopy. The methods proposed are exemplified in the analysis of pharmaceutical solutions and serum proteins.

    In Paper I a method is proposed for the determination of the content and identity of the active compound in pharmaceutical solutions by means of UV-Vis spectroscopy, orthogonal signal correction and multivariate calibration with PLS and SIMCA classification. Paper II proposes a new method for the rapid determination of pharmaceutical solutions by the use of non-column chromatographic diode array UV spectroscopy, i.e. a conventional HPLC-DAD system without any chromatographic column connected. In Paper III an investigation is made of the ability of a control sample, of known content and identity to diagnose and correct errors in multivariate predictions something that together with use of multivariate residuals can make it possible to use the same calibration model over time. In Paper IV a method is proposed for simultaneous determination of serum proteins with fluorescence spectroscopy and multivariate calibration. Paper V proposes a method for the determination of chromatographic peak purity by means of PCA of HPLC-DAD data. In Paper VI PARAFAC is applied for the decomposition of DAD data of some partially separated peaks into the pure chromatographic, spectral and concentration profiles.

  • 342.
    Wiberg, Kent
    et al.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Andersson, Mattias
    Hagman, Anders
    Jacobsson, Sven P.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Peak purity determination with principal component analysis of high-performance liquid chromatography-diode array detection data2004In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1029, no 1-2, p. 13-20Article in journal (Refereed)
    Abstract [en]

    A method is proposed for the determination of chromatographic peak purity by means of principal component analysis (PCA) of high-performance liquid chromatography with diode array detection (HPLC–DAD) data. The method is exemplified with analysis of binary mixtures of lidocaine and prilocaine with different levels of separation. Lidocaine and prilocaine have very similar spectra and the chromatograms used had substantial peak overlap. The samples analysed contained a constant amount of lidocaine and a minor amount of prilocaine (0.02–2 conc.%) and hence the focus was on determining the purity of the lidocaine peak in the presence of much smaller levels of prilocaine. The peak purity determination was made by examination of relative observation residuals, scores and loadings from the PCA decomposition of DAD data over a chromatographic peak. As a reference method, the functions for peak purity analysis in the chromatographic data system used (Chromeleon) were applied. The PCA method showed good results at the same level as the detection limit of baseline-separated prilocaine, outperforming the methods in Chromeleon by a factor of ten. There is a discussion of the interpretation of the result, with some comparisons with evolving factor analysis (EFA). The main advantage of the PCA method for determination of peak purity over methods like EFA lies in its simplicity, short time of calculation and ease of use.

  • 343.
    Wiberg, Kent
    et al.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Andersson, Mattias
    Hagman, Anders
    Jacobsson, Sven P.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Use of control sample for estimation of prediction error in multivariate determination of lidocaine solutions with non-column chromatographic diode array UV spectroscopy2003In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 33, no 5, p. 859-869Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate the ability of a control sample, of known content and identity, to diagnose and correct errors in the predictions when the same multivariate calibration model was used for analysis of new samples over time. A calibration set consisting of 16 samples with a known content of lidocaine was analysed and two external test sets, A and B, were used for the validation. Test set A contained 15 samples with different concentrations of lidocaine and test set B contained three samples with different lidocaine content, which were analysed six times in order to obtain a measure of repeatability. The multivariate calibration was done with PLS regression on UV spectra collected between 245 and 290 nm. A representative UV spectrum was exported from the collected DAD files by two methods, average spectrum over the whole file and average spectrum over the sample plug. Test set A was analysed further on another three occasions together with a control sample. The results showed that the control sample could be used to give a diagnosis and estimate of the prediction error. Moreover, the measured prediction error of the control sample could also be used to correct the predictions, thereby reducing the prediction error. Finally, some practical considerations regarding use of the proposed DAD method with a control sample are presented. The procedure suggested could lead to an efficient analytical approach where the same calibration model could be used over time without recalibration, which may be attractive in industrial quality control or screening analysis in pharmaceutical research.

  • 344.
    Wiberg, Kent
    et al.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Hagman, Anders
    Jacobsson, Sven P.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Rapid determination of lidocaine solutions with non-column chromatographic diode array UV spectroscopy and multivariate calibration2003In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 30, no 5, p. 1575-1586Article in journal (Refereed)
    Abstract [en]

    A new method for the rapid determination of pharmaceutical solutions is proposed. A conventional HPLC system with a Diode Array Detector (DAD) was used with no chromatographic column connected. As eluent, purified water (Milli Q) was used. The pump and autosampler of the HPLC system were mainly utilised as an automatic and convenient way of introducing the sample into the DAD. The method was tested on the local anaesthetic compound lidocaine. The UV spectrum (245–290 nm) from the samples analysed in the detector was used for multivariate calibration for the determination of lidocaine solutions. The content was determined with PLS regression. The effect on the predictive ability of three factors: flow, data-collection rate and rise time as well as two ways of exporting a representative UV spectrum from the DAD file collected was investigated by means of an experimental design comprising 11 experiments. For each experiment, 14 solutions containing a known content of lidocaine were analysed (0.02–0.2 mg ml−1). From these 14 samples two calibration sets and two test sets were made and as the response in the experimental design the Root Mean Square Error of Prediction (RMSEP) values from the predictions of the two test sets were used. When the factor setting giving the lowest RMSEP was found, this setting was used when analysing a new calibration set of 12 lidocaine samples (0.1–0.2 mg ml−1). This calibration model was validated by two external test sets, A and B, analysed on separate occasions for the evaluation of repeatability (test set A) and determination over time (test set B). For comparison, the reference method, liquid chromatography, was also used for analysis of the ten samples in test set B. This comparison of the two methods was done twice on different occasions. The results show that in respect of accuracy, precision and repeatability the new method is comparable to the reference method. The main advantages compared with liquid chromatography are the much shorter time of analysis (<30 s) as well as the automatic and simple analytical procedure and the low consumption of organic solvents.

  • 345.
    Wiberg, Kent
    et al.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Hagman, Anders
    Jacobsson, Sven P.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Burén, Peter
    Determination of the content and identity of lidocaine soluions with UV-visible spectroscopy and multivariate calibration2001In: The Analyst, ISSN 0003-2654, E-ISSN 1364-5528, Vol. 126, no 7, p. 1142-1148Article in journal (Refereed)
    Abstract [en]

    A method is proposed for the determination of the content and identity of the active compound in pharmaceutical solutions by means of ultraviolet-visible (UV–Vis) spectroscopy, orthogonal signal correction (OSC) and multivariate calibration with soft independent modelling of class analogy (SIMCA) classification and partial least squares (PLS) regression. The content was determined with PLS regression and the identity with PLS regression and SIMCA classification. The method was tested on the local anaesthetic compound lidocaine. For the validation, external test sets of both manufactured sample solutions and samples from a stability study were used. For comparison with this new method, liquid chromatography was used as a reference method. The results show that in respect of accuracy, precision and repeatability, the new method is comparable to the reference method. The main advantage over liquid chromatography is the much shorter time of analysis and the simpler analytical procedure. An estimate of the analysis time saved with the proposed method compared with using liquid chromatography, together with practical considerations, is given.

  • 346.
    Wiberg, Kent
    et al.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Jacobsson, Sven P.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Parallel factor analysis of HPLC-DAD data for binary mixtures of lidocaine and prilocaine with different levels of separation2004In: Analytica Chimica Acta, ISSN 0003-2670, E-ISSN 1873-4324, Vol. 514, no 2, p. 203-209Article in journal (Refereed)
    Abstract [en]

    A set of 17 samples containing a constant amount of lidocaine (667 muM) and a decreasing amount of prilocaine (667-0.3 muM) was analysed by LC-DAD at three different levels of separation, followed by parallel factor analysis (PARAFAC) of the data obtained. In Case 1 no column was connected, the chromatographic resolution (R-s) therefore being zero, while Cases 2 and 3 had partly separated peaks (R-s = 0.7 and 1.0). The results showed that in Case 1, analysed without any separation, the PARAFAC decomposition with a model consisting of two components gave a good estimate of the spectral and concentration profiles of the two compounds. In Cases 2 and 3, the use of PARAFAC models with two components resolved the underlying chromatographic, spectral and concentration profiles. The loadings related to the concentration profile of prilocaine were used for regression and prediction of the prilocaine content. The results showed that prediction of prilocaine content was possible with satisfactory prediction (RMSEP < 0.01). This study shows that PARAFAC is a powerful technique for resolving partly separated peaks into their pure chromatographic, spectral and concentration profiles, even with completely overlapping spectra and the absence or very low levels of separation.

  • 347.
    Wiberg, Kent
    et al.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Sterner-Molin, Agneta
    Jacobsson, Sven P.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Simultaneous determination of albumin and immunoglobulin G with fluorescence spectroscopy and multivariate calibration2004In: Talanta: The International Journal of Pure and Applied Analytical Chemistry, ISSN 0039-9140, E-ISSN 1873-3573, Vol. 62, no 3, p. 567-574Article in journal (Refereed)
    Abstract [en]

    A method is proposed for the simultaneous determination of albumin and immunoglobulin G (IgG1) with fluorescence spectroscopy and multivariate calibration with partial least squares regression (PLS). The influence of some instrumental parameters were investigated with two experimental designs comprising 19 and 11 experiments, respectively. The investigated parameters were excitation and emission slit, detection voltage and scan rate. When a suitable instrumental setting had been found, a minor calibration and test set were analysed and evaluated. Thereafter, a larger calibration of albumin and IgG1 was made out of 26 samples (0–42 μg ml−1 albumin and 0–12.7 μg ml−1 IgG1). This calibration was validated with a test set consisting of 14 samples in the same concentration range. The precision of the method was estimated by analysing two test set samples for six times each. The scan modes tested were emission scan and synchronous scan Δ60 nm. The results showed that the method could be used for determination of albumin and IgG1 (albumin, root mean square error of prediction (RMSEP) <2, relative standard error of prediction (RSEP) <6% and IgG1, RMSEP <1, RSEP <8%) in spite of the overlapping fluorescence of the two compounds. The estimated precision was relative standard deviation (R.S.D.) <1.7%. The method was finally applied for the analysis of some sample fractions from an albumin standard used in affinity chromatography.

  • 348.
    Wincent, Emma
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Amini, Nahid
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Luecke, Sandra
    Glatt, H.
    Bergman, Jan
    Crescenzi, Carlo
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Rannug, Agneta
    Rannug, Ulf
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    The suggested physiologic aryl hydrocarbon receptor activator and cytochrome P4501 substrate 6-formylindolo[3,2-b]carbazole is present in humans2009In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 284, no 5, p. 2690-2696Article in journal (Refereed)
    Abstract [en]

    Dioxins and other polycyclic aromatic compounds formed during the combustion of waste and fossil fuels represent a risk to human health, as well as to the well being of our environment. Compounds of this nature exert carcinogenic and endocrine-disrupting effects in experimental animals by binding to the orphan aryl hydrocarbon receptor (AhR). Understanding the mechanism of action of these pollutants, as well as the physiological role(s) of the AhR, requires identification of the endogenous ligand(s) of this receptor. We reported earlier that activation of AhR by ultraviolet radiation is mediated by the chromophoric amino acid tryptophan (Trp), and we suggested that a new class of compounds derived from Trp, in particular 6-formylindolo[3,2-b]carbazole (FICZ), acts as natural high affinity ligands for this receptor. Here we describe seven new FICZ-derived indolo[3,2-b]carbazole-6-carboxylic acid metabolites and two sulfoconjugates, and we demonstrate the following. (i) FICZ is formed efficiently by photolysis of Trp upon exposure to visible light. (ii) FICZ is an exceptionally good substrate for cytochromes P450 (CYP) 1A1, 1A2, and 1B1, and its hydroxylated metabolites are remarkably good substrates for the sulfotransferases (SULTs) 1A1, 1A2, 1B1, and 1E1. Finally, (iii) sulfoconjugates of phenolic metabolites of FICZ are present in human urine. Our findings indicate that formylindolo[3,2-b]carbazols are the most potent naturally occurring activators of the AhR signaling pathway and may be the key substrates of the CYP1 and SULT1 families of enzymes. These conclusions contradict the widespread view that xenobiotic compounds are the major AhR ligands and CYP1 substrates.

  • 349.
    Wincent, Emma
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Amini, Nahid
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Luecke, Sandra
    Institute of Environmental Medicine, Karolinska Institute.
    Glatt, Hansruedi
    Bergman, Jan
    Stockholm University, Faculty of Science, Department of Biosciences and Nutrition (together with KI).
    Crescenzi, Carlo
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Rannug, Agneta
    Institute of Environmental Medicine, Karolinska Institute.
    Rannug, Ulf
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    The Suggested Physiologic Aryl Hydrocarbon Receptor Activator and Cytochrome P4501 Substrate 6-Formylindolo[3,2-b]carbazole Is Present in Humans2009In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 284, no 5, p. 2690-2696Article in journal (Refereed)
    Abstract [en]

    Dioxins and other polycyclic aromatic compounds formed during the combustion of waste and fossil fuels represent a risk to human health, as well as to the well being of our environment. Compounds of this nature exert carcinogenic and endocrine disrupting effects in experimental animals by binding to the orphan aryl hydrocarbon receptor (AhR). Understanding the mechanism of action of these pollutants, as well as the physiological role(s) of the AhR, requires identification of the endogenous ligand(s) of this receptor. We reported earlier that activation of AhR by ultraviolet radiation is mediated by the chromophoric amino acid tryptophan (Trp), and we suggested that a new class of compounds derived from Trp, in particular 6-formylindolo[3,2-b]carbazole (FICZ), acts as natural high affinity ligands for this receptor. Here we describe seven new FICZ-derived indolo[3,2-b]carbazole-6-carboxylic acid metabolites and two sulfoconjugates, and we demonstrate the following. (i) FICZ is formed efficiently by photolysis of Trp upon exposure to visible light. (ii) FICZ is an exceptionally good substrate for cytochromes P450 (CYP) 1A1, 1A2, and 1B1, and its hydroxylated metabolites are remarkably good substrates for the sulfotransferases (SULTs) 1A1, 1A2, 1B1, and 1E1. Finally,(iii) sulfoconjugates of phenolic metabolites of FICZ are present in human urine. Our findings indicate that formylindolo[3,2-b]carbazols are the most potent naturally occurring activators ofthe AhR signaling pathway and may be the key substrates of the CYP1 and SULT1 families of enzymes. These conclusions contradict the wide spread view that xenobiotic compounds are the major AhR ligands and CYP1 substrates.

  • 350.
    Wincent, Emma
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Amini, Nahid
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Luecke, Sandra
    Institute for Environmental Medicine, Karolinska Institute.
    Glatt, Hansruedi
    German Institute of Human Nutrition Potsdam-Rehbruecke.
    Bergman, Jan
    Department of Biosciences at Novum, Karolinska Institute.
    Crescenzi, Carlo
    Rannug, Agneta
    Institute for Environmental Medicine, Karolinska Institute.
    Rannug, Ulf
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    The Suggested Physiologic Aryl Hydrocarbon ReceptorActivator and Cytochrome P4501 Substrate6-Formylindolo[3,2-b]carbazole Is Present in Humans2009In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 284, no 5, p. 2690-2696Article in journal (Refereed)
    Abstract [en]

    Dioxins and other polycyclic aromatic compounds formedduring the combustion of waste and fossil fuels represent a riskto human health, as well as to the well being of our environment.Compounds of this nature exert carcinogenic and endocrinedisruptingeffects in experimental animals by binding to theorphan aryl hydrocarbon receptor (AhR). Understanding themechanism of action of these pollutants, as well as the physiologicalrole(s) of the AhR, requires identification of the endogenousligand(s) of this receptor. We reported earlier that activationof AhR by ultraviolet radiation is mediated by thechromophoric amino acid tryptophan (Trp), and we suggestedthat a new class of compounds derived from Trp, in particular6-formylindolo[3,2-b]carbazole (FICZ), acts as natural highaffinity ligands for this receptor. Here we describe seven newFICZ-derived indolo[3,2-b]carbazole-6-carboxylic acid metabolitesand two sulfoconjugates, and we demonstrate the following.(i) FICZ is formed efficiently by photolysis of Trp uponexposure to visible light. (ii) FICZ is an exceptionally good substratefor cytochromes P450 (CYP) 1A1, 1A2, and 1B1, and itshydroxylated metabolites are remarkably good substrates forthe sulfotransferases (SULTs) 1A1, 1A2, 1B1, and 1E1. Finally,(iii) sulfoconjugates of phenolic metabolites of FICZ are presentin human urine. Our findings indicate that formylindolo[3,2-b]carbazols are the most potent naturally occurring activators ofthe AhR signaling pathway and may be the key substrates of theCYP1 and SULT1 families of enzymes. These conclusions contradictthe widespread view that xenobiotic compounds are themajor AhR ligands and CYP1 substrates.

45678 301 - 350 of 371
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