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- Friberg, Andrew S, 1979-
(författare)
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Standardization of Islet Isolation and Transplantation Variables
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Currently, the transplantation of islets of Langerhans is a viable means to maintain control of blood sugar levels and reduce the risk of hypoglycemia in defined populations with brittle type I diabetes mellitus or those requiring pancreatectomy. However, the process of islet isolation is highly variable and not all isolations result in islet numbers or quality suitable for transplantation. This thesis aimed to improve transplantation success through optimization and standardization of the isolation process and to identify pretransplant variables associated with early islet engraftment. A previously disregarded enzyme activity, tryptic-like activity (TLA), has been identified to influence pancreas digestion efficiency and islet isolation success in both the preclinical and clinical situations. For human pancreases, islet isolation success rates improved from 0% in the lowest TLA group to over 50% in the highest TLA groups without affecting islet quality. These findings should help standardize evaluation of enzymes for clinical islet isolation. A closed, automated, pump-made gradient system was compared to the open, manual method for islet separation. No differences were observed in expected gradient volumes, islet yields or total purities between the two methods. The pump-made gradient system successfully removed manual influences on density gradient production while fulfilling regulatory requirements for closed system processing. Islet quantification was evaluated with computer-assisted digital imaging analysis (DIA) and a semi-closed assessment system. By using the DIA system method, which measures islet purity and pellet volume instead of manual counting methods, variation in islet counts and purity reduced by almost half. By using a transplant outcome measurement of C-peptide adjusted by blood glucose and creatinine, we identified four pretransplant factors that affect early transplant outcome. Of the four factors, one was related to the organ transport time, one to function of the islets, and two to the transplanted tissue volume. When these four factors were put into a predictive model, it accounted for about 40% of the transplant outcome. The work contained in this thesis identifies and optimizes a number of critical elements related to islet isolation and transplantation protocols.
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| 3. |
- Artigas, J., et al.
(författare)
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Towards a renewed research agenda in ecotoxicology
- 2012
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Ingår i: Environmental Pollution. - : Elsevier BV. - 0269-7491. ; 160, s. 201-206
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Tidskriftsartikel (refereegranskat)abstract
- New concerns about biodiversity, ecosystem services and human health triggered several new regulations increasing the need for sound ecotoxicological risk assessment. The PEER network aims to share its view on the research issues that this challenges. PEER scientists call for an improved biologically relevant exposure assessment. They promote comprehensive effect assessment at several biological levels. Biological traits should be used for Environmental risk assessment (ERA) as promising tools to better understand relationships between structure and functioning of ecosystems. The use of modern high throughput methods could also enhance the amount of data for a better risk assessment. Improved models coping with multiple stressors or biological levels are necessary to answer for a more scientifically based risk assessment. Those methods must be embedded within life cycle analysis or economical models for efficient regulations. Joint research programmes involving humanities with ecological sciences should be developed for a sound risk management. (C) 2011 Elsevier Ltd. All rights reserved.
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| 5. |
- Bellec, G., et al.
(författare)
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A social network integrated game experiment to relate tapping to speed perception and explore rhythm reproduction
- 2013
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Ingår i: Proceedings of the Sound and Music Computing Conference 2013. - 9783832534721 ; , s. 19-26
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Konferensbidrag (refereegranskat)abstract
- During recent years, games with a purpose (GWAPs) have become increasingly popular for studying human behaviour [1–4]. However, no standardised method for web-based game experiments has been proposed so far. We present here our approach comprising an extended version of the CaSimIR social game framework [5] for data collection, mini-games for tempo and rhythm tapping, and an initial analysis of the data collected so far. The game presented here is part of the Spot The Odd Song Out game, which is freely available for use on Facebook and on the Web 1 .We present the GWAP method in some detail and a preliminary analysis of data collected. We relate the tapping data to perceptual ratings obtained in previous work. The results suggest that the tapped tempo data collected in a GWAP can be used to predict perceived speed. I toned down the above statement as I understand from the results section that our data are not as good as When averagingthe rhythmic performances of a group of 10 players in the second experiment, the tapping frequency shows a pattern that corresponds to the time signature of the music played. Our experience shows that more effort in design and during runtime is required than in a traditional experiment. Our experiment is still running and available on line.
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| 6. |
- Bender, Brendan, et al.
(författare)
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A Mechanistic Pharmacokinetic Model Elucidating the Disposition of Trastuzumab Emtansine (T-DM1), an Antibody-Drug Conjugate (ADC) for Treatment of Metastatic Breast Cancer
- 2014
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Ingår i: AAPS Journal. - : Springer Science and Business Media LLC. - 1550-7416. ; 16:5, s. 994-1008
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Tidskriftsartikel (refereegranskat)abstract
- Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) therapeutic for treatment of human epidermal growth factor receptor 2 (HER2)-positive cancers. The T-DM1 dose product contains a mixture of drug-to-antibody ratio (DAR) moieties whereby the small molecule DM1 is chemically conjugated to trastuzumab antibody. The pharmacokinetics (PK) underlying this system and other ADCs are complex and have not been elucidated. Accordingly, we have developed two PK modeling approaches from preclinical data to conceptualize and understand T-DM1 PK, to quantify rates of DM1 deconjugation, and to elucidate the link between trastuzumab, T-DM1, and DAR measurements. Preclinical data included PK studies in rats (n = 34) and cynomolgus monkeys (n = 18) at doses ranging from 0.3 to 30 mg/kg and in vitro plasma stability. T-DM1 and total trastuzumab (TT) plasma concentrations were measured by enzyme-linked immunosorbent assay. Individual DAR moieties were measured by affinity capture liquid chromatography-mass spectrophotometry. Two PK modeling approaches were developed for T-DM1 using NONMEM 7.2 software: a mechanistic model fit simultaneously to TT and DAR concentrations and a reduced model fit simultaneously to TT and T-DM1 concentrations. DAR moieties were well described with a three-compartmental model and DM1 deconjugation in the central compartment. DM1 deconjugated fastest from the more highly loaded trastuzumab molecules (i.e., DAR moieties that are a parts per thousand yen3 DM1 per trastuzumab). T-DM1 clearance (CL) was 2-fold faster than TT CL due to deconjugation. The two modeling approaches provide flexibility based on available analytical measurements for T-DM1 and a framework for designing ADC studies and PK-pharmacodynamic modeling of ADC efficacy- and toxicity-related endpoints.
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