| 1. |
- Fryknäs, Mårten, et al.
(författare)
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Screening for phenotype selective activity in multidrug resistant cells identifies a novel tubulin active agent insensitive to common forms of cancer drug resistance
- 2013
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 13, s. 374-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Drug resistance is a common cause of treatment failure in cancer patients and encompasses a multitude of different mechanisms. The aim of the present study was to identify drugs effective on multidrug resistant cells. Methods: The RPMI 8226 myeloma cell line and its multidrug resistant subline 8226/Dox40 was screened for cytotoxicity in response to 3,000 chemically diverse compounds using a fluorometric cytotoxicity assay (FMCA). Follow-up profiling was subsequently performed using various cellular and biochemical assays. Results: One compound, designated VLX40, demonstrated a higher activity against 8226/Dox40 cells compared to its parental counterpart. VLX40 induced delayed cell death with apoptotic features. Mechanistic exploration was performed using gene expression analysis of drug exposed tumor cells to generate a drug-specific signature. Strong connections to tubulin inhibitors and microtubule cytoskeleton were retrieved. The mechanistic hypothesis of VLX40 acting as a tubulin inhibitor was confirmed by direct measurements of interaction with tubulin polymerization using a biochemical assay and supported by demonstration of G2/M cell cycle arrest. When tested against a broad panel of primary cultures of patient tumor cells (PCPTC) representing different forms of leukemia and solid tumors, VLX40 displayed high activity against both myeloid and lymphoid leukemias in contrast to the reference compound vincristine to which myeloid blast cells are often insensitive. Significant in vivo activity was confirmed in myeloid U-937 cells implanted subcutaneously in mice using the hollow fiber model. Conclusions: The results indicate that VLX40 may be a useful prototype for development of novel tubulin active agents that are insensitive to common mechanisms of cancer drug resistance.
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| 2. |
- Gullbo, Joachim, et al.
(författare)
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Phenotype-based drug screening in primary ovarian carcinoma cultures identifies intracellular iron depletion as a promising strategy for cancer treatment
- 2011
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Ingår i: Biochemical Pharmacology. - : Elsevier BV. - 0006-2952 .- 1356-1839 .- 1873-2968. ; 82:2, s. 139-147
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Tidskriftsartikel (refereegranskat)abstract
- Primary cultures of patient tumor cells (PCPTC) have been used for prediction of diagnosis-specific activity and individual patient response to anticancer drugs, but have not been utilized as a model for identification of novel drugs in high throughput screening. In the present study, ovarian carcinoma cells from three patients were tested in response to a library of 3000 chemically diverse compounds. Eight hits were retrieved after counter screening using normal epithelial cells, and one of the two structurally related hit compounds was selected for further preclinical evaluation. This compound, designated VLX 50, demonstrated a broad spectrum of activity when tested in a panel of PCPTCs representing different forms of leukemia and solid tumors and displayed a high tumor to normal cell activity. VLX 50 induced delayed cell death with some features of classical apoptosis. Significant in vivo activity was confirmed on primary cultures of human ovarian carcinoma cells in mice using the hollow fiber model. Mechanistic exploration was performed using gene expression analysis of drug exposed tumor cells to generate a drug-specific signature. This query signature was analyzed using the Gene Set Enrichment Analysis and the Connectivity Map database. Strong connections to hypoxia inducible factor 1 and iron chelators were retrieved. The mechanistic hypothesis of intracellular iron depletion leading to hypoxia signaling was confirmed by a series of experiments. The results indicate the feasibility of using PCPTC for cancer drug screening and that intracellular iron depletion could be a potentially important strategy for cancer therapy.
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| 3. |
- Hermansson, Anne-Marie, 1945, et al.
(författare)
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Innovation genom forskning och långsiktig samverkan mellan akademi och näringsliv
- 2016
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Ingår i: Sveriges entreprenöriella ekosystem - Företag, akademi, politik. - 9789197772846 ; , s. 359-
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Detta kapitel handlar om forskning och innovation inom ett VINN Excellence Centre1 som heter SuMo Biomaterials.2 Författarna har alla varit verksamma vid centrumet, och kapitlet bygger på våra erfarenheter från det arbetet. Vi lyfter fram faktorer som har betydelse för en framgångsrik, långsiktig samverkan mellan akademi och näringsliv.InomSuMo möter företag från helt olika verksamhetsområden, men med likartade vetenskapliga frågeställningar, akademin. Forskningen sker i samverkan och har övergripande betydelse för företagens strategiska mål. Med utgångspunkt från en stark vision utvecklas samarbetsformer för näringslivssamverkan och excellensforskning i kluster över disciplingränser. I kapitlet lyfter vi betydelsen av timing, kommunikation, förväntningar och strategiska förändringar i ett långsiktigt perspektiv. SuMo är finansierat gemensamt av Vinnova, näringslivspartners, SP Food and Bioscience och Chalmers. Centrumet startades i mars 2007 och kommer att avslutas under 2016. Utvecklingen är indelad i fyra faser: initiering och uppstart, forskning i världsklass, implementering samt nyttiggörande. Vårtkoncept och sätt att arbeta bygger mycket på kommunikation och samarbete inom akademin, mellan akademi och näringsliv – men också mellan olika näringslivspartners.
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| 4. |
- Holm, Sture, 1936, et al.
(författare)
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Confidence intervals for distributional positions
- 2024
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Ingår i: Communications in Statistics - Theory and Methods. - : Informa UK Limited. - 0361-0926 .- 1532-415X. ; 53:7, s. 2645-2660
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Tidskriftsartikel (refereegranskat)abstract
- A common problem with ranking lists (e.g., regarding success/failure proportions of treatments at hospitals) is that smaller units tend to end up either in the top or in the bottom just by pure chance. To alleviate this problem, we propose a method that, for a given unit, gives a confidence interval for the position of this unit within the distribution of the other units. The confidence interval is based on asymptotic normality. The method is illustrated by an empirical example. The small sample confidence level is investigated in a simulation study.
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| 5. |
- Karlsson, Henning, et al.
(författare)
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Mechanistic characterization of a copper containing thiosemicarbazone with potent antitumor activity
- 2017
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 8:18, s. 30217-30234
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Tidskriftsartikel (refereegranskat)abstract
- Background: The thiosemicarbazone CD 02750 (VLX50) was recently reported as a hit compound in a phenotype-based drug screen in primary cultures of patient tumor cells. We synthesized a copper complex of VLX50, denoted VLX60, and characterized its antitumor and mechanistic properties. Materials and Methods: The cytotoxic effects and mechanistic properties of VLX60 were investigated in monolayer cultures of multiple human cell lines, in tumor cells from patients, in a 3-D spheroid cell culture system and in vivo and were compared with those of VLX50. Results: VLX60 showed ?3-fold higher cytotoxic activity than VLX50 in 2-D cultures and, in contrast to VLX50, retained its activity in the presence of additional iron. VLX60 was effective against non-proliferative spheroids and against tumor xenografts in vivo in a murine model. In contrast to VLX50, gene expression analysis demonstrated that genes associated with oxidative stress were considerably enriched in cells exposed to VLX60 as was induction of reactive oxygen. VLX60 compromised the ubiquitin-proteasome system and was more active in BRAF mutated versus BRAF wild-type colon cancer cells. Conclusions: The cytotoxic effects of the copper thiosemicarbazone VLX60 differ from those of VLX50 and shows interesting features as a potential antitumor drug, notably against BRAF mutated colorectal cancer.
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| 6. |
- Larsson, Lars, 1945, et al.
(författare)
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Principi di Yacht Design (in Italian)
- 2022
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Bok (övrigt vetenskapligt/konstnärligt)abstract
- Principles of Yacht Design has established itself as the standard book on the subject for practising designers, naval architecture students, discerning boat owners as well as the boatbuilding industry as a whole. The fifth edition is completely revised and expanded. It examines every aspect of the process of yacht and powerboat design. The new edition includes new findings from recent research in aero and hydrodynamics, as well as covering the most recent changes to building standards. The authors have used a newly built 41-foot performance cruiser to demonstrate the practical application of yacht design theory. This new edition includes photos of the building process and detailed explanations.
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| 9. |
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| 10. |
- Larsson, Lars, 1945, et al.
(författare)
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Principles of Yacht Design (4th ed.)
- 2013
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Bok (övrigt vetenskapligt/konstnärligt)abstract
- The first edition of the Principles of Yacht Design was published in 1994. Since then there have been two new editions, and the book has been translated into German, Japanese and Korean. A special edition is published in the United States. The book has thus been very well received, and in this fourth edition we have kept the structure and the main contents of the previous editions. The basic idea is to cover all aspects of yacht design, from the specification, through the hydro- and aerodynamic design, structural assessment and layout, to the final evaluation. Emphasis is placed on concept descriptions, but formulae, separated from the text, are included in sufficient depth for a complete design of a new yacht. An important feature of the book is the example yacht, used throughout the book to exemplify the use of the formulae. This is where the present edition differs most from the previous ones. A completely new modern performance cruiser, the YD–41 has replaced the original YD-40, designed for the first edition. This has called for a revision of most of the figures and important parts of the text. In connection with the new design, the statistics found in the design chapters have been completely revised, and are now based on yachts designed during the past ten years. The primary designer of the new yacht is Michal Orych, who is now welcomed as the third author of the book.Since the first edition there have been regular updates particularly in two areas: hydrodynamic formulas based on the Delft systematic yacht hull series (DSYHS), and ISO standards for the safety and structural integrity of sailing yachts. The authors are indebted to Dr Lex Keuning, the manager of DSHYS, for his advice in this matter. The ISO 12217-2 seaworthiness standard was developed under the chairmanship of Andrew Blyth, and the ISO scantlings standard 12215 under the late Fritz Hartz and more recently Gregoire Dolto. Thanks are due to all of them for their support, and for their permission to use unpublished parts of the standards. In the present edition, new resistance formulae are presented from DSHYS, and the ISO 12215 standard has been updated with respect to rudders and appendages.Since the first edition there has been a dramatic development in Computational Fluid Dynamics (CFD), and this is reflected in the present edition, where a considerably expanded section in the last chapter is devoted to this exciting technique.
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