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- Adolfsson, Per I., et al.
(författare)
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Characterization of EDG receptor expression and proliferative response in cultured human BPH smooth muscle cells
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The endogenous phospholipids, lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are both known to generate a Vvide variety of effects in various cell systems by the endothelial differentiation gene (Edg) receptor family, including 7 different G-protein coupled Edg receptors.In this study, expression of LPA- and SlP Edg receptors was examined, and so was the effect with respect to proliferation on cultured BPH smooth muscle cells smc. Mmeover, theresponse on cAMP levels was examined. Finally, a potential link between activation of the MAP kinase cascade and the LPA stimulated proliferation was investigated.First, the RT-PCR analysis of the Edg receptors in BPH smc, demonstrated a heterogeneous expression including all receptors except the Edg6 subtype. Further, in contrast to LPA, the mitogen effect of SIP, demonstrated a concentration-dependent biphasic response, including stimulation below 1μM, whereas inhibition was obtained at higher concentrations. Forskolin induced a rapid and transient cAMP response in LPA stimulated cells, with a peak-value after 3 minutes. After 15 minutes the cAMP level had retmned to base-line level. However a gradual increase to 15% of maximum value was obtained after additional 30 minutes, and thereafter a gradual reduction was observed. The mentioned antiproliferative response generated by SIP could not be conelated to an intracellular cAMP increase. Finally, when the LPA treated smc was co-incubated with the MAPK kinase inhibitor PD98059 (10 μM) the mitogen response was eliminated.The cAIVIP increase, which was induced by forskolin, corresponds with mentioned antiproliferative effect whereas a similar con-elation was not obtained regarding SIP. The intracellular signal mechanisms triggered by LPA and S1P in BPH smc remain to be further investigated.
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- Al-Amin, Rasel A., 1983-, et al.
(författare)
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Target Engagement-Mediated Amplification for Monitoring Drug-Target Interactions in Situ
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- It is important to determine the localization of drugs or drug candidates at cellular and subcellular resolution in relevant clinical specimens. This is necessary to evaluate drug candidates from early stages of drug development to clinical evaluation of mutations potentially causing resistance to targeted therapy. We describe a technology where oligonucleotide-conjugated drug molecules are used to visualize and measure target engagement in situ via rolling-circle amplification (RCA) of circularized oligonucleotide probes (padlock probes). We established this target engagement-mediated amplification (TEMA) technique using kinase inhibitor precursor compounds, and we applied the assay to investigate target interactions by microscopy in pathology tissue sections and using flow cytometry for blood samples from patients, as well as in commercial arrays including almost half of all human proteins. In the variant proxTEMAtechnique, in situ proximity ligation assays were performed by combining drug-DNA conjugates with antibody-DNA conjugates to specifically reveal drug binding to particular on- or off-targets in pathological tissues sections. In conclusion, the TEMA methods successfully visualize drug-target interaction by experimental and clinically approved kinase inhibitors in situ and with kinases among a large collection of arrayed proteins.
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- Gustafsson Stolt, Ulrica, et al.
(författare)
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The problems of obtaining informed consent in screening for Type 1 diabetes involving small children
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Purpose As part of a research ethical case study our objective was to explore existing and potential bioethical issues with regard to a research screening for Type 1 involving 17,000 children and their families (present outcome: 78.6%).Research design and methods The setting was ABIS (All Babies In Southeast Sweden), a presently ongoing Swedish research screening designed as a multi-centre, longitudinal and geographically located research screening for Type 1 Diabetes in an unselected birth cohort. From the perinatal questionnaire serial numbers we made a random selection of participating mothers. 293 completed the anonymous questionnaire, resulting in a response rate of 73.3%.Results The overall majority of respondents reported (1), being satisfied with the information, (2), looking upon the information as sufficient for their decision, (3), having fully understood the information and (4), having made a fully voluntary decision to participate. However, knowledge about the study varied widely and we found several variations of misunderstandings, even regarding basic facts. For example, one in three respondent was unsure (or indeed unaware) with regard to one aim being the identification of children at high risk.Condusions We have recorded flaws in research participants understanding of their own and their child's participation in a prospective screening programme, even though attention was paid to distributing information through a variety of methods. This points to the importance of giving information: in a variety of methods and also repeatedly in long-term studies.
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