| 1. |
- Holmgren, Per, et al.
(författare)
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Drug interactions : a challenge in interpreting postmortem toxicology results and a problem in the clinical practice
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Objective: Multiple drug intake is a problem in tbe clinical setting with potential to adverse drug reactions and certainly a problem in interpretation of forensic toxicology results. The aims of this investigation were to study the incidence of concomitant drugs in autopsy cases where citalopram or zopiclone were detected in femoral blood and to evaluate the potential of drug interactions.Methods: All medico-legal autopsy cases in Sweden during 1992 to 2003 where citalopram or zopiclone were detected in femoral blood at the toxicological analyses were selected. The number and occurrences of concomitant drugs were recorded together with the concentrations as well as the cause of death.Results: In the 2405 cases with citalopram, 123 different drugs, metabolites excluded, were detected 4679 times giving an average of 1.9 concomitant drugs and 1099 different dmg combinations were identified. The corresponding figures for the cases with zopiclone were 1557 cases, 118 different drugs detected 3984 times giving an average of 2.6 concomitant drugs and 977 different combinations. We found a strong positive correlation between the number of drugs detected and the frequency of cases judged to be intoxication.Conclusions: Pharmacokinetic and pharmacodynamic interactions are a potential problem when interpreting forensic toxicological results and the conclusions about the cause and manner of death in the single case must be based on all available information from the investigation and tbe autopsy and on tbe knowledge of tbe pharmacology of included drugs. A better control of prescriptions of what different drugs an individual is given together with a comprehensive therapy control may reduce the risks of adverse drug reactions and unintended or accidental intoxications.
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| 2. |
- Tjomsland, Vegard, et al.
(författare)
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IL-1α Sustains the Inflammation in Human Pancreatic Cancer Microenvironment by Targeting Cancer Associated Fibroblasts
- 2010
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) is dynamic with an extensive interaction between the stroma and tumor cells. Our aim for this study was to delineate the cross-talk between PDAC and cancer-associated fibroblasts (CAFs) with focus on the mechanism creating the chronic inflammatory tumor milieu. We assessed the effect cross talk between primary PDAC and CAF cell lines propagated from tumors had on the creation and sustenance of an inflammatory environment and what factors that were involved in establishing the inflammation. The coculture of PDAC and CAF cell lines, propagated from tumor tissues, enhanced the levels of inflammatory factors including IL-1α, IL-6, CXCL8, VEGFA, CCL20, and COX-2. The production of these factors correlated with the expression detected in vivo in PDAC tissues. The key producers of nearly all inflammatory factors were the CAFs and not the tumor cells. IL-1α was produced by the tumor cell lines, whereas almost all IL-1RI was expressed by CAFs thus corresponding to their in vivo expression profile in PDAC tissues, indicating a role for the IL-1 signaling cascade in a tumor favorable microenvironment. Neutralization of the IL-1α pathway efficiently diminished the cross talk induced production of inflammatory factors, both in stroma and tumor cells. These data suggest that the cross-talk between PDAC cells and the main stroma cell type, i.e. CAFs, is one contributing factor in the formation of the inflammatory tumor environment and we propose that the neutralization of IL-1α pathway might be a potential therapy for this cancer.
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| 3. |
- Tjomsland, Vegard, et al.
(författare)
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Pancreatic cancer microenvironment has a high degree of inflammation and infiltrating immune cells in its stroma
- 2010
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Tumor microenvironment is composed of tumor cells, fibroblasts, and infiltrating immune cells, and other cellular components, which work together and create an inflammatory environment favoring tumor progression. The present study aimed to characterize the expression and location of immune cells and investigate inflammatory factors that influence pancreatic ductal adenocarcinoma (PDAC). Methods: qPCRs and immunohistological stainings were performed for inflammatory factors and immune cells localized in tumor tissues from patients with PDAC (N=30). Results: All PDAC tissues had significant increased levels of inflammatory and chemotactic factors such as IL-1α, COX-2, CXCL8, CCL2, and CCL20 as compared to controls. The PDAC stroma, i.e. the fibrosis surrounding the tumor, was the main producer of these factors with the exception of IL-1α, which was expressed by tumor cells and some infiltrating immune cells. The gene expression for immune cell specific markers CD163, CD1c, CD303, and CD8, corresponding to macrophages, myeloid dendritic cells (DCs), plasmacytoid DCs, and cytotoxic T lymphocytes (CTL), respectively, were all significantly increased in PDAC tissues. Immunostaining of the tumor tissue confirmed the elevated levels of infiltrating macrophages, DCs, mature DCs, and cytotoxic T lymphocytes (CTL). The different immune cells were in nearly all cases localized in the fibrotic tissue adjacent to tumor nests. Production of CXCL8 mRNA and protein by the stroma was dependent on the tumor expression of IL-1α. Of importance, we found a correlation in expression of the proinflammatory factor IL-1α and the PDAC patients’ survival time. Conclusion: PDAC cells seem to take advantage of IL-1α to create an inflammatory microenvironment with high degree of fibrosis and the ability to both recruit and activate immune cells and the level of inflammation in this environment influenced the clinical outcome for the patients. Therapies targeting the inflammation might be beneficial for the survival of patients with PDAC.
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