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Sökning: WFRF:(Nygren Peter) > (2005-2009)

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  • Björn, Erik, et al. (författare)
  • Determination of platinum in human subcellular microsamples by inductively coupled plasma mass spectrometry
  • 2007
  • Ingår i: Analytical Biochemistry. ; 363, s. 135-42
  • Tidskriftsartikel (refereegranskat)abstract
    • A fast and robust method for the determination of platinum in human subcellular microsamples by inductively coupled plasma mass spectrometry was developed, characterized, and validated. Samples of isolated DNA and exosome fractions from human ovarian (2008) and melanoma (T289) cancer cell lines were used. To keep the sample consumption to approximately 10 μl and obtain a high robustness of the system, a flow injection sample introduction system with a 4.6-μl sample loop was used in combination with a conventional pneumatic nebulizer and a spray chamber. The system was optimized with respect to signal/noise ratio using a multivariate experimental design. The system proved to be well suited for routine analysis of large sample series, and several hundreds of samples could be analyzed without maintenance or downtime. The detection limit of the method was 0.12 pg (26 pg/g) platinum. To avoid systematic errors from nonspectral interferences, it was necessary to use reagent matched calibration standards or isotope dilution analysis. An uncertainty budget was constructed to estimate the total expanded uncertainty of the method, giving a quantification limit of 2.3 pg (0.5 ng/g) platinum in DNA samples. The uncertainty was sufficiently low to study quantitative differences in the formation of Pt–DNA adducts after treatment with cisplatin using different exposure times and concentrations.
  • Byström, Per, et al. (författare)
  • Early prediction of response to first-line chemotherapy by sequential [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography in patients with advanced colorectal cancer
  • 2009
  • Ingår i: Annals of Oncology. - 0923-7534 .- 1569-8041. ; 20:6, s. 1057-1061
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: To evaluate [(18)F]-2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET), for early evaluation of response to palliative chemotherapy and for prediction of long-term outcome, in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: In a randomized trial, patients with mCRC received irinotecan-based combination chemotherapy. FDG-PET was carried out before treatment and after two cycles in 51 patients at two centers. Visual changes in tumor FDG uptake and changes measured semi-automatically, as standard uptake values (SUVs), were compared with radiological response after four and eight cycles. RESULTS: The mean baseline SUV for all tumor lesions per patient was higher in nonresponders than in responders (mean 7.4 versus 5.6, P = 0.02). There was a strong correlation between metabolic response (changes in SUV) and objective response (r = 0.57, P = 0.00001), with a sensitivity of 77% and a specificity of 76%. There was no significant correlation between metabolic response and time to progression (P = 0.5) or overall survival (P = 0.1). CONCLUSIONS: Although metabolic response assessed by FDG-PET reflects radiological tumor volume changes, the sensitivity and specificity are too low to support the routine use of PET in mCRC. Furthermore, PET failed to reflect long-term outcome and can, thus, not be used as surrogate end point for hard endpoint benefit.
  • Dreilich, Martin, et al. (författare)
  • Telomerase activity is not a key determinant of sensitivity to standard cytotoxic drugs in human esophageal carcinoma cell lines
  • 2006
  • Ingår i: Anti-Cancer Drugs. - 0959-4973 .- 1473-5741. ; 17:5, s. 503-509
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim of the present study was to investigate if basal telomerase activity levels may predict sensitivity to cytotoxic drugs in a panel of human esophageal carcinoma cell lines. The TRAPeze telomerase detection assay was used to investigate telomerase activity in the cell lines. Cytotoxic drug sensitivity for 20 standard cytotoxic agents was assessed using the fluorometric microculture cytotoxicity assay (FMCA). Telomerase activity was detected in all cell lines with a broad range of activity levels. Drug sensitivity also varied considerably between the cell lines. Except for a P value towards a correlation between mitoxantrone and telomerase activity (P=0.054), no statistically significant correlation was found between telomerase activity levels and sensitivity to investigated drugs, including key drugs such as cisplatin (P=0.9), 5-fluorouracil (P=0.8) and doxorubicin (P=0.54). We therefore conclude that basal telomerase activity level is not a key determinant of sensitivity to standard cytotoxic drugs in esophageal carcinoma cell lines.
  • Fryknäs, Mårten, et al. (författare)
  • Phenotype-based screening of mechanistically annotated compounds in combination with gene expression and pathway analysis identifies candidate drug targets in a human squamous carcinoma cell model
  • 2006
  • Ingår i: Journal of Biomolecular Screening. - 1087-0571 .- 1552-454X. ; 11:5, s. 457-468
  • Tidskriftsartikel (refereegranskat)abstract
    • The squamous cell carcinoma HeLa cell line and an epithelial cell line hTERT-RPE with a nonmalignant phenotype were interrogated for HeLa cell selectivity in response to 1267 annotated compounds representing 56 pharmacological classes. Selective cytotoxic activity was observed for 14 of these compounds dominated by cyclic adenosine monophosphate (cAMP) selective phosphodiesterase (PDE) inhibitors, which tended to span a representation of the chemical descriptor space of the library. The PDE inhibitors induced delayed cell death with features compatible with classical apoptosis. The PDE inhibitors were largely inactive when tested against a cell line panel consisting of hematological and nonsquamous epithelial phenotypes. In a genome-wide DNA microarray analysis, PDE3A and PDE2A were found to be significantly increased in HeLa cells compared to the other cell lines. The pathway analysis software PathwayAssist was subsequently used to extract a list of proteins and small molecules retrieved from Medline abstracts associated with the hit compounds. The resulting list consisted of major parts of the cAMP-protein kinase A pathway linking to ERK, P38, and AKT. This molecular network may provide a basis for further exploitation of novel candidate targets for the treatment of squamous cell carcinoma.
  • Fryknäs, Mårten, et al. (författare)
  • STAT1 signaling is associated with acquired crossresistance to doxorubicin and radiation in myeloma cell lines
  • 2007
  • Ingår i: International Journal of Cancer. - 0020-7136 .- 1097-0215. ; 120:1, s. 189-195
  • Tidskriftsartikel (refereegranskat)abstract
    • The myeloma cell line RPMI 8226/S and its doxorubicin resistant subline 8226/Dox40 were used as models to explore the potential importance of the STAT1 signaling pathway in drug and radiation resistance. The 40-fold doxorubicin resistant subline 8226/Dox40 was found to be crossresistant to single doses of 4 and 8 Gy of radiation. A genome-wide mRNA expression study comparing the 8226/Dox40 cell line to its parental line was performed to identify the underlying molecular mechanisms. Seventeen of the top 50 overexpressed genes have previously been implicated in the STAT1 signaling pathway. STAT1 was over expressed both at the mRNA and protein level. Moreover, analyses of nuclear extracts showed higher abundance of phosphorylated STAT1 (Tyr 701) in the resistant subline. Preexposure of the crossresistant cells to the STAT1 inhibiting drug fludarabine reduced expression of overexpressed genes and enhanced the effects of both doxorubicin and radiation. These results show that resistance to doxorubicin and radiation is associated with increased STAT1 signaling and can be modulated by fludarabine. The data support further development of therapies combining fludarabine and radiation.
  • Hagell, Peter, et al. (författare)
  • The 39-item Parkinson's disease questionnaire (PDQ-39) revisited: implications for evidence-based medicine.
  • 2007
  • Ingår i: J Neurol Neurosurg Psychiatry. - BMJ Publishing Group. - 1468-330X. ; 78:Apr 18, s. 1191-1198
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The 39 item Parkinson's disease questionnaire (PDQ-39) is the most widely used patient reported rating scale in Parkinson's disease. However, several fundamental measurement assumptions necessary for confident use and interpretation of the eight PDQ-39 scales have not been fully addressed. Methods: Postal survey PDQ-39 data from 202 people with Parkinson's disease (54% men; mean age 70 years) were analysed regarding psychometric properties using traditional and Rasch measurement methods. Results: Data quality was good ( mean missing item responses, 2%) and there was general support for the legitimacy of summing items within scales without weighting or standardisation. Score reliabilities were adequate (Cronbach's alpha 0.72-0.95; test-retest 0.76-0.93). The validity of the current grouping of items into scales was not supported by scaling success rates ( mean 56.2%), or factor and Rasch analyses. All scales represented more health problems than that experienced by the sample ( mean floor effect 15%) and showed compromised score precision towards the less severe end. Conclusions: Our results provide general support for the acceptability and reliability of the PDQ-39. However, they also demonstrate limitations that have implications for the use of the PDQ-39 in clinical research. The grouping of items into scales appears overly complex and the meaning of scale scores is unclear, which hampers their interpretation. Suboptimal targeting limits measurement precision and, therefore, probably also responsiveness. These observations have implications for the role of the PDQ-39 in clinical trials and evidence based medicine. PDQ-39 derived endpoints should be interpreted and selected cautiously, particularly regarding small but clinically important effects among people with less severe problems.
  • Hansson, Johan, et al. (författare)
  • Postoperative adverse events and long-term survival after cytoreductive surgery and intraperitoneal chemotherapy
  • 2009
  • Ingår i: European Journal of Surgical Oncology. - 0748-7983 .- 1532-2157. ; 35:2, s. 202-208
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Peritoneal carcinomatosis (PC) is fatal without special combined cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC). This study was designed to identify factors that may increase the risk of postoperative morbidity and mortality from combined CRS and IPC interventions for PC. Survival based on primary tumour type and extent of surgery is reported. METHODS: Between May 1991 and November 2004, 123 patients were treated with CRS and IPC for PC. Based on the National Cancer Institute Common Toxicity Criteria for grade 3 and 4, data on 30 days postoperative morbidity and 90 days mortality were analysed. RESULTS: Grade 3-4 adverse events were observed in 51 patients (41%) and were associated with stoma formation, duration of surgery, peroperative blood loss and peritoneal cancer index (PCI). Excision, or electrocautery evaporation, of tumour from small bowel surface was correlated to bowel morbidity. Five patients had treatment-related mortality (4%) within 90 days. Survival was associated with macroscopic radical surgery, prior surgical score, PCI and primary tumour type. CONCLUSIONS: CRS and IPC for PC are associated with high morbidity and mortality. However, in light of the potential benefit indicated by long-term survival, the adverse event from this treatment is considered acceptable.
  • Hedström, Mariann, et al. (författare)
  • Accuracy of assessment of distress, anxiety, and depression by physicians and nurses in adolescents recently diagnosed with cancer
  • 2006
  • Ingår i: Pediatric Blood & Cancer. - 1545-5009 .- 1545-5017. ; 46:7, s. 773-9
  • Tidskriftsartikel (refereegranskat)abstract
    • Background. As staff members prioritize medical resources forpatients, it is imperative to find out whether their assessments ofpatients’ health status agree with patients’ assessments. The degree towhich physicians and nurses can identify the distress, anxiety, anddepression experienced by adolescents recently diagnosed withcancer was examined here. Procedure. Adolescents undergoingchemotherapy (13–19 years, n¼53), physicians (n¼48), and nurses(n¼53) completed a structured telephone interview, 4–8 weeksafter diagnosis or relapse, investigating disease and treatment-relateddistress, anxiety, and depression. Results. The accuracy of staffratings of physical distress could be considered acceptable.However, problems of a psychosocial nature, which were frequentlyoverestimated, were difficult for staff to identify. Staff underestimatedthe distress caused by mucositis and worry about missing schoolmore than they overestimated distress. These aspects were some ofthe most prevalent and overall worst according to the adolescents.Both physicians and nurses overestimated levels of anxiety anddepression. Nurses tended to show higher sensitivity than physiciansfor distress related to psychosocial aspects of distress, whilephysicians tended to show higher accuracy than nurses for physicaldistress. Conclusions. Staff was reasonably accurate at identifyingphysical distress in adolescents recently diagnosed with cancerwhereas psychosocial problems were generally poorly identified.Thus, the use of staff ratings as a ‘‘test’’ to guide specific supportseems problematic. Considering that the accuracy of staff ratingsoutside a research study is probably lower, identification of andaction taken on adolescent problems in relation to cancer diagnosisand treatment need to rely on direct communication.
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