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  • Larsson, Dhana E., et al. (författare)
  • Combination analyses of anti-cancer drugs on human neuroendocrine tumor cell lines
  • 2009
  • Ingår i: Cancer Chemotherapy and Pharmacology. - 0344-5704 .- 1432-0843. ; 65:1, s. 5-12
  • Tidskriftsartikel (refereegranskat)abstract
    • PURPOSE: There is a large need for better pharmacological treatment of neuroendocrine tumors. The aim of this study was to investigate and quantify the cytotoxic potentiating effects resulting from a combination of five substances, NSC 95397, emetine, CGP-74514A hydrochloride, Brefeldin A and sanguinarine chloride, chosen from a previous screening of 1,280 pharmacologically active agents on neuroendocrine tumor cells, with standard cytotoxic agents currently used in the treatment of neuroendocrine tumors. METHOD: The human pancreatic carcinoid cell line BON-1, human typical bronchial carcinoid cell line NCI-H727 and the human atypical bronchial carcinoid cell line NCI-H720 were used. Combinations between doxorubicin, etoposide, oxaliplatin, docetaxel, and each one of the five agents were studied and simultaneous exposures were explored using the median-effect method. RESULTS: Most of the combinations of NSC-95397 and emetine with doxorubicin, etoposide, docetaxel, and oxaliplatin showed synergism, and their remaining combinations were additive. Almost all of the CGP-74514A hydrochloride interactions were additive, while brefeldin A and sanguinarine displayed less synergy but more additive and antagonistic interactions in combination with the standard drugs. CONCLUSION: The synergistic and additive interactions make NSC-95397, emetine, and CGP-74514A hydrochloride potential candidates for incorporation into combination chemotherapy regimens and these drugs might be the suitable candidates for further clinical studies in patients with bronchial carcinoids and pancreatic endocrine tumors.
  • Larsson, Dhana E., et al. (författare)
  • Identification and evaluation of potential anti-cancer drugs on human neuroendocrine tumor cell lines
  • 2006
  • Ingår i: Anticancer Research. - 0250-7005 .- 1791-7530. ; 26:6B, s. 4125-4129
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim of this study was to investigate drug sensitivity in neuroendocrine tumor cell lines. Materials and Methods: In vitro drug sensitivity screening was performed using the fluorometric microculture cytotoxicity assay in one human pancreatic carcinoid and two human bronchial carcinoid cell lines. In addition, a normal human retinal pigment epithelial cell line was used for comparison. A total of 18 drugs with different mechanisms of action were tested. Results: The most active agents were brefeldin A, emetine, bortezomib and idarubicin, having IC50 values < 1 μM in all four cell lines. In addition, the three tumor cell lines showed sensitivity for sanguinarine, Bay11-7085, mitoxantrone, doxorubicin, β-lapachone, NSC 95397 and CGP-74514A. Conclusion: The cell lines were sensitive for several drugs acting in different ways, covering a broad spectrum of mechanisms of action. Some of these compounds may possibly be used in clinical trials and show therapeutic effect in patients with neuroendocrine tumors.
  • Larsson, Kjell, et al. (författare)
  • Effects of an extensive Prymnesium polylepis bloom on breeding eiders in the Baltic Sea
  • 2014
  • Ingår i: Journal of Sea Research. - : Elsevier. - 1385-1101 .- 1873-1414. ; 88, s. 21-28
  • Tidskriftsartikel (refereegranskat)abstract
    • The effects of an extensive bloom of the potentially toxic Prymnesium polylepis (Haptophyta) on breeding eiders (Somateria mollissima) in the Baltic Sea were analysed. Increasing abundances of the alternate stage P. polylepis was detected by a marine monitoring programme in the autumn 2007. The bloom peaked between March and May 2008 in the southern, central and northwestern Baltic Proper and abundances of up to 5 x 106 cells l- 1 were recorded. At several sites P. polylepis constituted between 30 and 90% of the total phytoplankton biovolume. The flagellate was only recorded in low numbers in the northeastern Baltic Proper and Gulf of Finland. The abundances were low in 2007, 2009 and 2010. In 28 eider colonies situated in the southern and central Baltic Proper, sharp and synchronous declines in the number of nesting eiders were observed from 2007 to 2008. In colonies on Gotland in the central Baltic Proper, a 76% decrease, from 6650 nests to 1620 nests, was followed by increases in 2009 and 2010, although not up to numbers observed in 2007. At Utklippan and Ertholmene in the southern Baltic Proper, the observed decreases of 55%, from 144 to 65 nests, and 36%, from 1660 to 1060 nests, respectively, between 2007 and 2008, were followed by increases in 2009 and 2010 up to the level observed in 2007. By contrast, no general decline of the number of nesting eiders was observed from 2007 to 2008 in 75 colonies in the northeastern Baltic Proper and Gulf of Finland. Hence, the spatial distribution of the P. polylepis bloom in 2008 closely matched the observed distribution of extensive non-breeding of female eiders. We suggest that the intensive spring bloom of P. polylepis, either through a toxic or non-toxic pathway, affected the main benthic food of eiders, i.e. blue mussels (Mytilus trossulus x Mytilus edulis), at pre-breeding foraging sites close to the breeding sites, and, subsequently, the body condition of adult female eiders and their breeding propensity.
  • Stranneheim, Henrik, et al. (författare)
  • Rapid pulsed whole genome sequencing for comprehensive acute diagnostics of inborn errors of metabolism
  • 2014
  • Ingår i: BMC Genomics. - 1471-2164 .- 1471-2164. ; 15
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Massively parallel DNA sequencing (MPS) has the potential to revolutionize diagnostics, in particular for monogenic disorders. Inborn errors of metabolism (IEM) constitute a large group of monogenic disorders with highly variable clinical presentation, often with acute, nonspecific initial symptoms. In many cases irreversible damage can be reduced by initiation of specific treatment, provided that a correct molecular diagnosis can be rapidly obtained. MPS thus has the potential to significantly improve both diagnostics and outcome for affected patients in this highly specialized area of medicine. Results: We have developed a conceptually novel approach for acute MPS, by analysing pulsed whole genome sequence data in real time, using automated analysis combined with data reduction and parallelization. We applied this novel methodology to an in-house developed customized work flow enabling clinical-grade analysis of all IEM with a known genetic basis, represented by a database containing 474 disease genes which is continuously updated. As proof-of-concept, two patients were retrospectively analysed in whom diagnostics had previously been performed by conventional methods. The correct disease-causing mutations were identified and presented to the clinical team after 15 and 18 hours from start of sequencing, respectively. With this information available, correct treatment would have been possible significantly sooner, likely improving outcome. Conclusions: We have adapted MPS to fit into the dynamic, multidisciplinary work-flow of acute metabolic medicine. As the extent of irreversible damage in patients with IEM often correlates with timing and accuracy of management in early, critical disease stages, our novel methodology is predicted to improve patient outcome. All procedures have been designed such that they can be implemented in any technical setting and to any genetic disease area. The strategy conforms to international guidelines for clinical MPS, as only validated disease genes are investigated and as clinical specialists take responsibility for translation of results. As follow-up in patients without any known IEM, filters can be lifted and the full genome investigated, after genetic counselling and informed consent.
  • Wickström, Malin, et al. (författare)
  • The novel melphalan prodrug J1 inhibits neuroblastoma growth in vitro and in vivo
  • 2007
  • Ingår i: Molecular Cancer Therapeutics. - 1535-7163 .- 1538-8514. ; 6:9, s. 2409-2417
  • Tidskriftsartikel (refereegranskat)abstract
    • Neuroblastoma is the most common extracranial solid tumor of childhood. The activity of J1 (l-melphalanyl-p-l-fluorophenylalanine ethyl ester), an enzymatically activated melphalan prodrug, was evaluated in neuroblastoma models in vitro and in vivo. Seven neuroblastoma cell lines with various levels of drug resistance were screened for cytotoxicity of J1 alone or in combination with standard cytotoxic drugs, using a fluorometric cytotoxicity assay. J1 displayed high cytotoxic activity in vitro against all neuroblastoma cell lines, with IC50 values in the submicromolar range, significantly more potent than melphalan. The cytotoxicity of J1, but not melphalan, could be significantly inhibited by the aminopeptidase inhibitor bestatin. J1 induced caspase-3 cleavage and apoptotic morphology, had additive effects in combination with doxorubicin, cyclophosphamide, carboplatin, and vincristine, and synergistically killed otherwise drug-resistant cells when combined with etoposide. Athymic rats and mice carrying neuroblastoma xenografts [SH-SY5Y, SK-N-BE(2)] were treated with equimolar doses of melphalan, J1, or no drug, and effects on tumor growth and tissue morphology were analyzed. Tumor growth in vivo was significantly inhibited by J1 compared with untreated controls. Compared with melphalan, J1 more effectively inhibited the growth of mice with SH-SY5Y xenografts, was associated with higher caspase-3 activation, fewer proliferating tumor cells, and significantly decreased mean vascular density. In conclusion, the melphalan prodrug J1 is highly active in models of neuroblastoma in vitro and in vivo, encouraging further clinical development in this patient group.
  • Carlier, Charlotte, et al. (författare)
  • Preclinical activity of melflufen (J1) in ovarian cancer
  • 2016
  • Ingår i: OncoTarget. - 1949-2553 .- 1949-2553. ; 7:37, s. 59322-59335
  • Tidskriftsartikel (refereegranskat)abstract
    • Ovarian cancer carries a significant mortality. Since symptoms tend to be minimal, the disease is often diagnosed when peritoneal metastases are already present. The standard of care in advanced ovarian cancer consists of platinum-based chemotherapy combined with cytoreductive surgery. Unfortunately, even after optimal cytoreduction and adjuvant chemotherapy, most patients with stage III disease will develop a recurrence. Intraperitoneal administration of chemotherapy is an alternative treatment for patients with localized disease. The pharmacological and physiochemical properties of melflufen, a peptidase potentiated alkylator, raised the hypothesis that this drug could be useful in ovarian cancer and particularily against peritoneal carcinomatosis. In this study the preclinical effects of melflufen were investigated in different ovarian cancer models. Melflufen was active against ovarian cancer cell lines, primary cultures of patient-derived ovarian cancer cells, and inhibited the growth of subcutaneous A2780 ovarian cancer xenografts alone and when combined with gemcitabine or liposomal doxorubicin when administered intravenously. In addition, an intra-and subperitoneal xenograft model showed activity of intraperitoneal administered melflufen for peritoneal carcinomatosis, with minimal side effects and modest systemic exposure. In conclusion, results from this study support further investigations of melflufen for the treatment of peritoneal carcinomatosis from ovarian cancer, both for intravenous and intraperitoneal administration.
  • Dahlqvist, Jenny Alenius, et al. (författare)
  • Heart Rate Variability in Children With Fontan Circulation: Lateral Tunnel and Extracardiac Conduit.
  • 2012
  • Ingår i: Pediatric cardiology. - New York : Springer-Verlag New York. - 1432-1971 .- 0172-0643. ; 33:2, s. 307-315
  • Tidskriftsartikel (refereegranskat)abstract
    • The technique in Fontan surgery has developed from the lateral tunnel (LT) toward the extracardiac conduit (EC) used to reduce long-term complications such as atrial arrhythmia and sinus node dysfunction. Heart rate variability (HRV) examines cardiac nervous activity controlling the sinus node. This study aimed to investigate HRV in a cohort of children with univentricular hearts, focusing on the relation between HRV and surgical procedure. For 112 children with Fontan circulation, HRV was analyzed using power spectral analysis. Spectral power was determined in three regions: very-low-frequency (VLF), low-frequency (LF), and high-frequency (HF) regions. Patients were compared with 66 healthy controls subject. Patients with LT were compared with patients who had EC. The children with Fontan circulation showed a significantly reduced HRV including total power (P < 0.0001), VLF (P < 0.0001), LF (P < 0.0001), and HF (P = 0.001) compared with the control subjects. The LT and EC patients did not differ significantly. Reduced HRV was found in both the LT and EC patients. In terms of HRV reduction, EC was not superior to LT.
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