| 41. |
- Hassan, Saadia B., et al.
(författare)
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CHS 828 kill tumour cells by inhibiting the nuclear factor-kappa B translocation but unlikely through down-regulation of proteasome
- 2006
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Ingår i: Anticancer Research. - 0250-7005 .- 1791-7530. ; 26:6B, s. 4431-4436
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Tidskriftsartikel (refereegranskat)abstract
- CHS 828 (N-(6-chlorophenoxyhexyl)-N'cyano-N"-4-pyridylguanidine) has shown promising activity in many preclinical systems and in phase I/II clinical trials. The nuclear transcription factor kappa B (NF-κB) has been identified as a target for CHS 828. The aim of this study was to confirm the inhibitory effect of CHS 828 on NF-κB translocation and to explore its possible effect on the proteasome using 7 cell lines. Translocation of NF-κB from the cytoplasm to the nucleus was analysed using a quantitative cytometric system, ArrayScan®. The activity of the proteasome was assayed by monitoring the hydrolysis of a fluorogenic substrate. In parallel, the in vitro cytotoxic effect of CHS 828 was analyzed using a 72-h microtiter plate-based cytotoxicity assay (FMCA). CHS 828 inhibited NF-κB translocation in the cell lines where it was able to inhibit the tumour cell growth. However, the results did not prove any effect of CHS 828 on proteasome activity when compared to a proteasome inhibitor activity.
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| 42. |
- Hassan, Saadia Bashir, et al.
(författare)
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Cytotoxic activity of a new paclitaxel formulation, Pacliex, in vitro and in vivo
- 2005
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Ingår i: Cancer Chemotherapy and Pharmacology. - : Springer Science and Business Media LLC. - 0344-5704 .- 1432-0843. ; 55:1, s. 47-54:1, s. 47-54
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The paclitaxel formulation, Taxol (Bristol-Myers Squibb), is one of the most effective anticancer agents used today. However; it is associated with serious side effects believed to be caused by the Cremophor EL used for its formulation. AIM: To evaluate the cytotoxic activity of a new paclitaxel formulation, Pacliex (developed by Oasmia Pharmaceutical, Uppsala, Sweden), a mixed micelles preparation in which an amphiphilic synthetic derivative of retinoic acid replaced Cremophor EL/ethanol vehicle. METHOD: In this study, three model systems were used to evaluate the cytotoxic activity of Pacliex and other paclitaxel preparations. The cytotoxic activities of Pacliex, Taxol and paclitaxel in ethanol were investigated against a panel of ten human tumor cell lines using the fluorometric microculture cytotoxicity assay (FMCA). Low- and high- proliferating in vitro hollow fiber model of two cell lines, the leukemia CCRF-CEM and the myeloma RPMI 8226/S cell lines, were used to assess the cytotoxic activity of the three formulations. The in vivo hollow fiber model of the two cell lines was used for assessment of Pacliex and Taxol activity. The [3-4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay was utilized to analyze the in vitro and in vivo hollow fiber data. RESULT: Pacliex was somewhat more effective than Taxol in the more sensitive cell lines. The activity of Taxol was more pronounced in the resistant cell lines due to an additive effect of the vehicle used. The three formulations showed similar activity in both the low- and high-proliferating in vitro hollow fiber cultures. The in vivo hollow fiber cytotoxic activity of Pacliex was similar to that of Taxol. Putting all the results together, it was found that all the three formulations had similar in vitro and in vivo activity. CONCLUSION: The three in vitro and in vivo models confirmed the similarity of the cytotoxic activities of Pacliex and Taxol. Considering the above, Pacliex could be an interesting alternative Cremophor EL-free formulation of paclitaxel.
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| 43. |
- Hassan, Saadia B., et al.
(författare)
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Primary lymphocytes as predictors for species differences in cytotoxic drug sensitivity
- 2007
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Ingår i: Toxicology in Vitro. - : Elsevier BV. - 0887-2333 .- 1879-3177. ; 21:6, s. 1174-1181
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Tidskriftsartikel (refereegranskat)abstract
- Several in vitro methods have been suggested to predict drug-induced haematotoxicity and species differences; the most commonly used being the clonogenic CFU-GM assay. The aim of the current study was to evaluate whether primary lymphocytes from peripheral blood, assayed with a short-term non-clonogenic assay, could be used to detect species differences in drug sensitivity, and offer an alternative to the CFU-GM assay. The effect of 17 different cytotoxic drugs on lymphocytes from human, dog, rat and mouse was evaluated. A higher sensitivity of human than mouse lymphocytes was seen for topotecan and for 3 of 5 antimetabolites tested. Clear species specificity was also seen for the proteasome inhibitor bortezomib where rodent cells were 50–300 times less sensitive than human cells. Good agreement between our data and published CFU-GM data was observed, suggesting that primary lymphocytes may be a useful model for species difference screening in drug development.
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| 44. |
- Hassan, Saadia, et al.
(författare)
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Gene expression signature-based chemcial genomics and activity pattern in a panel of tumour cell lines propose linalyl acetate as a protein kinase/NF-κB inhibitor
- 2008
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Ingår i: Gene Therapy and Molecular Biology. - 1529-9120. ; 12:B, s. 359-370
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Tidskriftsartikel (refereegranskat)abstract
- The essential oil of Lebanese sage, Salvia libanotica, was reported to have anti-tumour activity; however, the mechanism of action has not been identified yet. In this study, 14- cancer cell lines including drug-sensitive and resistant lung, leukaemia, and colon, as well as primary human tumours of chronic lymphocytic leukaemia (CLL) and primary normal mononuclear cells (PBMCs) were used to characterize the anti-tumour activity and mechanism of action of linalyl acetate, a component of the Lebanese sage essential oil. Drug activity and gene expression data sets were utilized to identify drugs with similar activity patterns and genes involved in drug sensitivity/resistance. In addition, the Connectivity Map, a gene expression signature-based screening approach, assisted in predicting further the molecular action of linalyl acetate. Small cell lung carcinoma and colorectal cancer cell lines were the most sensitive to the drug and greater tumour selectivity was observed against chronic lymphocytic leukaemia cells compared to normal mononuclear cells. Only limited effect of some of the classical mechanisms of multi-drug resistance on the activity of Linalyl acetate was noted which makes it potentially interesting for drug-resistant patients. There was high similarity between the activity-pattern/gene expression profile of linalyl acetate and that of protein kinase/NF-kappa B inhibitors. Validating this, linalyl acetate was found to strongly inhibit Janus kinase, JAK3, and p38 alpha kinases in a cell-free assay as well as the NF-kappa B translocation in a dose-dependent manner. Taken together, our results show that the NF-kappa B inhibitor, linalyl acetate, may represent a new therapeutic compound in the management of inflammation and cancer.
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| 45. |
- Holmén, Hans, 1948-, et al.
(författare)
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The African Food Crisis -- Lessons from the Asian Green Revolution
- 2005
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Bok (övrigt vetenskapligt/konstnärligt)abstract
- Why can Asia now feed its rapidly growing population, but Africa continues to experience famine? This book is the outcome of a three-year project coordinated by a group of Swedish researchers with collaborating scholars from Africa and Asia. It provides a comparative study between Asian agricultural development during the Green Revolution in food production and the current problematic agricultural situation in sub-Saharan Africa. Based on case studies of eight African and eight Asian countries (focusing on the early part of the Green Revolution), this book presents a causal and explanatory model of Asian green revolutions. It discusses why such progress has been made in Asia, but has not yet occurred in Africa. It also examines the implications of the case studies for future development in Africa.
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| 46. |
- Hovstadius, Peter, 1962-
(författare)
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Preclinical and Clinical Development of the Novel Cyanoguanidine CHS 828 for Cancer Treatment
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- CHS 828 is a cyanoguanidine with anti-tumour properties which has shown promising effects in several preclinical models. This thesis describes both preclinical and clinical studies aiming to investigate disease specific activity, clinical tolerability and efficacy of CHS 828.In paper I we investigated CHS 828 activity in a cell line panel with human myeloma cells, three of these cell-lines were also tested in vivo using a hollow fibre rat-model. In paper II we investigated CHS 828 activity in primary human tumour samples from patients. CHS 828 showed an effect on all tumour cell types tested both the primary human tumour samples and the myeloma cell lines. Notably, CHS 828 showed a high relative in vitro activity against tumour cells from chronic lymphocytic leukaemia and high-grade lymphoma. In a phase I trial we determined the maximum tolerated dose (MTD) of CHS 828. Haematological toxicity was generally mild and dominated by transient thrombocytopenia and lymphocytopenia. Non-haematological toxicity was mostly of gastrointestinal origin. The recommended phase two dose (RPTD) of CHS 828 was estimated to be 20 mg once daily for five days in cycles of 28 days duration.In a phase II trial we investigated the effect of CHS 828 on patients diagnosed with B-CLL. In total 12 patients were enrolled. CHS 828 was found to be well tolerated and the most common haematological toxicity was thrombocytopenia. Non-haematological toxicities were generally mild. Transient decreases in lymphocyte counts could be discerned coinciding with drug dosing, but no sustained clinical responses could be achieved.In conclusion, CHS 828 demonstrated marked effects in the preclinical investigations suggesting haematological malignancies as the main target. The clinical phase I study established a safe dose and the subsequent phase II trial in B-CLL patients showed biological effect but with no clinical disease response.
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| 47. |
- Hägglund, Gösta, et al.
(författare)
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Estimation of the correlation coefficient based on selected data
- 2006
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Ingår i: Journal of educational and behavioral statistics. - : American Educational Research Association (AERA). - 1076-9986 .- 1935-1054. ; 31:4, s. 377-411
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Tidskriftsartikel (refereegranskat)abstract
- In psychometrics, if is often the case that one encounters data that may not be considered random but selected in a systematic way according to some explanatory variable. In this article, maximum likelihood estimation is considered when data are supposed to arise from a bivariate normal distribution that is truncated in an extreme way. Two methods are presented and compared, one of them being purely numerical, while the other is based on an approximation. Both methods are tried on both simulated and on real data. The purely numerical method is shown to be the most reliable over all, but in some cases, the computationally less burdensome approximate method turns out to work almost as well.
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| 48. |
- Itani, Wafica, et al.
(författare)
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Anti colon cancer components from lebanese sage (Salvia libanotica) essential oil : Mechanistic basis
- 2008
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Ingår i: Cancer Biology & Therapy. - : Informa UK Limited. - 1538-4047 .- 1555-8576. ; 7:11, s. 1765-1773
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Tidskriftsartikel (refereegranskat)abstract
- Lebanese sage essential oil possesses antitumor properties, however, the bioactive components and antitumor mechanisms are not known. Here we show that combining the three sage bioactive compounds, Linalyl acetate (Ly), Terpeniol (Te) and Camphor (Ca), caused synergistic inhibition of the growth of two isogenic human colon cancer cell lines HCT-116 (p53(+/+) and p53(-/-)), and had no effect on growth of FHs74Int normal human intestinal cell line. In p53(+/+) cells, the combination of Ly + Te + Ca (10(-3) M of each) caused significant accumulation of cells in PreG(1) (64% at 48 h); less preG(1) increase was observed in response to Ly + Te (25%) or Ly + Ca (14%). In p53(-/-) cells, Ly + Te + Ca caused cell accumulation in PreG(1) and G(2)/M phases. In response to the three components, 58% apoptosis occurred in p53(+/+) cells and 38% in p53(-/-) cells. Apoptosis by Ly + Te + Ca, in p53(+/+) cells, was associated with increased Bax/Bcl-2 ratio and pp53/p53 ratio, cleavage and activation of caspase-3, loss of mitochondrial membrane potential and cytochrome c release. In p53(-/-) cells, the disruption of mitochondrial membrane potential was observed but to a lesser extent than in p53(+/+) cells and caspase activation or cleavage did not appear to be involved in drug-induced apoptosis. Sage components induced poly(ADP-ribose)-polymerase (PARP) cleavage in both p53(+/+) and p53(-/-) cell lines. Pretreatment with the caspase-3 inhibitor and pan caspase inhibitor abrogated drug-mediated apoptosis and blocked procaspase-3 activation and partially blocked PARP cleavage in p53(+/+) cells. Conversely, in p53(-/-) cells, pre-incubation with caspase inhibitors potentiated drug-induced cell death. It appears that apoptosis in p53(+/+) cells is through the mitochondrial-mediated, caspase-dependent pathway, while in p53(-/-) cells apoptosis is mostly caspase independent despite the presence and features indicating caspase-dependent cell death, such as cytochrome c release and PARP cleavage. Our findings encourage further studies of sage oil components as promising chemotherapeutic agents against colon cancer.
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| 49. |
- Jacobson, Tor, et al.
(författare)
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Inflation, Exchange Rates and PPP in a Multivariate Panel Cointegration Model
- 2008
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Ingår i: Econometrics Journal. - 1368-4221 .- 1368-423X. ; 11:1, s. 58-79
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Tidskriftsartikel (refereegranskat)abstract
- New multivariate panel cointegration methods are used to analyze nominal exchange rates and prices in four major economies in Europe: France, Germany, Italy and the United Kingdom for the post-Bretton Woods period. We test for purchasing power parity (PPP) between these four countries and find that the theoretical PPP relationship does not hold. However, the estimated unrestricted relationship is found to be remarkably close to the theoretical one (1, -1.5, 0.9 instead of 1, -1,1). Relevant asymptotic results are stated, proved, and evaluated using Monte Carlo simulations. The asymptotic results are general and may hence be used in similar empirical contexts using the same model structure. Parametric bootstrap inference is used in order to deal with test size distortions.
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| 50. |
- Jensen Waern, Marianne, et al.
(författare)
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Effects of streptozotocin-induced diabetes in domestic pigs with focus on the amino acid metabolism
- 2009
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Ingår i: Laboratory Animals. - : SAGE Publications. - 0023-6772 .- 1758-1117. ; 43:3, s. 249-254
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Tidskriftsartikel (refereegranskat)abstract
- Streptozotocin (STZ) given intravenously destroys pancreatic beta cells and is widely used in animal models to mimic type 1 diabetes. The effects of STZ on the clinical state of health and metabolism were studied in six high health certified domestic pigs weighing 19 +/- 1.3 kg at the start of the experiment. A single STZ dose of 150 mg/kg of body weight successfully induced hyperglycaemia and alterations in amino acid metabolism. Within 9 h after STZ administration, the blood glucose values fell from 5.4-7.5 mmol/L to 0.8-2.2 mmol/L. Hypoglycaemia was treated with 0.5 g glucose/kg body weight. In all pigs, hyperglycaemia was produced 24 h after STZ treatment, and 3 days after STZ injection, the glucose concentration was >25 mmol/L. Mean C-peptide concentration was 0.25 +/- 0.16 mug/L since 2 days after STZ injection until the end of the study. The serum concentration of the branched-chain amino acids (BCAA) increased four-fold, and alanine and taurine decreased by approximately 70% and 50%, respectively, after STZ treatment. All but one pig remained brisk and the physical examination was normal except for a retarded growth rate and a reduction of the skeletal muscle. At the end of the study, the pigs were moderately emaciated. Postmortem examination confirmed muscle wasting and a reduction of abdominal and subcutaneous fat. In conclusion, STZ-induced diabetes in pigs fulfils the requirements for a good animal model for type 1 diabetes with respect to clinical signs of the disease and alterations in the carbohydrate and amino acid metabolism.
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