| 1. |
- Bin Kaderi, Mohamed Arifin, 1978-
(författare)
-
Assessment of Novel Molecular Prognostic Markers in Chronic Lymphocytic Leukemia
- 2010
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The clinical course of chronic lymphocytic leukemia (CLL) is highly heterogeneous, which has prompted the search for biomarkers that can predict prognosis in this disease. The IGHV gene mutation status and certain genomic aberrations have been identified as reliable prognostic markers of clinical outcome for this disorder. However, the search for more feasible prognostic markers in CLL is still being pursued. Recently, certain single nucleotide polymorphisms (SNPs) in the GNAS1, BCL2 and MDM2 genes and the RNA expression levels of the LPL, ZAP70, TCL1, CLLU1 and MCL1 genes were suggested as novel prognostic markers in CLL. In papers I-III, we performed genotyping analyses of the GNAS1 T393C, BCL2 -938C>A and MDM2 SNP309 polymorphisms in 268-418 CLL patients and related the genotypes with clinical data. Association studies between the polymorphisms and established prognostic markers (i.e. IGHV mutation status, genomic aberrations, CD38 expression) were also performed. Our studies did not find any significant relationship between these SNPs with either clinical outcome or other known prognostic markers in CLL. In paper IV, we measured the RNA expression levels of LPL, ZAP70, TCL1, CLLU1 and MCL1 in 252 CLL cases and correlated these levels with clinical outcome. Here, we verified that high expression of all these RNA-based markers, except MCL1, were associated with an unfavourable prognosis. We also confirmed a close relationship between IGHV mutation status and the RNA-based markers, especially for LPL and CLLU1 expression. Among the RNA-based markers, multivariate analysis revealed LPL expression as the strongest independent prognostic marker for overall survival and time to treatment. Furthermore, the RNA-based markers could add further prognostic information to established markers in subgroups of patients, with LPL expression status giving the most significant results. In summary, data from papers I-III could not verify the GNAS1 T393C, BCL2 -938C>A and MDM2 SNP309 polymorphisms as prognostic markers in CLL. Future SNP markers must hence be confirmed in large, independent cohorts before being proposed as prognostic marker in CLL. In paper IV, we conclude that LPL expression appears to be the strongest among the RNA-based markers for CLL prognostication. Further efforts to standardize LPL quantification are required before it can be applied in the clinical laboratory to predict clinical outcome in this disease.
|
|
| 2. |
- Yu, Di, 1985-
(författare)
-
Adenovirus for Cancer Therapy : With a Focus on its Surface Modification
- 2013
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Adenovirus serotype 5 (Ad5) is widely used as an oncolytic agent for cancer therapy. However, its infectivity is highly dependent on the expression level of coxsackievirus-adenovirus receptor (CAR) on the surface of tumor cells. We engineered Ad5 virus with the protein transduction domain (PTD) from the HIV-1 Tat protein (Tat-PTD) inserted in the hypervariable region 5 (HVR5) of the hexon protein in the virus capsid. Tat-PTD-modified Ad5 shows a dramatically increased transduction level of CAR-negative cells and bypassed fiber-mediated transduction. It also overcomes the fiber-masking problem, which is caused by release of excess fiber proteins from infected cells. To achieve specific viral replication in neuroblastoma and neuroendocrine tumor cells, we identified the secretogranin III (SCG3) promoter and constructed an adenovirus Ad5PTD(ASH1-SCG3-E1A) wherein E1A gene expression is controlled by the SCG3 promoter and the achaete-scute complex homolog 1 (ASH1) enhancer. This virus shows selective and efficient killing of neuroblastoma cell lines in vitro, and delays human neuroblastoma xenograft tumor growth on nude mice. To further enhance the viral oncolytic efficacy, we also switched the fiber 5 to fiber 35 to generate Ad5PTDf35. This vector shows dramatically increased transduction capacity of primary human cell cultures including hematopoietic cells and their derivatives, pancreatic islets and exocrine cells, mesenchymal stem cells and primary tumor cells including primary cancer initiating cells. Ad5PTDf35-based adenovirus could be a useful platform for gene delivery and oncolytic virus development. Viral oncolysis alone cannot completely eradicate tumors. Therefore, we further armed the Ad5PTDf35-D24 virus with a secreted form of Helicobacter pylori Neutrophil Activating Protein (HP-NAP). Expression of HP-NAP recruits neutrophils to the site of infection, activates an innate immune response against tumor cells and provokes a Th1-type adaptive immune response. Established tumor on nude mice could be completely eradicated in some cases after treatment with this virus and the survival of mice was significantly prolonged.
|
|
| 3. |
- Kallak, Theodora Kunovac, 1985-, et al.
(författare)
-
Higher than expected estradiol levels in aromatase inhibitor-treated, postmenopausal breast cancer patients
- 2012
-
Ingår i: Climacteric. - London, United Kingdom : Informa Healthcare. - 1369-7137 .- 1473-0804. ; 15:5, s. 473-480
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: Vaginal estradiol is considered contraindicated in aromatase inhibitor (AI)-treated patients because of the risk of elevated estrogen levels. This leaves limited treatment options for patients experiencing gynecological symptoms. However, in clinical practice, no precise estimation has been performed of circulating estrogens and aromatase index in postmenopausal breast cancer patients on long-lasting AI or tamoxifen treatment.Methods: Steroid hormones were measured using liquid chromatography tandem mass spectrometry (LC-MS/MS) and extraction radioimmunoassay (RIA). Postmenopausal AI-treated patients (n =33) were compared with tamoxifen-treated patients (n =34) and controls without vaginal treatment (n =56), with vaginal estradiol (n =25), or with estriol (n =11) treatment.Results: By use of LC-MS/MS, median (range) estradiol plasma concentrations were 16.7 (2.4-162.6), 31.0 (13.4-77.1), 27.2 (7.8-115.8) and 33.3 (20.3-340.1) pmol/l in AI-treated breast cancer patients, tamoxifen-treated breast cancer patients, postmenopausal controls and postmenopausal controls on vaginal estradiol, respectively. The AI-treated group and subgroups had significantly lower estradiol and estrone concentrations than all other groups (p <0.05). There was extensive interindividual variation in estradiol concentration within the AI-treated group, measured using both LC-MS/MS (2.3-182.0 pmol/l) and extraction RIA (2.4-162.6 pmol/l). The AI-treated group had lower aromatase index compared to all other groups (p <0.05-0.001).Conclusion: Circulating estrogen levels may have been underestimated in previous longitudinal studies of AI-treated breast cancer patients. Additional studies are required to further evaluate the role of circulating estrogens in breast cancer patients suffering from gynecological symptoms.
|
|
| 4. |
- Olsson, Marie, et al.
(författare)
-
Effects of extracts of apple peel from organically and integrated production cultivated apples and ursolic acid on cancer cell proliferation
- 2014
-
Ingår i: Acta Horticulturae. - 0567-7572 .- 2406-6168. - 9789462610286 ; 1040, s. 227-230
-
Konferensbidrag (refereegranskat)abstract
- The effects of extract of apple peel, 'Aroma', organically cultivated or cultivated according to integrated production, on cell proliferation in vitro of colon cancer HT29 cells and breast cancer MCF-7 cells, were investigated. Different sequences of solvents were used, and the inhibiting effect on cancer cell proliferation of the different extracts was investigated. The solvents used were ethanol, methanol, DMSO and hexane in different sequences. The extracts decreased the proliferation of both HT29 and MCF-7 cells, the effect was different for the different extracts, and ethanol showed the highest inhibition effect. The inhibiting effect of the extracts also varied between both apple production methods, and extracts from peels of organically produced apples showed in some cases higher inhibition effects, while sometimes no differences were found. In addition, as ursolic acid, a component of apple peel, has been proposed to inhibit cancer cell proliferation, the inhibiting effect of pure ursolic acid on cancer cell proliferation was compared with the effect of the apple peel solvent fraction with the highest ursolic acid concentration. The inhibiting effect was higher in the apple fraction extract than in pure ursolic acid. Further, a range of different apple cultivars, integrated production and organically cultivated, were analysed by HPLC for their content of ursolic acid to investigate possible differences in concentrations.
|
|
| 5. |
- Brennan, Donal J., et al.
(författare)
-
Tumour-specific HMG-CoAR is an independent predictor of recurrence free survival in epithelial ovarian cancer
- 2010
-
Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407 .- 1471-2407. ; 10, s. 125-
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Our group previously reported that tumour-specific expression of the rate-limiting enzyme in the mevalonate pathway, 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMG-CoAR) is associated with more favourable tumour parameters and a good prognosis in breast cancer. In the present study, the prognostic value of HMG-CoAR expression was examined in tumours from a cohort of patients with primary epithelial ovarian cancer. Methods: HMG-CoAR expression was assessed using immunohistochemistry (IHC) on tissue microarrays (TMA) consisting of 76 ovarian cancer cases, analysed using automated algorithms to develop a quantitative scoring model. Kaplan Meier analysis and Cox proportional hazards modelling were used to estimate the risk of recurrence free survival (RFS). Results: Seventy-two tumours were suitable for analysis. Cytoplasmic HMG-CoAR expression was present in 65% (n = 46) of tumours. No relationship was seen between HMG-CoAR and age, histological subtype, grade, disease stage, estrogen receptor or Ki-67 status. Patients with tumours expressing HMG-CoAR had a significantly prolonged RFS (p = 0.012). Multivariate Cox regression analysis revealed that HMG-CoAR expression was an independent predictor of improved RFS (RR = 0.49, 95% CI (0.25-0.93); p = 0.03) when adjusted for established prognostic factors such as residual disease, tumour stage and grade. Conclusion: HMG-CoAR expression is an independent predictor of prolonged RFS in primary ovarian cancer. As HMG-CoAR inhibitors, also known as statins, have demonstrated anti-neoplastic effects in vitro, further studies are required to evaluate HMG-CoAR expression as a surrogate marker of response to statin treatment, especially in conjunction with current chemotherapeutic regimens.
|
|
| 6. |
- Skiöld, Sara, et al.
(författare)
-
Radiation-induced stress response in peripheral blood of breast cancer patients differs between patients with severe acute skin reactions and patients with no side effects to radiotherapy
- 2013
-
Ingår i: Mutation research. Genetic toxicology and environmental mutagenesis. - : Elsevier BV. - 1383-5718 .- 1879-3592. ; 756:1-2, s. 152-157
-
Tidskriftsartikel (refereegranskat)abstract
- The aim of the study was to compare the radiation-induced oxidative stress response in blood samples from breast cancer patients that developed severe acute skin reactions during the radiotherapy, with the response in blood samples from patients with no side effects. Peripheral blood was collected from 12 breast cancer patients showing no early skin reactions after radiotherapy (RTOG grade 0) and from 14 breast cancer patients who developed acute severe skin reactions (RTOG grade 3-4). Whole blood was irradiated with 0, 5 and 2000 mGy gamma-radiation and serum was isolated. The biomarker for oxidative stress, 8-oxo-dG, was analyzed in the serum by a modified ELISA. While a significant radiation-induced increase of serum 8-oxo-dG levels was observed in serum of the RTOG 0 patients, no increase was seen in serum of the RTOG 3-4 patients. The radiation induced increase in serum 8-oxo-dG levels after 5 mGy did not differ significantly from the increase observed for 2000 mGy in the RTOG 3-4 cohort, thus no dose response relation was observed. A receiver operating characteristic (ROC) value of 0.97 was obtained from the radiation-induced increase in 8-oxo-dG indicating that the assay could be used to identify patients with severe acute adverse reactions to radiotherapy. The results show that samples of whole blood from patients, classified as highly radiosensitive (RTOG 3-4) based on their skin reactions to radiotherapy, differ significantly in their oxidative stress response to ionizing radiation compared to samples of whole blood from patients with no skin reactions (RTOG 0). Extracellular 8-oxo-dG is primarily a biomarker of nucleotide damage and the results indicate that the patients with severe acute skin reactions differ in their cellular response to ionizing radiation at the level of induction of oxidative stress or at the level of repair or both.
|
|
| 7. |
- Guidi, Riccardo, et al.
(författare)
-
Chronic exposure to the cytolethal distending toxins of Gram-negative bacteria promotes genomic instability and altered DNA damage response
- 2013
-
Ingår i: Cellular Microbiology. - : John Wiley & Sons. - 1462-5814 .- 1462-5822. ; 15:1, s. 98-113
-
Tidskriftsartikel (refereegranskat)abstract
- Epidemiological evidence links chronic bacterial infections to the increased incidence of certain types of cancer but the molecular mechanisms by which bacteria contribute to tumour initiation and progression are still poorly characterized. Here we show that chronic exposure to the genotoxin cytolethal distending toxin (CDT) of Gram-negative bacteria promotes genomic instability and acquisition of phenotypic properties of malignancy in fibroblasts and colon epithelial cells. Cells grown for more than 30 weeks in the presence of sublethal doses of CDT showed increased mutation frequency, and accumulation of chromatin and chromosomal aberrations in the absence of significant alterations of cell cycle distribution, decreased viability or senescence. Cell survival was dependent on sustained activity of the p38 MAP kinase. The ongoing genomic instability was associated with impaired activation of the DNA damage response and failure to efficiently activate cell cycle checkpoints upon exposure to genotoxic stress. Independently selected sublines showed enhanced anchorage-independent growth as assessed by the formation of colonies in semisolid agarose. These findings support the notion that chronic infection by CDT-producing bacteria may promote malignant transformation, and point to the impairment of cellular control mechanisms associated with the detection and repair of DNA damage as critical events in the process.
|
|
| 8. |
- Sadeghi, B., et al.
(författare)
-
Early-phase GVHD gene expression profile in target versus non-target tissues : kidney, a possible target?
- 2013
-
Ingår i: Bone Marrow Transplantation. - : Springer Science and Business Media LLC. - 0268-3369 .- 1476-5365. ; 48:2, s. 284-293
-
Tidskriftsartikel (refereegranskat)abstract
- GVHD is a major complication after allo-SCT. In GVHD, some tissues like liver, intestine and skin are infiltrated by donor T cells while others like muscle are not. The mechanism underlying targeted tropism of donor T cells is not fully understood. In the present study, we aim to explore differences in gene expression profile among target versus non-target tissues in a mouse model of GVHD based on chemotherapy conditioning. Expression levels of JAK-signal transducers and activators of transcription (STAT), CXCL1, ICAM1 and STAT3 were increased in the liver and remained unchanged (or decreased) in the muscle and kidney after conditioning. At the start of GVHD the expression levels of CXCL9, ITGb2, SAA3, MARCO, TLR and VCAM1 were significantly higher in the liver or kidney compared with the muscle of GVHD animals. Moreover, biological processes of inflammatory reactions, leukocyte migration, response to bacterium and chemotaxis followed the same pattern. Our data show that both chemotherapy and allogenicity exclusively induce expression of inflammatory genes in target tissues. Moreover, gene expression profile and histopathological findings in the kidney are similar to those observed in the liver of GVHD mice. Bone Marrow Transplantation (2013) 48, 284-293; doi:10.1038/bmt.2012.120; published online 23 July 2012
|
|
| 9. |
- Lewander, Andreas, et al.
(författare)
-
NF-kappa B p65 phosphorylated at serine-536 is an independent prognostic factor in Swedish colorectal cancer patients
- 2012
-
Ingår i: International Journal of Colorectal Disease. - : Springer. - 0179-1958 .- 1432-1262. ; 27:4, s. 447-452
-
Tidskriftsartikel (refereegranskat)abstract
- The NF-kappa B transcription factor protein family has diverse cellular and biological functions, and posttranslational modification is important to regulate these functions. An important site of phosphorylation of NF-kappa B p65 subunit is at serine-536 (phospho-Ser536-p65), and this phosphorylation is involved in regulation of transcriptional activity, nuclear localization, and protein stability. In this study, we investigated expression of phospho-Ser536-p65 in colorectal cancers and its relationships with clinicopathological factors. The expression of phospho-Ser536-p65 was examined by immunohistochemistry in 203 primary colorectal cancers, 156 normal mucosa specimens, and 18 metastases in the lymph nodes. The expression of phospho-Ser536-p65 increased from normal mucosa to primary tumor (p < 0.0001). Further, the increased expression of phospho-Ser536-p65 in the cytoplasm of the primary tumors correlated with worse survival of the patients independently of gender, age, tumor location, stage, and differentiation (p = 0.04; hazard ratio, 1.89; 95% CI 1.03-3.47). The NF-kappa B p65 subunit phosphorylated at serine-536 is an independent prognostic factor in colorectal cancer patients.
|
|
| 10. |
- Dalmo, Johanna, et al.
(författare)
-
Potential renal toxicity biomarkers indicating radiation injury after 177Lu-octreotate treatment
- 2013
-
Ingår i: Annual congress of the European association of nuclear medicine, october 19-23, 2013, Lyon, France. Posterwalk.
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- The kidneys are one of the most exposed non-tumor tissues and regarded as one of the main dose-limiting organs in peptide receptor radionuclide therapy (PRRT). [177Lu-DOTA0, Tyr3]-octreotate (177Lu-octreotate) has shown promising results in the treatment of somatostatin receptor overexpressing neuroendocrine tumors, but optimization is still needed. The ability to give each patient as much 177Lu-octreotate as possible without inducing nephrotoxicity is necessary for an efficient treatment. However, due to large inter-individual differences in uptake and retention in the kidneys, there is a need for efficient Methods that early can indicate renal injury. A possible way is to identify biomarkers for high risk of radiation nephrotoxicity. The aim of this study was to investigate the potential of using urinary retinol binding protein (RBP), and blood valinhydantoin (VH) as biomarkers of nephrotoxicity on adult mice after 177Lu-octreotate treatment. BALB/c nude mice (n=6/group) were i.v. injected with 60 MBq or 120 MBq of 177Lu-octreotate. The control group was mock treated with saline. Spot urine samples were collected before injection, and 14, 30, 60 and 90 days after injection. Analysis of RBP4 and creatinine was performed using Mouse RBP4 ELISA kit and Creatinine kit from R&D Systems, respectively. Erythrocytes were separated from whole blood samples collected 90 days after injection, and analysed for VH by LC-MS/MS. The ratio between VH and a volumetric standard was calculated. The RBP/creatinine level increased with time in both groups given 177Lu-octreotate, with earlier and higher response for the 120 MBq group. No clear change in VH level between the different groups was observed. The result show that RBP may be a promising new biomarker for radiation induced kidney toxicity. The presently used method based on VH was not sensitive enough to be used as kidney toxicity marker. Further studies on mice are ongoing to validate if RBP4 may be efficient in predicting late nephrotoxicity. In patients, RBP/creatinine levels are followed in urine samples after treatment with 177Lu-octreotate.
|
|
