| 1. |
- Berglund, Erik, et al.
(författare)
-
Intracellular concentration of the tyrosine kinase inhibitor imatinib in gastrointestinal stromal tumor cells.
- 2014
-
Ingår i: Anti-Cancer Drugs. - 0959-4973 .- 1473-5741. ; 25:4, s. 415-22
-
Tidskriftsartikel (refereegranskat)abstract
- Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm in the gastrointestinal tract. In most GISTs, the underlying mechanism is a gain-of-function mutation in the KIT or the PDGFRA gene. Imatinib is a tyrosine kinase inhibitor that specifically blocks the intracellular ATP-binding sites of these receptors. A correlation exists between plasma levels of imatinib and progression-free survival, but it is not known whether the plasma concentration correlates with the intracellular drug concentration. We determined intracellular imatinib levels in two GIST cell lines: the imatinib-sensitive GIST882 and the imatinib-resistant GIST48. After exposing the GIST cells to imatinib, the intracellular concentrations were evaluated using LC-MS (TOF). The concentration of imatinib in clinical samples from three patients was also determined to assess the validity and reliability of the method in the clinical setting. Determination of imatinib uptake fits within detection levels and values are highly reproducible. The GIST48 cells showed significantly lower imatinib uptake compared with GIST882 in therapeutic doses, indicating a possible difference in uptake mechanisms. Furthermore, imatinib accumulated in the tumor tissues and showed intratumoral regional differences. These data show, for the first time, a feasible and reproducible technique to measure intracellular imatinib levels in experimental and clinical settings. The difference in the intracellular imatinib concentration between the cell lines and clinical samples indicates that drug transporters may contribute toward resistance mechanisms in GIST cells. This highlights the importance of further clinical studies to quantify drug transporter expression and measure intracellular imatinib levels in GIST patients.
|
|
| 2. |
- Norenstedt, Sophie, et al.
(författare)
-
Breast cancer associated with primary hyperparathyroidism : a nested case control study
- 2011
-
Ingår i: Clinical Epidemiology. - 1179-1349. ; 3, s. 103-106
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Primary hyperparathyroidism (pHPT) is associated with an increased risk of developing breast cancer, but little is known about the underlying factors. The aim of this study was to compare women with a history of pHPT and a reference population in terms of standard factors predictive of prognosis and response to therapy for breast cancer. METHODS: We analyzed data collected from the National Swedish Cancer Register and from two regional oncologic center registries. Seventy-one women with breast cancer and a history of parathyroid adenomectomy were compared with 338 matched controls with breast cancer only. Tumor size, stage, hormone receptor status, lymph node status, cause of death, and cumulative survival were analyzed. RESULTS: The mean age was 69 ± 11 years (95% confidence interval [CI]: 68-70) in both groups and the mean time interval between the parathyroid surgery and breast cancer diagnosis was 91 ± 68 months (95% CI: 72-111). There were no differences between the two groups regarding size, stage, lymph node metastases, or survival, but none of the cases with a history of pHPT were found in Stage III or IV. CONCLUSION: In conclusion, factors predictive of prognosis and response to therapy in women with a history of pHPT and breast cancer are similar to those in breast cancer patients without pHPT.
|
|
| 3. |
- Berglund, Erik, et al.
(författare)
-
Evidence for Ca2+-regulated ATP release in gastrointestinal stromal tumors
- 2013
-
Ingår i: Experimental Cell Research. - : Elsevier BV. - 0014-4827 .- 1090-2422. ; 319:8, s. 1229-1238
-
Tidskriftsartikel (refereegranskat)abstract
- Gastrointestinal stromal tumors (GISTs) are thought to originate from the electrically active pacemaker cells of the gastrointestinal tract. Despite the presence of synaptic-like vesicles and proteins involved in cell secretion it remains unclear whether GIST cells possess regulated release mechanisms. The GIST tumor cell line GIST882 was used as a model cell system, and stimulus-release coupling was investigated by confocal microscopy of cytoplasmic free Ca2+ concentration ([Ca(2+)1](i)), flow cytometry, and luminometric measurements of extracellular ATP. We demonstrate that GIST cells have an intact intracellular Ca2+-signaling pathway that regulates ATP release. Cell viability and cell membrane integrity was preserved, excluding ATP leakage due to cell death and suggesting active ATP release. The stimulus-secretion signal transduction is at least partly dependent on Ca2+ influx since exclusion of extracellular Ca2+ diminishes the ATP release. We conclude that measurements of ATP release in GISTs may be a useful tool for dissecting the signal transduction pathway, mapping exocytotic components, and possibly for the development and evaluation of drugs. Additionally, release of ATP from GISTs may have importance for tumor tissue homeostasis and immune surveillance escape.
|
|
| 4. |
|
|
| 5. |
- Berglund, Erik, et al.
(författare)
-
Functional role of the Ca2+-activated Cl- channel DOG1/TMEM16A in gastrointestinal stromal tumor cells
- 2014
-
Ingår i: Experimental Cell Research. - : Elsevier BV. - 0014-4827 .- 1090-2422. ; 326:2, s. 315-325
-
Tidskriftsartikel (refereegranskat)abstract
- DOG1, a Ca2+-activated Cl- channel (CaCC), was identified in 2004 to be robustly expressed in gastrointestinal stromal tumors (GIST). It was rapidly included as a tumor marker in routine diagnostics, but the functional role remained unknown. CaCCs are important regulators of normal physiological functions, but also implicated in tumorigenesis, cancer progression, metastasis, cell migration, apoptosis, proliferation and viability in several malignancies. We therefore investigated whether DOG1 plays a role in the three latter in GIST by utilizing in vitro cell model systems. Confocal microscopy identified different subcellular localizations of DOG1 in imatinib-sensitive and imatinib-resistant cells. Electrophysiological studies confirmed that DOG1-specific pharmacological agents possess potent activating and inhibiting properties. Proliferation assays showed small effects up to 72 h, and flow cytometric analysis of adherent cells with 7-AAD/Annexin V detected no pharmacological effects on viable GIST cells. However, inhibition of DOG1 conveyed pro-apoptotic effects among early apoptotic imatinib-resistant cells. In conclusion, DOG1 generates Cl- currents in GIST that can be regulated pharmacologically, with small effects on cell viability and proliferation in vitro. Inhibition of DOG1 might act pro-apoptotic on some early apoptotic GIST cell populations. Further studies are warranted to fully illuminate the function of DOG1 and its potential as therapeutic target.
|
|
| 6. |
- Nilsson, Inga-Lena, et al.
(författare)
-
Thyroid incidentaloma detected by fluorodeoxyglucose positron emission tomography/computed tomography : practical management algorithm
- 2011
-
Ingår i: World Journal of Surgery. - : Springer Science and Business Media LLC. - 0364-2313 .- 1432-2323. ; 35:12, s. 2691-2697
-
Tidskriftsartikel (refereegranskat)abstract
- BackgroundOur aim was to design a practical algorithm for management of an increasing number of incidental findings of thyroid lesions identified by 18F-fluorodeoxyglucose positron emission tomography with computed tomography (FDG-PET/CT).MethodsThe reports of 3641 patients examined by FDG-PET/CT for evaluation of nonthyroid cancer were reviewed. The anatomic locations and standardized uptake values (SUV) of any focally increased thyroid FDG uptake were reanalyzed and related to surrounding normal thyroid (TSUVmax/thySUVmean ratio) and liver (TSUVmax/liverSUVmean).ResultsFocal FDG uptakes in the thyroid were reported in 37 cases (1%; 26 women). Neoplastic thyroid lesions were diagnosed in 16 patients: papillary thyroid cancer in 9, follicular neoplasia in 5, and metastatic lesions (lung cancer and squamous cell carcinoma) in 2. Benign lesions were diagnosed in 11 patients. Ten patients with malignancy elsewhere did not undergo thyroid examination. In all, 11 patients underwent thyroid surgery (8 with papillary cancer, 3 with follicular adenoma); the median tumor size was 12 mm (8–40 mm). The TSUVmax/thySUVmean ratio was higher for the malignant lesions [median 5.53 (2.75–30.81) vs. 3.70 (1.82–31.70); P < 0.05], albeit with a considerable overlap between individual patients. The TSUVmax and TSUVmax/liverSUVmean did not differ between groups. The TSUVmax/thySUVmean and / thySUVmean ratios correlated with the tumor size (r = 0.64 and r = 0.66; P < 0.05).ConclusionsAn incidental finding of focal uptake of FDG in the thyroid is associated with a significant risk of thyroid cancer. If the patient would benefit from thyroidectomy if a malignancy were identified, further diagnostic workup with ultrasonography-guided fine-needle aspiration and cytology is recommended.
|
|
| 7. |
- Sofiadis, Anastasios, et al.
(författare)
-
Proteomic profiling of follicular and papillary thyroid tumors
- 2012
-
Ingår i: European Journal of Endocrinology. - 0804-4643 .- 1479-683X. ; 166:4, s. 657-667
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: Thyroid proteomics is a new direction in thyroid cancer research aiming at etiological understanding and biomarker identification for improved diagnosis. Methods: Two-dimensional electrophoresis was applied to cytosolic protein extracts from frozen thyroid samples (ten follicular adenomas, nine follicular carcinomas, ten papillary carcinomas, and ten reference thyroids). Spots with differential expression were revealed by image and multivariate statistical analyses, and identified by mass spectrometry. Results: A set of 25 protein spots significant for discriminating between the sample groups was identified. Proteins identified for nine of these spots were studied further including 14-3-3 protein beta/alpha, epsilon, and zeta/delta, peroxiredoxin 6, selenium-binding protein 1, protein disulfide-isomerase precursor, annexin A5 (ANXA5), tubulin alpha-1B chain, and alpha 1-antitrypsin precursor. This subset of protein spots carried the same predictive power in differentiating between follicular carcinoma and adenoma or between follicular and papillary carcinoma, as compared with the larger set of 25 spots. Protein expression in the sample groups was demonstrated by western blot analyses. For ANXA5 and the 14-3-3 proteins, expression in tumor cell cytoplasm was demonstrated by immunohistochemistry both in the sample groups and an independent series of papillary thyroid carcinomas. Conclusion: The proteins identified confirm previous findings in thyroid proteomics, and suggest additional proteins as dysregulated in thyroid tumors.
|
|
| 8. |
- Wennerberg, Erik, et al.
(författare)
-
Human anaplastic thyroid carcinoma cells are sensitive to NK cell-mediated lysis via ULBP2/5/6 and chemoattract NK cells
- 2014
-
Ingår i: Clinical Cancer Research. - 1078-0432. ; 20:22, s. 5733-5744
-
Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Anaplastic thyroid carcinoma (ATC) is one of the most aggressive forms of cancer with no curative therapies available. To date, strategies to target ATC by immunotherapy have not been evaluated. We investigated whether ATC would be a suitable target for natural killer (NK) cell-based immunotherapy.EXPERIMENTAL DESIGN: We first established seven new cell lines from ATC tumors, three from papillary thyroid carcinoma tumors and analyzed them together with eight additional ATC cell lines. Cells were analyzed for sensitivity to lysis by NK cells and their ability to chemoattract and regulate the activity of NK cells. In addition, fresh tumor samples and peripheral blood from six patients with ATC were analyzed for NK cell infiltration and phenotype.RESULTS: We observed that ATC cell lines are sensitive to lysis by ex vivo expanded NK cells and that the lysis was abrogated upon blockade of NKG2D. Sensitivity of thyroid cancer cell lines to NK cell-mediated lysis correlated with surface expression of UL16-binding protein 2 on tumor cells. Moreover, ATC cell lines produced high levels of CXCL10 and stimulated migration of expanded NK cells and ATC tumors were enriched for NK cells expressing the cognate chemokine receptor CXCR3. However, compared with NK cells in peripheral blood, ATC tumor-derived NK cells displayed a suppressed phenotype with a downregulated expression of NKG2D. In vitro, suppression of NK cell-mediated lysis and NKG2D expression by ATC cells was restored upon neutralization of prostaglandin-E2.CONCLUSIONS: ATC cell lines are sensitive to NK cell-mediated lysis via ULBP2/5/6 and chemoattract CXCR3-positive NK cells. Patients with ATC may benefit from NK cell-based immunotherapy.
|
|
| 9. |
- Zedenius, Jan, et al.
(författare)
-
Endokrina organ
- 2013. - 8
-
Ingår i: Kirurgi. - Stockholm : Liber. - 9789147108114 - 9789147105700 ; , s. 383-416
-
Bokkapitel (refereegranskat)
|
|
| 10. |
- Åkerström, Tobias, et al.
(författare)
-
Comprehensive Re-Sequencing of Adrenal Aldosterone Producing Lesions Reveal Three Somatic Mutations near the KCNJ5 Potassium Channel Selectivity Filter.
- 2012
-
Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 7:7
-
Tidskriftsartikel (refereegranskat)abstract
- Aldosterone producing lesions are a common cause of hypertension, but genetic alterations for tumorigenesis have been unclear. Recently, either of two recurrent somatic missense mutations (G151R or L168R) was found in the potassium channel KCNJ5 gene in aldosterone producing adenomas. These mutations alter the channel selectivity filter and result in Na(+) conductance and cell depolarization, stimulating aldosterone production and cell proliferation. Because a similar mutation occurs in a Mendelian form of primary aldosteronism, these mutations appear to be sufficient for cell proliferation and aldosterone production. The prevalence and spectrum of KCNJ5 mutations in different entities of adrenocortical lesions remain to be defined.
|
|
