| 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 .- 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. |
- Fotouhi, Omid, et al.
(författare)
-
Proteomics identifies neddylation as a potential therapy target in small intestinal neuroendocrine tumors
- 2019
-
Ingår i: Oncogene. - : NATURE PUBLISHING GROUP. - 0950-9232 .- 1476-5594. ; 38:43, s. 6881-6897
-
Tidskriftsartikel (refereegranskat)abstract
- Patients with small intestinal neuroendocrine tumors (SI-NETs) frequently develop spread disease; however, the underlying molecular mechanisms of disease progression are not known and effective preventive treatment strategies are lacking. Here, protein expression profiling was performed by HiRIEF-LC-MS in 14 primary SI-NETs from patients with and without liver metastases detected at the time of surgery and initial treatment. Among differentially expressed proteins, overexpression of the ubiquitin-like protein NEDD8 was identified in samples from patients with liver metastasis. Further, NEDD8 correlation analysis indicated co-expression with RBX1, a key component in cullin-RING ubiquitin ligases (CRLs). In vitro inhibition of neddylation with the therapeutic agent pevonedistat (MLN4924) resulted in a dramatic decrease of proliferation in SI-NET cell lines. Subsequent mass spectrometry-based proteomics analysis of pevonedistat effects and effects of the proteasome inhibitor bortezomib revealed stabilization of multiple targets of CRLs including p27, an established tumor suppressor in SI-NET. Silencing of NEDD8 and RBX1 using siRNA resulted in a stabilization of p27, suggesting that the cellular levels of NEDD8 and RBX1 affect CRL activity. Inhibition of CRL activity, by either NEDD8/RBX1 silencing or pevonedistat treatment of cells resulted in induction of apoptosis that could be partially rescued by siRNA-based silencing of p27. Differential expression of both p27 and NEDD8 was confirmed in a second cohort of SI-NET using immunohistochemistry. Collectively, these findings suggest a role for CRLs and the ubiquitin proteasome system in suppression of p27 in SI-NET, and inhibition of neddylation as a putative therapeutic strategy in SI-NET.
|
|
| 7. |
- Fotouhi, Omid, et al.
(författare)
-
Regional differences in somatostatin receptor 2 (SSTR2) immunoreactivity is coupled to level of bowel invasion in small intestinal neuroendocrine tumors
- 2018
-
Ingår i: Neuro - endocrinology letters. - Stockholm, Sweden : Maghira & Maas Publications. - 0172-780X. ; 39:4, s. 305-309
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Somatostatin receptor (SSTR) expression constitutes a pivotal cornerstone for accurate radiological detection and medical treatment of small intestinal neuroendocrine tumors (SI-NETs), and the development of somatostatin analogues for these purposes have revolutionized the clinical work-up. Previous assessments of SSTR isoform expression in SI-NETs have found correlations to overall prognosis and treatment response, however these analyses usually report overall tumoral immunoreactivity, and little is reported regarding histo-regional differences in expressional patterns.METHODS: Thirty-seven primary SI-NETs (WHO grade I, n=32 and WHO grade II, n=5) were collected and assessed for SSTR2 immunohistochemistry. Samples were stratified with regards to histological level of bowel infiltration and spread (mucosal region, muscularis propria region, subserosal region) and each of these tumoral regions was separately scored by SSTR2 staining localization (membrane, cytoplasmic), overall staining intensity and local staining differences within each region.RESULTS: SSTR2 immunoreactivity was progressively weaker as the tumor cells advanced through the small intestinal layers. This was exemplified by a reduction in the amount of tumor samples with strong SSTR2 expression in the deeper histological levels of the section; 56% of tumors displayed strong SSTR2 expression in the mucosal region, as compared to 29% and 30% of tumors within muscularis propria and subserosal layers, respectively.CONCLUSIONS: This observation indicates a down-regulation of SSTR2 expression as the tumors progress through the intestinal wall, which might signify underlying biological processes of importance for SI-NET invasion behavior.
|
|
| 8. |
- Muth, Andreas, et al.
(författare)
-
[Many adrenal incidentalomas are not adequately evaluated - updated guidelines to improve follow-up are presented].
- 2023
-
Ingår i: Läkartidningen. - 0023-7205 .- 1652-7518. ; 120
-
Tidskriftsartikel (refereegranskat)abstract
- The use of cross-sectional imaging in Sweden has increased more than twofold in the last 20 years. Inadvertently discovered adrenal lesions, adrenal incidentalomas, are reported in about one per cent of abdominal investigations. The first Swedish guidelines for the management of adrenal incidentalomas were published in 1996 and have since then been regularly revised. Still, data indicate that less than half of patients receive adequate follow-up. Here we comment on the newly updated guidelines and briefly review the recommended clinical and radiological work-up.
|
|
| 9. |
- 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.
|
|
| 10. |
|
|
