| 1. |
- Hedborg, Fredrik, et al.
(författare)
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Evidence for hypoxia-induced neuronal-to-chromaffin metaplasia in neuroblastoma
- 2003
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Ingår i: The FASEB Journal. - : Wiley. - 0892-6638 .- 1530-6860. ; 17, s. 598-
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Tidskriftsartikel (refereegranskat)abstract
- We present evidence that in neuroblastoma, a pediatric malignancy of embryonal sympathetic origin, hypoxia, underlies a phenotypic switch from a primitive neuronal to a chromaffin cell type. This conclusion is based on morphological and molecular data on 116 clinical tumors and is supported by data on the phenotypic effects of hypoxia on neuroblastoma cell lines when studied in monolayer culture and as tumor xenografts. In the clinical material, extensive chromaffin features were seen in regions of chronic tumor hypoxia. This was the exclusive form of intra-tumoral maturation of stroma-poor tumors and was also seen in stroma-rich tumors, either exclusively or in combination with ganglion-like cells. In neuroblastoma cell lines, hypoxia induced changes in gene expression associated with the chromaffin features observed in vivo. We therefore propose tumor hypoxia as a major cue determining phenotype in sympathetic tumors of neuroblastic origin. Because it appears to be reversible upon reoxygenation in monolayer culture, we suggest the term metaplasia for the phenomenon.
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| 4. |
- Ekman, Simon, et al.
(författare)
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A novel oral insulin-like growth factor-1 receptor pathway modulator and its implications for patients with non-small cell lung carcinoma : A phase I clinical trial
- 2016
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Ingår i: Acta Oncologica. - 0284-186X .- 1651-226X. ; 55:2, s. 140-148
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: A phase Ia/b dose-escalation study was performed to characterize the safety, efficacy and pharmacokinetic properties of the oral small molecule insulin-like growth factor-1-receptor pathway modulator AXL1717 in patients with advanced solid tumors.MATERIAL AND METHODS: This was a prospective, single-armed, open label, dose-finding phase Ia/b study with the aim of single day dosing (phase Ia) to define the starting dose for multi-day dosing (phase Ib), and phase Ib to define and confirm recommended phase II dose (RP2D) and if possible maximum tolerated dose (MTD) for repeated dosing.RESULTS AND CONCLUSION: Phase Ia enrolled 16 patients and dose escalations up to 2900 mg BID were successfully performed without any dose limiting toxicity (DLT). A total of 39 patients were treated in phase Ib. AXL1717 was well tolerated with neutropenia as the only dose-related, reversible, DLT. RP2D dose was found to be 390 mg BID for four weeks. Some patients, mainly with NSCLC, demonstrated signs of clinical benefit, including four partial tumor responses (one according to RECIST and three according to PET). The 15 patients with NSCLC with treatment duration longer than two weeks with single agent AXL1717 in third or fourth line of therapy showed a median progression-free survival of 31 weeks and overall survival of 60 weeks. Down-regulation of IGF-1R on granulocytes and increases of free serum levels of IGF-1 were seen in patients treated with AXL1717. AXL1717 had an acceptable safety profile and demonstrated promising efficacy in this heavily pretreated patient cohort, especially in patients with NSCLC. RP2D was concluded to be 390 mg BID for four weeks. Trial number is NCT01062620.
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| 5. |
- Granfeldt, Hans, et al.
(författare)
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Experience with the Impella (R) recovery axial-flow system for acute heart failure at three cardiothoracic centers in Sweden
- 2009
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Ingår i: Scandinavian Cardiovascular Journal. - : Informa UK Limited. - 1401-7431 .- 1651-2006. ; 43:4, s. 233-239
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Tidskriftsartikel (refereegranskat)abstract
- Objectives. The Impella (R) recovery axial-flow system is a mechanical assist system for use in acute heart failure. This retrospective study reports the use of the device at three cardiothoracic units in Sweden. Design. Fifty patients (35 men, mean age 55.8 years, range 26 to 84 years) underwent implantation of 26 Impella (R) LP 2.5/5.0 (support-time 0.1 to 14 days), 16 Impella (R) LD (support-time 1 to 7 days) and 8 Impella (R) RD (support-time 0.1 to 8 days) between 2003 and 2007. Implantation was performed because of postcardiotomy heart failure (surgical group, n=33) or for various states of heart failure in cardiological patients (non-surgical group, n=17). The intention for the treatments was mainly to use the pump as a obridge-to-recoveryo. Results. Early mortality in the surgical and non-surgical groups was 45% and 23%, respectively. Complications included infection, 36% and right ventricular failure, 28%. Cardiac output and cardiac power output postoperatively were significantly higher among survivors than non-survivors. Conclusions. The Impella (R) recovery axial-flow system facilitates treatment in acute heart failure. Early intervention in patients with acute heart failure and optimized hemodynamics in the post-implantation period seem to be of importance for long-term survival. Insufficient early response to therapy should urge to consider further treatment options.
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| 6. |
- Larsson, Annika, et al.
(författare)
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Lactadherin binds to elastin -a starting point for medin amyloid formation?
- 2006
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Ingår i: Amyloid. - : Informa UK Limited. - 1350-6129 .- 1744-2818. ; 13:2, s. 78-85
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Tidskriftsartikel (refereegranskat)abstract
- Medin amyloid is found in the medial layer of the aorta in almost 100% of the Caucasian population over 50 years of age. The medin fragment is 5.5 kDa and derives from the C2-like domain of the precursor protein lactadherin. We have previously reported immunohistochemical findings showing that medin amyloid co-localizes with elastic fibers of arteries and herein we show that lactadherin also is associated with elastic structures of human aortic material. In addition, results from in vitro binding assays demonstrate that both medin and lactadherin bind to tropoelastin in a concentration-dependent fashion, suggesting that the lactadherin-tropoelastin interaction is mediated via the medin domain. It is possible that lactadherin, which is a cell adhesion protein, in this way connects smooth muscle cells to the elastic fibers of arteries. Given that both medin and lactadherin interact with elastic fibers, elastin is probably an important component in the formation of medin amyloid.
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| 8. |
- Peng, Siwei, et al.
(författare)
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Role of aggregated medin in the pathogenesis of thoracic aortic aneurysm and dissection
- 2007
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Ingår i: Laboratory Investigation. - : Elsevier BV. - 0023-6837 .- 1530-0307. ; 87:12, s. 1195-1205
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Tidskriftsartikel (refereegranskat)abstract
- The pathogenesis of sporadic thoracic aortic aneurysm and dissection, which may lead to rupture of the aorta, remains largely unknown. Amyloid deposits, formed from the medin peptide, are very prevalent in the media of the thoracic aorta. We have studied the occurrence of medin-derived amyloid in specimens from patients with thoracic aortic aneurysm, aortic dissection type A and normal dimensioned aorta. Surprisingly, the amount of amyloid was significantly lower in the aneurysm and dissection groups (0.63+/-0.13 and 0.36+/-0.24 amyloid particles per mm2, respectively) compared to the control material (2.37+/-0.58). However, focal medin immunoreactivity not associated with amyloid was found more conspicuously in the media of the two diseased groups. Recent amyloid research indicates that prefibrillar oligomeric aggregates, rather than mature amyloid fibrils, are toxic to the surrounding cells. The non-amyloid medin immunoreactivity observed may represent such toxic oligomers. This is supported by the fact that aggregated medin induced death of aortic smooth muscle cells in vitro. In addition, cells incubated together with medin increased the production of matrix metalloproteinase-2, a protease that degrades elastin and collagen and subsequently weakens the vessel wall. We therefore propose that medin oligomers are involved in the degeneration process of sporadic thoracic aortic aneurysm and dissection.
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| 11. |
- Probst, Johan, et al.
(författare)
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Thoracoscopic epicardial left atrial ablation in symptomatic patients with atrial fibrillation
- 2016
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Ingår i: Europace. - : Oxford University Press (OUP). - 1099-5129 .- 1532-2092. ; 18:10, s. 1538-1544
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Tidskriftsartikel (refereegranskat)abstract
- The low efficacy rates reported for conventional catheter ablation of longstanding persistent atrial fibrillation (LPAF) have led to the development of alternative techniques such as minimal invasive surgical ablation, aiming for durable and contiguous transmural lesions. The aim was to evaluate the efficacy and safety of total thoracoscopic epicardial left atrial ablation (TELA-AF) procedures in a prospective study of severely symptomatic patients with either drug-resistant AF and/or failed attempts of catheter ablation. The TELA-AF surgical technique includes pulmonary vein isolation, left atrial (LA) 'box lesion', and partial vagal denervation. The LA appendage was excluded if deemed safe. Patients were followed with clinical evaluations and 12-lead electrocardiograms at 3, 6, and 12 months after the surgical intervention, complemented with a 7-day Holter monitoring after 6 and 12 months. Sixty patients, of whom 38 (63%) suffered from LPAF, underwent TELA-AF between November 2008 and December 2010. One patient with LPAF was lost to follow-up. At 12-month follow-up, 55/59 patients (93%) were free from atrial fibrillation (AF), while 7/59 patients (12%) suffered from recurrent LA tachycardia. Among patients with LPAF, 32/37 (86%) maintained sinus rhythm after 12 months. Adverse events included four perioperative bleedings requiring conversion to sternotomy in three cases, two ischaemic strokes and one transient ischaemic attack. The total thoracoscopic surgical ablation procedure is highly effective even in patients with LPAF, and it seems safe. The high rate of iatrogenic LA re-entrant tachycardia, however, warrants further improvement of the technique.
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| 12. |
- Wassberg, Erik
(författare)
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Angiostatic treatment of neuroblastoma
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Neuroblastoma is a malignant solid tumor of childhood with a poor prognosis. The growth of solid tumors has been shown to be dependent on new blood vessel formation, i.e. angiogenesis. Several steps in the metastatic process have also been found to be angiogenesis-dependent. The mediators of tumor angiogenesis are now being elucidated, and angiostatic agents have been developed. Some of these agents are currently undergoing clinical trials. Neuroblastomas grow quickly, are highly vascularized, and metastasize early, and hence inhibition of angiogenesis - angiostatic therapy - may be indicated in this disease. In order to investigate the effects of angiostatic agents in this disease, a new animal experimental model for human neuroblastoma was developed. This model can be used for investigations of effects of angiogenesisinhibitors, as well as of chemotherapy, radiotherapy, and/or surgery. When characterizing the model, we found that plasma levels of chromogranin A were directly proportional to the tumor burden and increased in parallel with tumor growth, and could therefore be used as a neuroblastoma marker. Three angiostatic agents were tested in the model: TNR-470, the synthetic analogue of fumagillin, given subcutaneously, and the endogenous steroid 2-methoxyestradiol and its derivative 2-propynylestradiol, given orally. TNP-470 administration resulted in a significant reduction of the tumor growth rate and microvascular counts, and of the fraction of viable tumor cells, compared to controls. The fraction of apoptotic tumor cells increased threefold, while that of proliferative cells remained unaltered. This can explain the reduced net growth. Treatment with the angiostatic and chemotherapeutic steroids 2-methoxyestradiol and 2-propynylestradiol yielded similar results. However, the mechanism of action of these steroids was bimodal; the effect occurring both through inhibition of tumor angiogenesis and through induction of tumor cell apoptosis. It was shown for the first time that inhibition of angiogenesis regardless of agent induces striking chromaffin differentiation, observed as increased expression of insulin-like growth factor II gene, tyrosine hydroxylase, and chromogranin A, and increased formation of cellular processes. It is suggested that inhibition of angiogenesis induces metabolic stress, resulting in chromaffin differentiation and apoptosis. Such agonal differentiation may be the link between angiostatic therapy and tumor cell apoptosis.Angiostatic agents administered as single therapy have an objective tumoristatic effect in our neuroblastoma model. Angiostatic treatment of neuroblastoma is a new and promising treatment modality that merits clinical investigation.
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