| 1. |
- Althini, Susanna
(författare)
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Experimental Studies of BMP Signalling in Neuronal Cells
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The developing nervous system depends largely on extracellular cues to shape its complex network of neurons. Classically, neurotrophins are known to be important mediators in this process. More recently, Bone Morphogenetic Proteins (BMPs), belonging to the Transforming Growth Factor beta (TGFβ) superfamily of secreted cytokines, have been shown to exert a wide range of effects, such as cellular growth, differentiation, survival and apoptosis, both in the developing and adult nervous system. They signal via serine/threonine kinase receptor essentially to the Smad pathway, which carries the signal to the nucleus where the transcription of target genes is regulated.This thesis investigates the functions of BMPs in the nervous system, using a set of different models. Firstly, a targeted deletion of GDF10 (BMP3b) in the mouse was established to evaluate the role of this growth/differentiation factor in the hippocampal formation, a brain area known to be involved in memory processing. Other members of the TGFβ superfamily likely compensate for the lack of GDF10, since no detectable alterations in hippocampal function or gene transcription profile have been found. Secondly, a mouse model was set up, with the aim to study impaired BMP-signalling in dopaminergic neurons. The tyrosine hydroxylase (TH) locus was used to drive the expression of dominant negative BMP receptors by means of bicistronic mRNAs. TH is the rate-limiting enzyme in the biosynthesis of catecholamine and the mice described, show a graded decrease of TH-activity resulting in severe to mild dopamine deficiency. The contribution of the dominant negative BMP receptors to the phenotype is however secondary to the apparent TH hypomorphism. The final theme of this thesis is the potentiating effects of BMPs on neurotrophin-induced neurite outgrowth as studied in explanted ganglia from chick embryos and in the rat phaeochromocytoma cell line PC12. A number of pharmacological inhibitors of intracellular signalling kinases were applied to the cultures in order to reveal the contribution of different pathways to the enhanced neurite outgrowth. We made the unexpected finding that inhibition of MEK signalling mimicked the potentiating effects of BMP stimulation in the chick system. The underlying mechanisms for the synergistic effects, however, are still an enigma.
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| 2. |
- Ansari, Daniel, et al.
(författare)
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Early-onset pancreatic cancer : a population-based study using the SEER registry
- 2019
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Ingår i: Langenbeck's Archives of Surgery. - : Springer Science and Business Media LLC. - 1435-2443 .- 1435-2451. ; 404:5, s. 565-571
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Tidskriftsartikel (refereegranskat)abstract
- Background: Early-onset pancreatic cancer (< 50 years, EOPC) is uncommon and limited data exist on clinical presentation and long-term survival. The aim of this study was to compare outcomes between patients with EOPC and those with later-onset pancreatic cancer (≥ 50 years, LOPC) using a large population-based cohort. Methods: The Surveillance, Epidemiology, and End Results (SEER) database was queried to identify patients with a microscopically confirmed pancreatic ductal adenocarcinoma for the period 2004 to 2016. Propensity score matching was used to compare overall survival (OS) and cancer-specific survival (CSS) between patients with EOPC and LOPC. The EOPC and LOPC patients were paired 1:1 on propensity scores based on gender, tumor location, tumor size, AJCC stage, and treatment details. Results: The overall cohort included 72,906 patients with pancreatic ductal adenocarcinoma, including 4523 patients with EOPC (6.2%). EOPC patients were diagnosed at a more advanced AJCC stage (p < 0.001) compared with LOPC patients and received significantly more treatment, including surgery (p < 0.001), radiation (p < 0.001), and chemotherapy (p < 0.001). Following propensity score matching, 3172 EOPC patients were matched to 3172 LOPC patients, alleviating any covariate differences between the groups. The matched analysis showed that EOPC was associated with poorer 5-year OS (6.1% vs 8.6%, p = 0.003) and 5-year CSS (6.7% vs 9.7%, p < 0.001). In multivariable Cox regression analysis, EOPC remained significantly associated with adverse OS and CSS. Subgroup analyses showed that EOPC was associated with adverse 5-year OS (17.7% vs 26.9%, p < 0.001) and 5-year CSS (18.9% vs 29.7%, p < 0.001) in operated patients. After multivariable analysis, EOPC remained significantly associated with OS and CSS. For patients that did not undergo surgery, the OS and CSS remained dismal without any significant differences between the groups. Conclusion: To our knowledge, this is the largest study to compare the outcome of EOPC vs LOPC, as well as the first to use propensity score matching methodology for this purpose. The findings demonstrate that EOPC is diagnosed at a later stage and the matched survival analysis demonstrated reduced OS and CSS. We suggest that pancreatic cancer in young patients may have a unique tumor biology, which may be of importance for risk stratification and patient counseling.
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| 3. |
- Ansari, Daniel, et al.
(författare)
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The hippo signaling pathway in pancreatic cancer
- 2019
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Ingår i: Anticancer research. - : Anticancer Research USA Inc.. - 0250-7005 .- 1791-7530. ; 39:7, s. 3317-3321
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Forskningsöversikt (refereegranskat)abstract
- Hippo signaling is a key regulator of organ size, tissue hemostasis and regeneration. Dysregulation of the Hippo pathway has been recognized in a variety of human cancers, including pancreatic cancer. YES-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are the two major downstream effectors of the Hippo pathway. YAP and TAZ have been found to promote pancreatic tumor development and progression, even in the absence of mutant Kirsten RAS (KRAS). Pancreatic cancer is associated with an abundant stromal reaction leading to tumor growth and immune escape. It has been found that YAP and TAZ modulate behavior of pancreatic stellate cells and recruitment of tumor-associated macrophages and myeloid-derived suppressor cells. Moreover, YAP and TAZ are associated with chemoresistance and poor prognosis in pancreatic cancer. This review dissects the role of Hippo signaling in pancreatic cancer, focusing on molecular mechanisms and prospects for future intervention.
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| 4. |
- Ansari, Daniel, et al.
(författare)
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The role of PEDF in pancreatic cancer
- 2019
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Ingår i: Anticancer research. - : Anticancer Research USA Inc.. - 0250-7005 .- 1791-7530. ; 39:7, s. 3311-3315
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Forskningsöversikt (refereegranskat)abstract
- Pigment epithelium-derived factor (PEDF) is an important antiangiogenic and antitumorigenic factor in a variety of cancer forms, including pancreatic cancer. PEDF is mainly secreted as a soluble monomeric glycoprotein. In human pancreatic cancer PEDF levels are decreased, both in the tissue and serum. The decrease is associated with increased tumor angiogenesis, fibrosis, inflammation, autophagy, occurrence of liver metastasis and worse prognosis. In murine models, loss of PEDF is sufficient to induce invasive carcinoma and this phenotype is associated with large lesions characterized by poor differentiation. Lentiviral gene transfer of PEDF has resulted in decreased microvessel density and has inhibited tumor growth. Herein we review the multifunctional role of PEDF in pancreatic cancer and its therapeutic potential.
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