| 1. |
- Karpanen, Terhi, et al.
(författare)
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Overexpression of vascular endothelial growth factor-B in mouse heart alters cardiac lipid metabolism and induces myocardial hypertrophy
- 2008
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Ingår i: Circulation Research. - : American Heart Association. - 0009-7330 .- 1524-4571. ; 103:9, s. 1018-1026
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Tidskriftsartikel (refereegranskat)abstract
- Vascular endothelial growth factor (VEGF)-B is poorly angiogenic but prominently expressed in metabolically highly active tissues, including the heart. We produced mice expressing a cardiac-specific VEGF-B transgene via the alpha-myosin heavy chain promoter. Surprisingly, the hearts of the VEGF-B transgenic mice showed concentric cardiac hypertrophy without significant changes in heart function. The cardiac hypertrophy was attributable to an increased size of the cardiomyocytes. Blood capillary size was increased, whereas the number of blood vessels per cell nucleus remained unchanged. Despite the cardiac hypertrophy, the transgenic mice had lower heart rate and blood pressure than their littermates, and they responded similarly to angiotensin II-induced hypertension, confirming that the hypertrophy does not compromise heart function. Interestingly, the isolated transgenic hearts had less cardiomyocyte damage after ischemia. Significantly increased ceramide and decreased triglyceride levels were found in the transgenic hearts. This was associated with structural changes and eventual lysis of mitochondria, resulting in accumulation of intracellular vacuoles in cardiomyocytes and increased death of the transgenic mice, apparently because of mitochondrial lipotoxicity in the heart. These results suggest that VEGF-B regulates lipid metabolism, an unexpected function for an angiogenic growth factor.
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| 2. |
- Andersson, Roland, et al.
(författare)
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Pancreatic cancer–the past, the present, and the future
- 2022
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 57:10, s. 1169-1177
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Forskningsöversikt (refereegranskat)abstract
- Background: Pancreatic cancer has been and still is associated with a very poor prognosis. This is due to a lack of major breakthroughs with respect to early diagnosis, prognostication, prediction, as well as novel, targeted therapies. The benefits of surgery and chemotherapy are evident, but the fact that only some 10% of all patients have early, localized disease highlights the unmet need for new early detection methods. An improved understanding of tumor biology and the development of molecular markers detectable both in the circulation and in cancer tissues may underlie the development of new tools for optimizing both diagnosis and treatment. Material and methods: Review of the literature. Results and conclusion: If we do not improve precision oncology for pancreatic ductal adenocarcinoma, the prognosis will still remain dismal and the” burden” on society will increase substantially.
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| 3. |
- Ansari, Daniel, et al.
(författare)
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Surveillance after surgery for pancreatic cancer : a global scoping review of guidelines and a nordic survey of contemporary practice
- 2024
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Ingår i: Scandinavian Journal of Gastroenterology. - : Taylor & Francis. - 0036-5521 .- 1502-7708.
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Forskningsöversikt (refereegranskat)abstract
- Objectives: Most patients with pancreatic cancer who have undergone surgical resection eventually develop disease recurrence. This study aimed to investigate whether there is evidence to support routine surveillance after pancreatic cancer surgery, with a secondary aim of analyzing the implementation of surveillance strategies in the Nordic countries.Materials and Methods: A scoping review was conducted to identify clinical practice guidelines globally and research studies relating to surveillance after pancreatic cancer resection. This was followed by a survey among 20 pancreatic units from four Nordic countries to assess their current practice of follow-up for operated patients.Results: Altogether 16 clinical practice guidelines and 17 research studies were included. The guidelines provided inconsistent recommendations regarding postoperative surveillance of pancreatic cancer. The clinical research data were mainly based on retrospective cohort studies with low level of evidence and lead-time bias was not addressed. Active surveillance was recommended in Sweden and Denmark, but not in Norway beyond the post-operative/adjuvant period. Finland had no national recommendations for surveillance. The Nordic survey revealed a wide variation in reported practice among the different units. About 75% (15 of 20 units) performed routine postoperative surveillance. Routine CA 19-9 testing was used by 80% and routine CT by 67% as part of surveillance. About 73% of centers continued follow-up until 5 years postoperatively.Conclusion: Evidence for routine long-term (i.e. 5 years) surveillance after pancreatic cancer surgery remains limited. Most pancreatic units in the Nordic countries conduct regular follow-up, but protocols vary.
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| 4. |
- Bertonnier-Brouty, Ludivine, et al.
(författare)
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E2F transcription factors promote tumorigenicity in pancreatic ductal adenocarcinoma
- 2024
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Ingår i: Cancer Medicine. - 2045-7634. ; 13:9
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with limited treatment options, illustrating an urgent need to identify new drugable targets in PDACs.OBJECTIVE: Using the similarities between tumor development and normal embryonic development, which is accompanied by rapid cell expansion, we aimed to identify and characterize embryonic signaling pathways that were reinitiated during tumor formation and expansion.METHODS AND RESULTS: Here, we report that the transcription factors E2F1 and E2F8 are potential key regulators in PDAC. E2F1 and E2F8 RNA expression is mainly localized in proliferating cells in the developing pancreas and in malignant ductal cells in PDAC. Silencing of E2F1 and E2F8 in PANC-1 pancreatic tumor cells inhibited cell proliferation and impaired cell spreading and migration. Moreover, loss of E2F1 also affected cell viability and apoptosis with E2F expression in PDAC tissues correlating with expression of apoptosis and mitosis pathway genes, suggesting that E2F factors promote cell cycle regulation and tumorigenesis in PDAC cells.CONCLUSION: Our findings illustrate that E2F1 and E2F8 transcription factors are expressed in pancreatic progenitor and PDAC cells, where they contribute to tumor cell expansion by regulation of cell proliferation, viability, and cell migration making these genes attractive therapeutic targets and potential prognostic markers for pancreatic cancer.
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| 5. |
- Flanagan, Sarah E, et al.
(författare)
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Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease.
- 2014
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 46:8, s. 812-814
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Tidskriftsartikel (refereegranskat)abstract
- Monogenic causes of autoimmunity provide key insights into the complex regulation of the immune system. We report a new monogenic cause of autoimmunity resulting from de novo germline activating STAT3 mutations in five individuals with a spectrum of early-onset autoimmune disease, including type 1 diabetes. These findings emphasize the critical role of STAT3 in autoimmune disease and contrast with the germline inactivating STAT3 mutations that result in hyper IgE syndrome.
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| 6. |
- Heby, Margareta, et al.
(författare)
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Additive clinical impact of epidermal growth factor receptor and podocalyxin-like protein expression in pancreatic and periampullary adenocarcinomas
- 2020
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- The outcome of periampullary adenocarcinomas remains poor with few treatment options. Podocalyxin-like protein (PODXL) is an anti-adhesive protein, the high expression of which has been shown to confer a poor prognosis in numerous malignancies. A correlation and adverse prognostic synergy between PODXL and the epidermal growth factor receptor (EGFR) has been observed in colorectal cancer. Here, we investigated whether this also applies to periampullary adenocarcinomas. We analyzed the immunohistochemical expression of PODXL and EGFR in tissue microarrays with tumors from two patient cohorts; (Cohort 1, n = 175) and (Cohort 2, n = 189). The effect of TGF-β-induced expression and siRNA-mediated knockdown of PODXL and EGFR, were investigated in pancreatic cancer cells (PANC-1) in vitro. We found a correlation between PODXL and EGFR in these cancers, and a synergistic adverse effect on survival. Furthermore, silencing PODXL in pancreatic cancer cells resulted in the down-regulation of EGFR, but not vice versa. Consequently, these findings suggest a functional link between PODXL and EGFR, and the potential combined utility as biomarkers possibly improving patient stratification. Further studies examining the mechanistic basis underlying these observations may open new avenues of targeted treatment options for subsets of patients affected by these particularly aggressive cancers.
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| 7. |
- Kaasinen, Mirjami, et al.
(författare)
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Matrix Metalloproteinase 8 Expression in a Tumour Predicts a Favourable Prognosis in Pancreatic Ductal Adenocarcinoma
- 2022
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 23:6
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Tidskriftsartikel (refereegranskat)abstract
- Pancreatic ductal adenocarcinoma (PDAC) is a significant cause of cancer-related death globally, and, despite improvements in diagnostics and treatment, survival remains poor. Matrix metalloproteinases (MMPs) are enzymes involved in stroma remodelling in inflammation and cancer. MMP-8 plays a varied prognostic role in cancers of the gastrointestinal tract. We examined the prognostic value of MMP-8 immunoexpression in tumour tissue and the amount of MMP-8-positive polymorphonuclear cells (PMNs) in PDAC and their association with immune responses using C-reactive protein (CRP) as a marker of systemic inflammation. Tumour samples from 141 PDAC patients undergoing surgery in 2002–2011 at the Department of Surgery, Helsinki University Hospital were stained immunohistochemically, for which we evaluated MMP-8 expression in cancer cells and the amount of MMP-8-positive PMNs. We assessed survival using the Kaplan–Meier analysis while uni-and multivariable analyses relied on the Cox proportional hazards model. A negative MMP-8 stain and elevated CRP level predicted a poor prognosis (hazard ratio [HR] = 6.95; 95% confidence interval (CI) 2.69–17.93; p < 0.001) compared to a positive stain and low CRP level (<10 mg/L). The absence of PMNs together with an elevated CRP level also predicted an unfavourable outcome (HR = 3.17; 95% CI 1.60–6.30; p = 0.001). MMP-8 expression in the tumour served as an independent positive prognostic factor (HR = 0.33; 95% CI 0.16–0.68; p = 0.003). Tumour MMP-8 expression and a low CRP level may predict a favourable outcome in PDAC with similar results for MMP-8-positive PMNs and low CRP levels. Tumoural MMP-8 expression represents an independent positive prognostic factor in PDAC.
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| 8. |
- Lankinen, Maria, et al.
(författare)
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Fatty fish intake decreases lipids related to inflammation and insulin signaling : a lipidomics approach
- 2009
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Ingår i: PLOS ONE. - : PLOS. - 1932-6203. ; 4:4
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The evidence of the multiple beneficial health effects of fish consumption is strong, but physiological mechanisms behind these effects are not completely known. Little information is available on the effects of consumption of different type of fish. The aim of this study was to investigate how fatty fish or lean fish in a diet affect serum lipidomic profiles in subjects with coronary heart disease.METHODOLOGY AND PRINCIPAL FINDINGS: A pilot study was designed which included altogether 33 subjects with myocardial infarction or unstable ischemic attack in an 8-week parallel controlled intervention. The subjects were randomized to either fatty fish (n = 11), lean fish (n = 12) or control (n = 10) groups. Subjects in the fish groups had 4 fish meals per week and subjects in the control group consumed lean beef, pork and chicken. A fish meal was allowed once a week maximum. Lipidomics analyses were performed using ultra performance liquid chromatography coupled to electrospray ionization mass spectrometry and gas chromatography. Multiple bioactive lipid species, including ceramides, lysophosphatidylcholines and diacylglycerols, decreased significantly in the fatty fish group, whereas in the lean fish group cholesterol esters and specific long-chain triacylglycerols increased significantly (False Discovery Rate q-value <0.05).CONCLUSIONS/SIGNIFICANCE: The 8-week consumption of fatty fish decreased lipids which are potential mediators of lipid-induced insulin resistance and inflammation, and may be related to the protective effects of fatty fish on the progression of atherosclerotic vascular diseases or insulin resistance.TRIAL REGISTRATION: ClinicalTrials.gov NCT00720655.
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| 9. |
- Pirhonen, Juho, et al.
(författare)
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Lipid Metabolic Reprogramming Extends beyond Histologic Tumor Demarcations in Operable Human Pancreatic Cancer
- 2022
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Ingår i: Cancer Research. - 0008-5472. ; 82:21, s. 3932-3949
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Tidskriftsartikel (refereegranskat)abstract
- Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest malignancies and potentially curable only with radical surgical resection at early stages. The tumor microenvironment has been shown to be central to the development and progression of PDAC.A better understanding of how early human PDAC metabolically communicates with its environment and differs from healthy pancreas could help improve PDAC diagnosis and treatment. Here we performed deep proteomic analyses from diagnostic specimens of operable, treatment-naive PDAC patients (n 14), isolating four tissue compartments by laser-capture microdissection: PDAC lesions, tumor-adjacent but morphologically benign exocrine glands, and connective tissues neighboring each of these compartments. Protein and pathway levels were compared between compartments and with control pancreatic proteomes. Selected targets were studied immunohistochemically in the 14 patients and in additional tumor microarrays, and lipid deposition was assessed by nonlinear label-free imaging (n = 16). Widespread downregulation of pancreatic secretory functions was observed, which was paralleled by high cholesterol biosynthetic activity without prominent lipid storage in the neoplastic cells. Stromal compartments harbored ample blood apolipoproteins, indicating abundant microvasculature at the time of tumor removal. The features best differentiating the tumor-adjacent exocrine tissue from healthy control pancreas were defined by upregulation of proteins related to lipid transport. Importantly, histologically benign exocrine regions harbored the most significant prognostic pathways, with proteins involved in lipid transport and metabolism, such as neutral cholesteryl ester hydrolase 1, associating with shorter survival. In conclusion, this study reveals prognostic molecular changes in the exocrine tissue neighboring pancreatic cancer and identifies enhanced lipid transport and metabolism as its defining features.
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| 10. |
- Vehviläinen, Sini, et al.
(författare)
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Single-operator peroral pancreatoscopy in the preoperative diagnostics of suspected main duct intraductal papillary mucinous neoplasms : efficacy and novel insights on complications
- 2022
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Ingår i: Surgical Endoscopy. - : Springer. - 0930-2794 .- 1432-2218. ; 36, s. 7431-7443
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Tidskriftsartikel (refereegranskat)abstract
- Background: Distinguishing intraductal papillary mucinous neoplasms (IPMNs) from other pancreatic cystic lesions is essential since IPMNs carry the risk of becoming malignant. Differentiating the main pancreatic duct involving IPMNs (MD-IPMNs) through conventional imaging is deficient. Single-operator peroral pancreatoscopy (SOPP) represents a promising method offering additional information on suspected lesions in the pancreatic main duct (MD). We aimed to determine the role of SOPP in the preoperative diagnostics of suspected MD-IPMNs and identify factors contributing to SOPP-related complications.Materials and Methods: In this primarily retrospective study, SOPPs were performed at three high-volume centers on suspected MD-IPMNs. Primary outcome was the clinical impact of SOPP to subsequent patient care. Additionally, we documented post-SOPP complications and analyzed several assumed patient- and procedure-related risk factors.Results: One hundred and one (101) SOPPs were performed. Subsequent clinical management was affected due to the findings in 86 (85%) cases. Surgery was planned for 29 (29%) patients. A condition other than IPMN explaining MD dilatation was found in 28 (28%) cases. In 35 (35%) cases, follow-up with MRI was continued. Post-SOPP pancreatitis occurred in 20 (20%) patients and one of them was fatal. A decrease in odds of post-SOPP pancreatitis was seen as the MD diameter increases (OR 0.714 for 1.0 mm increase in MD diameter, CI 95% 0.514–0.993, p = 0.045). Furthermore, a correlation between lower MD diameter values and higher severity post-SOPP pancreatitis was seen (TJT = 599, SE = 116.6, z = − 2.31; p = 0.020). History of pancreatitis after endoscopic retrograde cholangiopancreatography was a confirmed risk factor for post-SOPP pancreatitis. Conclusions between complications and other risk factors could not be drawn.Conclusion: SOPP aids clinical decision-making in suspected MD-IPMNs. Risk for post-SOPP pancreatitis is not negligible compared to non-invasive imaging methods. The risk for pancreatitis decreases as the diameter of the MD increases.
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