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- Haglund, Ellinor, et al.
(författare)
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The HD-exchange motions of ribosomal protein S6 are insensitive to reversal of the protein-folding pathway
- 2009
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 106:51, s. 21619-21624
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Tidskriftsartikel (refereegranskat)abstract
- An increasing number of protein structures are found to encompass multiple folding nuclei, allowing their structures to be formed by several competing pathways. A typical example is the ribosomal protein S6, which comprises two folding nuclei (sigma1 and sigma2) defining two competing pathways in the folding energy landscape: sigma1 --> sigma2 and sigma2 --> sigma1. The balance between the two pathways, and thus the order of folding events, is easily controlled by circular permutation. In this study, we make use of this ability to manipulate the folding pathway to demonstrate that the dynamic motions of the S6 structure are independent of how the protein folds. The HD-exchange protection factors remain the same upon complete reversal of the folding order. The phenomenon arises because the HD-exchange motions and the high-energy excitations controlling the folding pathway occur at separated free-energy levels: the Boltzmann distribution of unproductive unfolding attempts samples all unfolding channels in parallel, even those that end up in excessively high barriers. Accordingly, the findings provide a simple rationale for how to interpret native-state dynamics without the need to invoke fluctuations off the normal unfolding reaction coordinate.
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| 3. |
- Sandzén, Birger, 1944-, et al.
(författare)
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Cholecystectomy and sphincterotomy in patients with mild acute biliary pancreatitis in Sweden 1988 - 2003 : a nationwide register study
- 2009
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Ingår i: BMC Gastroenterology. - : BioMed Central. - 1471-230X. ; 9, s. 80-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Gallstones represent the most common cause of acute pancreatitis in Sweden. Epidemiological data concerning timing of cholecystectomy and sphincterotomy in patients with first attack of mild acute biliary pancreatitis (MABP) are scarce. Our aim was to analyse readmissions for biliary disease, cholecystectomy within one year, and mortality within 90 days of index admission for MABP.METHODS: Hospital discharge and death certificate data were linked for patients with first attack acute pancreatitis in Sweden 1988-2003. Mortality was calculated as case fatality rate (CFR) and standardized mortality ratio (SMR). MABP was defined as acute pancreatitis of biliary aetiology without mortality during an index stay of 10 days or shorter. Patients were analysed according to four different treatment policies: Cholecystectomy during index stay (group 1), no cholecystectomy during index stay but within 30 days of index admission (group 2), sphincterotomy but not cholecystectomy within 30 days of index admission (group 3), and neither cholecystectomy nor sphincterotomy within 30 days of index admission (group 4).RESULTS: Of 11636 patients with acute biliary pancreatitis, 8631 patients (74%) met the criteria for MABP. After exclusion of those with cholecystectomy or sphincterotomy during the year before index admission (N = 212), 8419 patients with MABP remained for analysis. Patients in group 1 and 2 were significantly younger than patients in group 3 and 4. Length of index stay differed significantly between the groups, from 4 (3-6) days, (representing median, 25 and 75 percentiles) in group 2 to 7 (5-8) days in groups 1. In group 1, 4.9% of patients were readmitted at least once for biliary disease within one year after index admission, compared to 100% in group 2, 62.5% in group 3, and 76.3% in group 4. One year after index admission, 30.8% of patients in group 3 and 47.7% of patients in group 4 had undergone cholecystectomy. SMR did not differ between the four groups.CONCLUSION: Cholecystectomy during index stay slightly prolongs this stay, but drastically reduces readmissions for biliary indications.
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| 4. |
- Sandzén, Birger, et al.
(författare)
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First attack of acute pancreatitis in Sweden 1988 - 2003 : incidence, aetiological classification, procedures and mortality - a register study
- 2009
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Ingår i: BMC Gastroenterology. - : BioMed Central. - 1471-230X. ; 9, s. 18-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Population-based studies suggest that the incidence of first attack of acute pancreatitis (FAAP) is increasing and that old age is associated with increased mortality. Because nationwide data are limited and information on standardized mortality ratio (SMR) versus age is lacking, we wanted to describe incidence and mortality of first attack acute pancreatitis (FAAP) in Sweden.METHODS: Hospital discharge data concerning diagnoses and surgical procedures and death certificate data were linked for patients with FAAP in Sweden. Mortality was calculated as case fatality rate (CFR), i.e. deaths per 1000 patients and SMR using age-, gender- and calendar year-specific expected survival estimates, and is given as mean with 95% confidence intervals. Data are presented as median values with 25% and 75% percentiles, means and standard deviations, or proportions. Proportions have been compared using the chi square test, Poisson-regression test or Fisher exact test. Location of two groups of ratio scale variables were compared using independent samples t-test or Mann-Whitney U-test.RESULTS: From 1988 through 2003, 43415 patients (23801 men and 19614 women) were admitted for FAAP. Age adjusted incidence rose from 27.0 to 32.0 per 100000 individuals and year. Incidence increased with age for both men and women. At index stay 19.7% of men and 35.4% of women had biliary diagnoses, and 7.1% of men and 2.1% of women alcohol-related diagnoses. Of 10072 patients who underwent cholecystectomy, 7521 (74.7%) did so after index stay within the audit period. With increasing age CFR increased and SMR decreased. For the whole period studied SMR was 11.75 (11.34-12.17) within 90 days of index admission and 2.03 (1.93-2.13) from 91 to 365 days. Alcohol-related diagnoses and young age was associated with increased SMR. Length of stay and SMR decreased significantly during the audit period.CONCLUSION: Incidence of FAAP increased slightly from 1988 to 2003. Incidence increased and SMR declined with increasing patient age. Although the prognosis for patients with FAAP has improved it remains an important health problem. Aetiological classification at index stay and timing of cholecystectomy should be improved.
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- Öhlund, Daniel, 1979-, et al.
(författare)
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Expression pattern and circulating levels of endostatin in patients with pancreas cancer
- 2008
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 122:12, s. 2805-2810
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Tidskriftsartikel (refereegranskat)abstract
- Endostatin is a potent inhibitor of angiogenesis that is cleaved from the basement membrane protein type XVIII collagen. Expression of endostatin has recently been shown by Western blot analysis of tissue lysates in normal pancreas and pancreas cancer tissue. We show here that the expression pattern of type XVIII collagen/endostatin is shifted from a general basement membrane staining and is mainly located in the vasculature during tumor progression. This shift in type XVIII collagen/endostatin expression pattern coincides with an up-regulation of MMPs involved in endostatin processing in the tumor microenvironment, such as MMP-3, MMP-9 and MMP-13. The circulating levels of endostatin was analyzed in patients with pancreas cancer and compared to that of healthy controls, as well as after surgical treatment or in a group of nonoperable patients after intraperitoneal fluorouracil (5-FU) chemotherapy. The results show that patients with pancreas cancer have increased circulating levels of endostatin and that these levels are normalized after surgery or intraperitoneal chemotherapy. These findings indicate that endostatin could be used as a biomarker for pancreas cancer progression.
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| 6. |
- Öhlund, Daniel, 1979-, et al.
(författare)
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Type IV collagen is a tumour stroma-derived biomarker for pancreas cancer
- 2009
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Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 101:1, s. 91-97
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Pancreas cancer is a dreaded disease with high mortality, despite progress in surgical and oncological treatments in recent years. The field is hampered by a lack of good prognostic and predictive tumour biomarkers to be used during follow-up of patients. METHODS: The circulating level of type IV collagen was measured by ELISA in pancreas cancer patients and controls. The expression pattern of type IV collagen in normal pancreas, pancreas cancer tissue and in pancreas cancer cell lines was studied by immunofluorescence and Western blot techniques. RESULTS: Patients with pancreas cancer have significantly increased circulating levels of type IV collagen. In pancreas cancer tissue high levels of type IV collagen expression was found in close proximity to cancer cells in the tumour stroma. Furthermore, pancreas cancer cells were found to produce and secrete type IV collagen in vitro, which in part can explain the high type IV collagen expression observed in pancreas cancer tissue, and the increased circulating levels in pancreas cancer patients. Of clinical importance, our results show that the circulating level of type IV collagen after surgery is strongly related to prognosis in patients treated for pancreas cancer by pancreatico-duodenectomy with curative intent. Persisting high levels of circulating type IV collagen after surgery indicates a quick relapse in disease and poor survival. CONCLUSION: Our results most importantly show that stroma related substances can be evaluated as potential cancer biomarkers, and thereby underline the importance of the tumour microenvironment also in this context.
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| 7. |
- Öman, Mikael, et al.
(författare)
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Phase I/II trial of intraperitoneal 5-Fluorouracil with and without intravenous vasopressin in non-resectable pancreas cancer
- 2005
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Ingår i: Cancer Chemother Pharmacol. - : Springer Science and Business Media LLC. - 0344-5704 .- 1432-0843. ; 56:6, s. 603-9
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Systemic palliative treatment with chemotherapy against advanced pancreas cancer has low effectiveness despite considerable toxicity. AIM: To investigate the safety, toxicity and tumour response of intraperitoneal 5-Fluorouracil (5-FU) with intravenous Leucovorin and to monitor 5-FU pharmacokinetics in plasma during intraperitoneal instillation with and without vasopressin in patients with non-resectable pancreas cancer. PATIENTS/METHODS: Between 1994 and 2003, 68 patients with non-resectable pancreas cancer TNM stage III and IV, were enrolled to receive intraperitoneal5-FU instillation 750-1500 mg/m2 and intravenous Leucovorin 100 mg/m2 for two days every third week. Tumour response, performance status and toxicity were recorded. Seventeen patients were also treated with intravenous vasopressin 0.1 IU/minute for 180 minutes, during intraperitoneal 5-FU instillation. Area under the curve (AUC) and peak concentration (Cmax) of 5-FU in plasma were analysed. RESULTS: The treatment was well tolerated with minor toxicity. One complete response (54.1+ months) and 2 partial responses were observed. Time to progression was 4.4 months (0.8-54.1+), and median survival was 8.0 months (0.8-54.1+). There was a significant reduction of 5-FU Cmax in plasma the second day of treatment if vasopressin was used (3.4+/-2.5 and 6.1+/-5.4 mumol/l, respectively, p<0.05). 5-FU AUC in plasma was not significantly affected by vasopressin either day of treatment. CONCLUSION: Intraperitoneal 5-FU is a safe treatment with low toxicity to patients with non-resectable pancreas cancer. Tumour response was 4.4% and median survival time 8.0 months. Addition of vasopressin did not significantly decrease plasma 5-FU AUC but reduced Cmax on day 2 of treatment.
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