| 1. |
- Breugom, A. J., et al.
(författare)
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Adjuvant chemotherapy and relative survival of patients with stage II colon cancer - A EURECCA international comparison between the Netherlands, Denmark, Sweden, England, Ireland, Belgium, and Lithuania
- 2016
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 0959-8049 .- 1879-0852. ; 63, s. 110-117
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Tidskriftsartikel (refereegranskat)abstract
- Background: The aim of the present EURECCA international comparison is to compare adjuvant chemotherapy and relative survival of patients with stage II colon cancer between European countries.Methods: Population-based national cohort data (2004-2009) from the Netherlands (NL), Denmark (DK), Sweden (SE), England (ENG), Ireland (IE), and Belgium (BE) were obtained, as well as single-centre data from Lithuania. All surgically treated patients with stage II colon cancer were included. The proportion of patients receiving adjuvant chemotherapy was calculated and compared between countries. Besides, relative survival was calculated and compared between countries.Results: Overall, 59,154 patients were included. The proportion of patients receiving adjuvant chemotherapy ranged from 7.1% to 29.0% (p < 0.001). Compared with NL, a better adjusted relative survival was observed in SE (stage II: relative excess risks (RER) 0.53, 95% confidence interval (CI) 0.44-0.64; p < 0.001), and BE (stage II: RER 0.84, 95% CI 0.76-0.92; p < 0.001), and in IE for patients with stage IIA disease (RER 0.80, 95% CI 0.65-0.98; p = 0.03).Conclusion: The proportion of patients with stage II colon cancer receiving adjuvant chemotherapy varied largely between seven European countries. No clear linear pattern between adjuvant chemotherapy and adjusted relative survival was observed. Compared with NL, SE and BE showed an improved adjusted relative survival for stage II disease, and IE for patients with stage IIA disease only. Further research into selection criteria for adjuvant chemotherapy could eventually lead to individually tailored, optimal treatment of patients with stage II colon cancer.
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| 2. |
- Mahadeva, R, et al.
(författare)
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Polymers of Z alpha(1)-antitrypsin co-localize with neutrophils in emphysematous alveoli and are chemotactic in vivo
- 2005
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Ingår i: American Journal of Pathology. - 1525-2191. ; 166:2, s. 377-386
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Tidskriftsartikel (refereegranskat)abstract
- The molecular mechanisms that cause emphysema are complex but most theories suggest that an excess of proteinases is a crucial requirement. This paradigm is exemplified by severe deficiency of the key antielastase within the lung: alpha(1)-antitrypsin. The Z mutant of alpha(1)-antitrypsin has a point mutation Glu342Lys in the hinge region of the molecule that renders it prone to intermolecular linkage and loop-sheet polymerization. Polymers of Z alpha(1)-antitrypsin aggregate within the liver leading to juvenile liver cirrhosis and the resultant plasma deficiency predisposes to premature emphysema. We show here that polymeric alpha(1)-antitrypsin co-localizes with neutrophils in the alveoli of individuals with Z alpha(1)-antitrypsin-related emphysema. The significance of this finding is underscored by the excess of neutrophils in these individuals and the demonstration that polymers cause an influx of neutrophils when instilled into murine lungs. Polymers exert their effect directly on neutrophils rather than via inflammatory cytokines. These data provide an explanation for the accelerated tissue destruction that is characteristic of Z alpha(1)-antitrypsin-related emphysema. The transition of native Z alpha(1)-antitrypsin to polymers inactivates its anti-proteinase function, and also converts it to a proinflammatory stimulus. These findings may also explain the progression of emphysema in some individual despite alpha(1)-antitrypsin replacement therapy.
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| 3. |
- Breugom, A. J., et al.
(författare)
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Oncologic treatment strategies and relative survival of patients with stage I-III rectal cancer - A EURECCA international comparison between the Netherlands, Belgium, Denmark, Sweden, England, Ireland, Spain, and Lithuania
- 2018
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Ingår i: European Journal of Surgical Oncology. - : Elsevier. - 0748-7983 .- 1532-2157. ; 44:9, s. 1338-1343
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The aim of this EURECCA international comparison is to compare oncologic treatment strategies and relative survival of patients with stage I-III rectal cancer between European countries.Material and methods: Population-based national cohort data from the Netherlands (NL), Belgium (BE), Denmark (DK), Sweden (SE), England (ENG), Ireland (IE), Spain (ES), and single-centre data from Lithuania (LT) were obtained. All operated patients with (y)pTNM stage I-III rectal cancer diagnosed between 2004 and 2009 were included. Oncologic treatment strategies and relative survival were calculated and compared between neighbouring countries.Results: We included 57,120 patients. Treatment strategies differed between NL and BE (p < 0.001), DK and SE (p < 0.001), and ENG and IE (p < 0.001). More preoperative radiotherapy as single treatment before surgery was administered in NL compared with BE (59.7% vs. 13.1%), in SE compared with DK (55.1% vs. 10.4%), and in ENG compared with IE (15.2% vs. 9.6%). Less postoperative chemotherapy was given in NL (9.6% vs. 39.1%), in SE (7.9% vs. 14.1%), and in IE (12.6% vs. 18.5%) compared with their neighbouring country. In ES, 55.1% of patients received preoperative chemoradiation and 62.3% post-operative chemotherapy. There were no significant differences in relative survival between neighbouring countries.Conclusion: Large differences in oncologic treatment strategies for patients with (y)pTNM I-III rectal cancer were observed across European countries. No clear relation between oncologic treatment strategies and relative survival was observed. Further research into selection criteria for specific treatments could eventually lead to individualised and optimal treatment for patients with non-metastasised rectal cancer.
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| 4. |
- Janciauskiene, Sabina, et al.
(författare)
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{alpha}1-antitrypsin Inhibits the Activity of the Matriptase Catalytic Domain in vitro.
- 2008
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Ingår i: American Journal of Respiratory Cell and Molecular Biology. - 1535-4989. ; 39:6, s. 631-637
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Tidskriftsartikel (refereegranskat)abstract
- Matriptase is a type II transmembrane protease which is characterized by an N-terminal transmembrane and multiple extracellular domains, in addition to the conserved extracellular serine protease catalytic domain. The expression pattern of matriptase suggests that this protease may play broad roles in the biology of surface lining epithelial cells. In this study we report that alpha1-antitrypsin (AAT), an endogenous inhibitor of serine proteases, inhibits the catalytic domain of human recombinant matriptase in vitro. Co-incubation of alpha1-antitrypsin with matriptase (at a molar ratio 1:2) resulted in the formation of heat stable complexes, clearly seen in sodium dodecyl sulfate (SDS) electrophoresis and Western blots. AAT was found to be a slow, tight-binding inhibitor of the catalytic domain of matriptase with a second order reaction rate constant of 0.31 x10(3) M(-1)s(-1). Notably, the oxidised form of AAT, which lacks serine protease inhibitor activity, failed to generate matriptase complexes and to inhibit matriptase activity. Since matriptase is involved in a number of physiological processes including activation of epithelial sodium channels, our findings offer considerable new insights into new regulatory function of AAT in vivo.
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| 5. |
- Janciauskiene, Sabina, et al.
(författare)
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Indirect effect of alpha-1-antitrypsin on endotoxin-induced IL-1β secretion from human PBMCs
- 2022
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Ingår i: Frontiers in Pharmacology. - : Frontiers Media SA. - 1663-9812. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Human alpha-1-antitrypsin (AAT) encoded by the SERPINA1 gene, is an acute phase glycoprotein that regulates inflammatory responses via both protease inhibitory and non-inhibitory activities. We previously reported that AAT controls ATP-induced IL-1β release from human mononuclear cells by stimulating the release of small bioactive molecules. In the current study, we aimed to elucidate the identity of these putative effectors released from human PBMCs in response to AAT, which may inhibit the LPS-induced release of IL-1β. We pre-incubated human PBMCs alone or with different preparations of AAT (4 mg/ml) for 30 min at 37°C, 5% CO2, and collected cell supernatants filtered through centrifugal filters (cutoff 3 kDa) to eliminate AAT and other high molecular weight substances. Supernatants passed through the filters were used to culture PBMCs isolated from the autologous or a heterologous donors with or without adding LPS (1 μg/ml) for 6 h. Unexpectedly, supernatants from PBMCs pre-incubated with AAT (Zemaira®), but not with other AAT preparations tested or with oxidized AAT (Zemaira®), lowered the LPS-induced release of IL-1β by about 25%–60% without affecting IL1B mRNA. The reversed-phase liquid chromatography coupled with mass spectrometry did not confirm the hypothesis that small pro-resolving lipid mediators released from PBMCs after exposure to AAT (Zemaira®) are responsible for lowering the LPS-induced IL-1β release. Distinctively from other AAT preparations, AAT (Zemaira®) and supernatants from PBMCs pre-treated with this protein contained high levels of total thiols. In line, mass spectrometry analysis revealed that AAT (Zemaira®) protein contains freer Cys232 than AAT (Prolastin®). Our data show that a free Cys232 in AAT is required for controlling LPS-induced IL-1β release from human PBMCs. Further studies characterizing AAT preparations used to treat patients with inherited AAT deficiency remains of clinical importance.
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| 8. |
- Sandström, Caroline, et al.
(författare)
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An association between Type 2 diabetes and alpha(1)-antitrypsin deficiency
- 2008
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Ingår i: Diabetic Medicine. - : Wiley. - 1464-5491 .- 0742-3071. ; 25:11, s. 1370-1373
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Tidskriftsartikel (refereegranskat)abstract
- Aims alpha(1)-Antitrypsin (AAT) is a serine protease inhibitor which recently has been shown to prevent Type 1 diabetes development, to prolong islet allograft survival and to inhibit pancreatic B-cell apoptosis in vivo. It has also been reported that Type 1 diabetic patients have significantly lower plasma concentrations of AAT, suggesting the potential role of AAT in the pathogenesis of Type 1 diabetes. We have investigated whether plasma AAT levels are altered in Type 2 diabetes. Methods The study included patients with Type 2 diabetes (n = 163) and non-diabetic control subjects matched for age, sex and smoking habits (n = 158) derived from the population-based Malmo Diet and Cancer study. Plasma samples were analysed for AAT concentration and phenotype and serum glucose, insulin, C-reactive protein and lipid levels were measured. Glycated haemoglobin was also measured. Results In the diabetic group, the women had higher mean plasma AAT levels than men ( P < 0.05). The mean plasma AAT levels did not differ between diabetic and control subjects. However, the number of individuals with low AAT levels (< 1.0 mg/ml) was 50% higher in the diabetic group (P < 0.05) and the frequency of AAT deficiency genotypes was 50% higher (NS) in diabetic compared with control subjects. In the group of diabetic patients with AAT < 1 mg/ml, AAT directly correlated with systolic blood pressure (P = 0.048) and inversely correlated with waist-hip ratio (P = 0.031). Conclusions Our results provide evidence that deficiency of AAT may be associated with an increased risk of developing Type 2 diabetes.
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| 10. |
- Schiopu, Alexandru, et al.
(författare)
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Recombinant human antibodies against aldehyde-modified apolipoprotein B-100 peptide sequences inhibit atherosclerosis
- 2004
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Ingår i: Circulation. - 1524-4539. ; 110:14, s. 2047-2052
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Tidskriftsartikel (refereegranskat)abstract
- Background-Accumulation and oxidation of LDL are believed to be important initiating factors in atherosclerosis. Oxidized LDL is recognized by the immune system, and animal studies have suggested that these immune responses have a protective effect against atherosclerosis. Aldehyde-modified peptide sequences in apolipoprotein B-100 (apoB-100) are major targets for these immune responses. Methods and Results-Human IgG1 antibodies against 2 malondialdehyde (MDA)-modified apoB-100 peptide sequences were produced through screening of a single-chain antibody-fragment library and subsequent cloning into a pcDNA3 vector. Three weekly doses of these antibodies were injected into male apoE(-/-) mice. Phosphate-buffered saline and human IgG1 antibodies against fluorescein isothiocyanate were used as controls. One of the IgG1 antibodies significantly and dose-dependently reduced the extent of atherosclerosis as well as the plaque content of oxidized LDL epitopes and macrophages. In cell culture studies, human monocytes were incubated with native LDL or oxidized LDL, in the presence of antibodies. The same antibody induced an increase in monocyte binding and uptake of oxidized LDL. Conclusions-These findings suggest that antibodies are important mediators of atheroprotective immune responses directed to oxidized LDL. Thus, passive immunization against MDA-modified apoB-100 peptide sequences may represent a novel therapeutic approach for prevention and treatment of cardiovascular disease.
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