| 1. |
- Kaschina, Elena, et al.
(författare)
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Angiotensin II type 2 receptor stimulation : a novel option of therapeutic interference with the renin-angiotensin system in myocardial infarction?
- 2008
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Ingår i: Circulation. - 0009-7322 .- 1524-4539. ; 118:24, s. 2523-32
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: This study is the first to examine the effect of direct angiotensin II type 2 (AT(2)) receptor stimulation on postinfarct cardiac function with the use of the novel nonpeptide AT(2) receptor agonist compound 21 (C21). METHODS AND RESULTS: Myocardial infarction (MI) was induced in Wistar rats by permanent ligation of the left coronary artery. Treatment with C21 (0.01, 0.03, 0.3 mg/kg per day IP) was started 24 hours after MI and was continued until euthanasia (7 days after MI). Infarct size was assessed by magnetic resonance imaging, and hemodynamic measurements were performed via transthoracic Doppler echocardiography and intracardiac Millar catheter. Cardiac tissues were analyzed for inflammation and apoptosis markers with immunoblotting and real-time reverse transcription polymerase chain reaction. C21 significantly improved systolic and diastolic ventricular function. Scar size was smallest in the C21-treated rats. In regard to underlying mechanisms, C21 diminished MI-induced Fas-ligand and caspase-3 expression in the peri-infarct zone, indicating an antiapoptotic effect. Phosphorylation of the p44/42 and p38 mitogen-activated protein kinases, both involved in the regulation of cell survival, was strongly reduced after MI but almost completely rescued by C21 treatment. Furthermore, C21 decreased MI-induced serum monocyte chemoattractant protein-1 and myeloperoxidase as well as cardiac interleukin-6, interleukin-1beta, and interleukin-2 expression, suggesting an antiinflammatory effect. CONCLUSIONS: Direct AT(2) receptor stimulation may be a novel therapeutic approach to improve post-MI systolic and diastolic function by antiapoptotic and antiinflammatory mechanisms.
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| 2. |
- Bernhard, Jürg, et al.
(författare)
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Clinical benefit and quality of life in patients with advanced pancreatic cancer receiving gemcitabine plus capecitabine versus gemcitabine alone : a randomized multicenter phase III clinical trial--SAKK 44/00-CECOG/PAN.1.3.001
- 2008
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Ingår i: Journal of Clinical Oncology. - 0732-183X .- 1527-7755. ; 26:22, s. 3695-3701
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To compare clinical benefit response (CBR) and quality of life (QOL) in patients receiving gemcitabine (Gem) plus capecitabine (Cap) versus single-agent Gem for advanced/metastatic pancreatic cancer. PATIENTS AND METHODS: Patients were randomly assigned to receive GemCap (oral Cap 650 mg/m(2) twice daily on days 1 through 14 plus Gem 1,000 mg/m(2) in a 30-minute infusion on days 1 and 8 every 3 weeks) or Gem (1,000 mg/m(2) in a 30-minute infusion weekly for 7 weeks, followed by a 1-week break, and then weekly for 3 weeks every 4 weeks) for 24 weeks or until progression. CBR criteria and QOL indicators were assessed over this period. CBR was defined as improvement from baseline for >or= 4 consecutive weeks in pain (pain intensity or analgesic consumption) and Karnofsky performance status, stability in one but improvement in the other, or stability in pain and performance status but improvement in weight. RESULTS: Of 319 patients, 19% treated with GemCap and 20% treated with Gem experienced a CBR, with a median duration of 9.5 and 6.5 weeks, respectively (P < .02); 54% of patients treated with GemCap and 60% treated with Gem had no CBR (remaining patients were not assessable). There was no treatment difference in QOL (n = 311). QOL indicators were improving under chemotherapy (P < .05). These changes differed by the time to failure, with a worsening 1 to 2 months before treatment failure (all P < .05). CONCLUSION: There is no indication of a difference in CBR or QOL between GemCap and Gem. Regardless of their initial condition, some patients experience an improvement in QOL on chemotherapy, followed by a worsening before treatment failure.
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| 3. |
- Boeing, Heiner, et al.
(författare)
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Intake of fruits and vegetables and risk of cancer of the upper aero-digestive tract: the prospective EPIC-study
- 2006
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Ingår i: Cancer Causes and Control. - : Springer Science and Business Media LLC. - 1573-7225 .- 0957-5243. ; 17:7, s. 957-969
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Tidskriftsartikel (refereegranskat)abstract
- Epidemiologic studies suggest that a high intake of fruits and vegetables is associated with decreased risk of cancers of the upper aero-digestive tract. We studied data from 345,904 subjects of the prospective European Investigation into Cancer and Nutrition (EPIC) recruited in seven European countries, who had completed a dietary questionnaire in 1992-1998. During 2,182,560 person years of observation 352 histologically verified incident squamous cell cancer (SCC) cases (255 males; 97 females) of the oral cavity, pharynx, larynx, and esophagus were identified. Linear and restricted cubic spline Cox regressions were fitted on variables of intake of fruits and vegetables and adjusted for potential confounders. We observed a significant inverse association with combined total fruits and vegetables intake (estimated relative risk (RR) = 0.91; 95% confidence interval (95% CI) 0.83-1.00 per 80 g/d of consumption), and nearly significant inverse associations in separate analyses with total fruits and total vegetables intake (RR: 0.97 (95% CI: 0.92-1.02) and RR = 0.89 (95% CI: 0.78-1.02) per 40 g/d of consumption). Overall, vegetable subgroups were not related to risk with the exception of intake of root vegetables in men. Restricted cubic spline regression did not improve the linear model fits except for total fruits and vegetables and total fruits with a significant decrease in risk at low intake levels (< 120 g/d) for fruits. Dietary recommendations should consider the potential benefit of increasing fruits and vegetables consumption for reducing the risk of cancers of the upper aero-digestive tract, particularly at low intake.
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| 4. |
- Brown, Kevin M., et al.
(författare)
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Common sequence variants on 20q11.22 confer melanoma susceptibility
- 2008
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 40:7, s. 838-840
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Tidskriftsartikel (refereegranskat)abstract
- We conducted a genome-wide association pooling study for cutaneous melanoma and performed validation in samples totaling 2,019 cases and 2,105 controls. Using pooling, we identified a new melanoma risk locus on chromosome 20 (rs910873 and rs1885120), with replication in two further samples (combined P < 1 x 10(-15)). The per allele odds ratio was 1.75 (1.53, 2.01), with evidence for stronger association in early-onset cases.
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| 5. |
- Herrmann, Richard, et al.
(författare)
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Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer : a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group
- 2007
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Ingår i: Journal of Clinical Oncology. - 0732-183X .- 1527-7755. ; 25:16, s. 2212-2217
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: This phase III trial compared the efficacy and safety of gemcitabine (Gem) plus capecitabine (GemCap) versus single-agent Gem in advanced/metastatic pancreatic cancer. Patients and Methods: Patients were randomly assigned to receive GemCap (oral capecitabine 650 mg/m2 twice daily on days 1 to 14 plus Gem 1,000 mg/m2 by 30-minute infusion on days 1 and 8 every 3 weeks) or Gem (1,000 mg/m2 by 30-minute infusion weekly for 7 weeks, followed by a 1-week break, and then weekly for 3 weeks every 4 weeks). Patients were stratified according to center, Kamofsky performance score (KPS), presence of pain, and disease extent. Results: A total of 319 patients were enrolled between June 2001 and June 2004. Median overall survival (OS) time, the primary end point, was 8.4 and 7.2 months in the GemCap and Gem arms, respectively (P = .234). Post hoc analysis in patients with good KPS (score of 90 to 100) showed a significant prolongation of median OS time in the GemCap arm compared with the Gem arm (10.1 v 7.4 months, respectively; P = .014). The overall frequency of grade 3 or 4 adverse events was similar in each arm. Neutropenia was the most frequent grade 3 or 4 adverse event in both arms. Conclusion: GemCap failed to improve OS at a statistically significant level compared with standard Gem treatment. The safety of GemCap and Gem was similar. In the subgroup of patients with good performance status, median OS was improved significantly. GemCap is a practical regimen that may be considered as an alternative to single-agent Gem for the treatment of advanced/metastatic pancreatic cancer patients with a good performance status.
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| 6. |
- Hess, Viviane, et al.
(författare)
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CA 19-9 tumour-marker response to chemotherapy in patients with advanced pancreatic cancer enrolled in a randomised controlled trial
- 2008
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Ingår i: The Lancet Oncology. - 1470-2045 .- 1474-5488. ; 9:2, s. 132-8
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Several studies in patients undergoing chemotherapy for advanced pancreatic carcinoma have linked a decrease in the concentration of the tumour marker carbohydrate antigen (CA) 19-9 to lengthened survival. The aim of this study was to test the hypotheses that an early decrease in baseline serum CA 19-9 concentration (on day 42, after two cycles of chemotherapy) by at least 50% is associated with lengthened survival, and that a decrease in CA 19-9 concentration of at least 50% from the baseline concentration to the lowest value measured at any time during treatment (nadir) is of prognostic significance, enabling its use as a surrogate endpoint for survival. METHODS: CA 19-9 serum concentration was measured at baseline and every 3 weeks thereafter in patients with histologically proven advanced pancreatic carcinoma enrolled in a randomised trial of gemcitabine versus gemcitabine plus capecitabine. Patients were excluded if baseline serum CA 19-9 concentration was below the upper limit of normal (ULN) in the laboratory or if this measurement was missing. Comparisons of survival between patients with and without a CA 19-9 response were corrected for the guarantee-time bias by the landmark method. The trial on which this study is based is registered on the clinical trials site of the US National Cancer Institute website http://www.clinicaltrials.gov/ct/show/NCT00030732. FINDINGS: 247 of 319 randomised patients were assessable for analysis of baseline serum CA 19-9 concentration, and, of these, 175 patients were assessable for tumour-marker response to treatment. Median overall survival for patients with a baseline CA 19-9 concentration equal to or above the median value (ie, 59xULN) was 5.8 months (95% CI 5.1-7.0), which was significantly shorter than that for patients with baseline concentrations below the median value (10.3 months [95% CI 8.6-12.8], p<0.0001). An early decrease in CA 19-9 concentration of at least 50% after two cycles of chemotherapy was not associated with a longer overall survival compared with patients who did not have a decrease of at least 50% (median 10.1 months [9.2-12.7] vs 8.6 months [6.9-11.2], p=0.53; hazard ratio for death 1.11 [0.81-1.52]). Furthermore, a decrease in CA 19-9 concentration of at least 50% reached at the CA 19-9 nadir concentration was not associated with a longer overall survival compared with those patients who did not have a decrease of at least 50% (median 7.8 months [6.5.10.1] vs 6.7 months [5.5-9.8], p=0.74; 0.95 [0.69-1.31]) after adjusting for the guarantee-time bias. INTERPRETATION: Pretreatment serum CA 19-9 concentration is an independent prognostic factor for survival, but a decrease in concentration during chemotherapy is not significantly associated with lengthened survival compared with those who did not have a corresponding decrease. Our data suggest that CA 19-9 response during chemotherapy is not a valid surrogate endpoint for survival in clinical trials.
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| 7. |
- Mathew, Thomas, et al.
(författare)
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Nonnegative estimation of variance components in heteroscedastic one-way random effects ANOVA models
- 2007
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Ingår i: Research Report, Centre of Biostochastics, Swedish University of Agricultural Sciences. - Umeå : Centre of Biostochastics. - 1651-8543. ; :1
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- There is a considerable amount of literature dealing with inference about the parameters in a heteroscedastic one-way random-effects ANOVA model. In this paper, we primarily address the problem of improved quadratic estimation of the random-effect variance component. It turns out that such estimators with a smaller mean squared error compared with some standard unbiased quadratic estimators exist under quite general conditions. Improved estimators of the error variance components are also established.
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| 8. |
- Steffen, Annika, et al.
(författare)
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Anthropometry and Esophageal Cancer Risk in the European Prospective Investigation into Cancer and Nutrition
- 2009
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Ingår i: Cancer Epidemiology Biomarkers & Prevention. - 1538-7755 .- 1055-9965. ; 18:7, s. 2079-2089
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Tidskriftsartikel (refereegranskat)abstract
- Background: Increasing evidence suggests that general obesity [measured by body mass index (BMI)] is positively associated with risk of esophageal adenocarcinoma (EAC). In contrast, previous studies have shown inverse relations with esophageal squamous cell carcinoma (ESCC). However, it is still unclear whether body fat distribution, particularly abdominal obesity, is associated with each type of esophageal cancer. Methods: We applied multivariable adjusted Cox proportional hazards regression to investigate the association between anthropometric measures and risk of EAC and ESCC among 346,554 men and women participating in the European Prospective Investigation into Cancer and Nutrition. All statistical tests were two sided. Results: During 8.9 years of follow-up, we documented 88 incident cases of EAC and 110 cases of ESCC. BMI, waist circumference, and waist-to-hip ratio (WHR) were positively associated with EAC risk [highest versus lowest quintile; relative risk (RR), 2.60; 95% confidence interval (95% CI), 1.23-5.51; P-trend < 0.01; RR, 3.07; 95% CI, 1.35-6.98; P-trend < 0.003; and RR, 2.12; 95% CI, 0.98-4.57; P-trend < 0.004]. In contrast, BMI and waist circumference were inversely related to ESCC risk, whereas WHR showed no association with ESCC. In stratified analyses, BMI and waist circumference were significantly inversely related to ESCC only among smokers but not among nonsmokers. However, when controlled for BMI, we found positive associations for waist circumference and WHR with ESCC, and these associations were observed among smokers and nonsmokers. Conclusion: General and abdominal obesity were associated with higher EAC risk. Further, our study suggests that particularly an abdominal body fat distribution might also be a risk factor for ESCC. (Cancer Epidemiol Biomarkers Prev 2009;18(7):2079-89)
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| 9. |
- Valdiosera, Cristina E., et al.
(författare)
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Staying out in the cold : glacial refugia and mitochondrial DNA phylogeography in ancient European brown bears.
- 2007
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Ingår i: Molecular Ecology. - 0962-1083 .- 1365-294X. ; 16:24, s. 5140-5148
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Tidskriftsartikel (refereegranskat)abstract
- Models for the development of species distribution in Europe typically invoke restriction in three temperate Mediterranean refugia during glaciations, from where recolonization of central and northern Europe occurred. The brown bear, Ursus arctos, is one of the taxa from which this model is derived. Sequence data generated from brown bear fossils show a complex phylogeographical history for western European populations. Long-term isolation in separate refugia is not required to explain our data when considering the palaeontological distribution of brown bears. We propose continuous gene flow across southern Europe, from which brown bear populations expanded after the last glaciation.
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| 10. |
- Weikert, Cornelia, et al.
(författare)
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Lifetime and baseline alcohol intake and risk of cancer of the upper aero-digestive tract in the European prospective investigation into cancer and nutrition (EPIC) study
- 2009
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Ingår i: International Journal of Cancer. - Geneve : Wiley. - 0020-7136 .- 1097-0215. ; 125:2, s. 406-412
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Tidskriftsartikel (refereegranskat)abstract
- Recent alcohol consumption is all established risk factor for squamous cell carcinoma (SCC) or the upper aero-digestive tract. In contrast, the role or lifetime exposure to alcohol with regard to risk of SCC is not well established. Historical data oil alcohol use are available in 271,253 participants of the European Prospective Investigation into Cancer and Nutrition (EPIC). During 2,330,381 person years, 392 incident SCC cases (279 men and 113 women) were identified. Cox regression vas applied to model sex-specific associations between lifetime alcohol intake and SCC risk adjusting for potential confounders including smoking. Compared to men who drank 0.1-6.0 g/day alcohol at lifetime, the relative risks (RR) for developing SCC were significantly increased for men who drank 30.1-60.0 g/day (RR 1.65, 95% confidence interval: 1.00-2.71), 60.1-96.0 g/day (RR 2.20, 95%CI 1.23-3.95), and >96.0 g/day, (RR 4.63, 95% CI 2.52-8.48), and for former drinkers (RR 4.14, 95% CI 2.38-7.19). These risk estimates did not considerably change when baseline alcohol intake was analyzed. Compared to women who drank 0.1-6.0 g/day alcohol intake at lifetime, the RR were significantly increased for women who drank >30 g/d (RR 6.05, 95% CI 2.98-12.3). Applying similar categories, the relative risk for baseline alcohol intake was 3.26 (95%CI 1.82-5.87). We observed a stronger association between alcohol intake at lifetime and risk of SCC in women compared to men (p for interaction = 0.045). The strong dose-response relation for lifetime alcohol use underscores that alcohol is an important risk factor of SCC of the upper aero-digestive tract throughout life. (C) 2009 UICC
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