| 1. |
- Birney, Ewan, et al.
(författare)
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Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project
- 2007
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 447:7146, s. 799-816
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Tidskriftsartikel (refereegranskat)abstract
- We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.
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| 2. |
- Setlur, Sunita R., et al.
(författare)
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Estrogen-dependent signaling in a molecularly distinct subclass of aggressive prostate cancer
- 2008
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Ingår i: Journal of the National Cancer Institute. - Oxford : Oxford University Press. - 0027-8874 .- 1460-2105. ; 100:11, s. 815-825
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The majority of prostate cancers harbor gene fusions of the 5'-untranslated region of the androgen-regulated transmembrane protease serine 2 (TMPRSS2) promoter with erythroblast transformation-specific transcription factor family members. The common fusion between TMPRESS2 and v-ets erythroblastosis virus E26 oncogene homolog (avian) (ERG) is associated with a more aggressive clinical phenotype, implying the existence of a distinct subclass of prostate cancer defined by this fusion. METHODS: We used complementary DNA-mediated annealing, selection, ligation, and extension to determine the expression profiles of 6144 transcriptionally informative genes in archived biopsy samples from 455 prostate cancer patients in the Swedish Watchful Waiting cohort (1987-1999) and the United States-based Physicians(') Health Study cohort (1983-2003). A gene expression signature for prostate cancers with the TMPRSS2-ERG fusion was determined using partitioning and classification models and used in computational functional analysis. Cell proliferation and TMPRSS2-ERG expression in androgen receptor-negative (NCI-H660) prostate cancer cells after treatment with vehicle or estrogenic compounds were assessed by viability assays and quantitative polymerase chain reaction, respectively. All statistical tests were two-sided. RESULTS: We identified an 87-gene expression signature that distinguishes TMPRSS2-ERG fusion prostate cancer as a discrete molecular entity (area under the curve = 0.80, 95% confidence interval [CI] = 0.792 to 0.81; P < .001). Computational analysis suggested that this fusion signature was associated with estrogen receptor (ER) signaling. Viability of NCI-H660 cells decreased after treatment with estrogen (viability normalized to day 0, estrogen vs vehicle at day 8, mean = 2.04 vs 3.40, difference = 1.36, 95% CI = 1.12 to 1.62) or ERbeta agonist (ERbeta agonist vs vehicle at day 8, mean = 1.86 vs 3.40, difference = 1.54, 95% CI = 1.39 to 1.69) but increased after ERalpha agonist treatment (ERalpha agonist vs vehicle at day 8, mean = 4.36 vs 3.40, difference = 0.96, 95% CI = 0.68 to 1.23). Similarly, expression of TMPRSS2-ERG decreased after ERbeta agonist treatment (fold change over internal control, ERbeta agonist vs vehicle at 24 hours, NCI-H660, mean = 0.57- vs 1.0-fold, difference = 0.43-fold, 95% CI = 0.29- to 0.57-fold) and increased after ERalpha agonist treatment (ERalpha agonist vs vehicle at 24 hours, mean = 5.63- vs 1.0-fold, difference = 4.63-fold, 95% CI = 4.34- to 4.92-fold). CONCLUSIONS: TMPRSS2-ERG fusion prostate cancer is a distinct molecular subclass. TMPRSS2-ERG expression is regulated by a novel ER-dependent mechanism.
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| 3. |
- Brekke, Helge R., et al.
(författare)
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Identification of p53 as a strong predictor of survival for patients with malignant peripheral nerve sheath tumors
- 2009
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Ingår i: Neuro-Oncology. - : Oxford University Press (OUP). - 1523-5866 .- 1522-8517. ; 11:5, s. 514-528
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this study was to identify new prognostic biomarkers with clinical impact in malignant peripheral nerve sheath tumor (MPNST), a highly aggressive malignancy for which no consensus therapy exists besides surgery. We have used tissue microarrays (TMAs) to assess in situ expression of 14 cell-cycle-regulating proteins in 64 well-characterized MPNST patients: 36 sporadic and 28 with neurofibromatosis type 1 (NF1). We developed a new software application for evaluation and logistics of the TMA images and performed a literature survey of cell cycle proteins in MPNST. For NF1-associated patients, there was a clear association between nuclear expression of p53 and poor survival (p = 0.004). Among the other proteins analyzed, we also found significant associations between survival and clinical variables, but none were as strong as that for p53. For the total series of MPNSTs, p53 was shown to be an independent predictor of survival, and patients without remission, with tumor size larger than 8 cm, and with positive p53 expression had a 60 times greater risk of dying within the first 5 years compared with the remaining patients (p = 0.000002). This is the most comprehensive study of in situ protein expression in MPNST so far, and expressed p53 was found to be a strong surrogate marker for outcome. Patients in complete remission with a primary p53-positive MPNST diagnosis may be considered in a high-risk subgroup and candidates for adjuvant treatment. Neuro-Oncology 11, 514-528, 2009 (Posted to Neuro-Oncology [serial online], Doc. D08-00271, January 30, 2009.)
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| 4. |
- de Groot, Kirsten, et al.
(författare)
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Pulse Versus Daily Oral Cyclophosphamide for Induction of Remission in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis A Randomized Trial
- 2009
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Ingår i: Annals of Internal Medicine. - 0003-4819. ; 150:10, s. 3-670
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Tidskriftsartikel (refereegranskat)abstract
- Background: Current therapies for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis are limited by toxicity. Objective: To compare pulse cyclophosphamide with daily oral cyclophosphamide for induction of remission. Design: Randomized, controlled trial. Random assignments were computer-generated; allocation was concealed by faxing centralized treatment assignment to providers at the time of enrollment. Patients, investigators, and assessors of outcomes were not blinded to assignment. Setting: 42 centers in 12 European countries. Patients: 149 patients who had newly diagnosed generalized ANCA-associated vasculitis with renal involvement but not immediately life-threatening disease. Intervention: Pulse cyclophosphamide, 15 mg/kg every 2 to 3 weeks (76 patients), or daily oral cyclophosphamide, 2 mg/kg per day (73 patients), plus prednisolone. Measurement: Time to remission (primary outcome); change in renal function, adverse events, and cumulative dose of cyclophosphamide (secondary outcomes). Results: Groups did not differ in time to remission (hazard ratio, 1.098 [95% CI, 0.78 to 1.55]; P = 0.59) or proportion of patients who achieved remission at 9 months (88.1% vs. 87.7%). Thirteen patients in the pulse group and 6 in the daily oral group achieved remission by 9 months and subsequently had relapse. Absolute cumulative cyclophosphamide dose in the daily oral group was greater than that in the pulse group (15.9 g [interquartile range, 11 to 22.5 g] vs. 8.2 g [interquartile range, 5.95 to 10.55 g]; P < 0.001). The pulse group had a lower rate of leukopenia (hazard ratio, 0.41 [CI, 0.23 to 0.71]). Limitations: The study was not powered to detect a difference in relapse rates between the 2 groups. Duration of follow-up was limited. Conclusion: The pulse cyclophosphamide regimen induced remission of ANCA-associated vasculitis as well as the daily oral regimen at a reduced cumulative cyclophosphamide dose and caused fewer cases of leukopenia. Primary Funding Source: The European Union.
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| 5. |
- Helldal, Lisa, et al.
(författare)
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Increasing prevalence of ESBL but not AmpC in Escherichia coli and Klebsiella pneumoniae, in Göteborg, 2004-2008
- 2009
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Ingår i: Scandinavian Society for Antimicrobial Chemotherapy - 2009, September 3, Tromsø, Norway.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: The increasing prevalence of transferable broad-spectrum resistance to beta-lactams, such as Extended Spectrum Beta Lactamases (ESBL) and AmpC, is troublesome, since they confer resistance to cephalosporins and penicillins, and often also are associated with additional resistance. Materials and methods: Resistance for E. coli and Klebsiella pneumoniae isolated from urine (~10.000 isolates/year) and blood (~xxx isolates/year), during 2004-2008 were determined. Cephalosporin resistant isolates were examined for presence of ESBL with a double-disk-assay using clavulanic acid as inhibitory substance. Cefoxitine-resistant strains were analyzed for presence of AmpC with a second double-disk-assay using cloxacillin as inhibitory substance. Positive strains where further tested with PCR assays for ESBL and plasmid AmpC. Results: During 2004-2008 presence of ESBL increased from 0,3–1,5% in urinary and 0,0–1,4 % in blood E. coli. For Klebsiella the corresponding figures were 0,08–0,68% and 0%, respectively. For ESBL-producing E. coli, 60–80% were resistant also to quinolones and trimetoprime. In 2008, the vast a majority of the ESBL-isolates carried CTX-M subtype 1. Approximately 50 % is community-acquired isolates. 0,15-0,23% of the urinary E. coli-strains had phenotypical characteristics indicating AmpC-production. Presence of plasmid-mediated AmpC will be tested. Approximately 50% of these were multidrug resistant. In blood E coli isolates as well as in Klebsiella from urine and blood AmpC was rarely detected (0-2 isolates/year). Discussion and Conclusion: There is a steady increase in ESBL-producing bacteria in our region. However, the frequency of isolates with AmpC is still low. In addition, a majority of these strains are multidrug resistant which is particularly alarming.
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| 6. |
- Jebsen, Nina L, et al.
(författare)
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Radiotherapy to Improve Local Control Regardless of Surgical Margin and Malignancy Grade in Extremity and Trunk Wall Soft Tissue Sarcoma: A Scandinavian Sarcoma Group Study
- 2008
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Ingår i: International Journal of Radiation Oncology, Biology, Physics. - : Elsevier BV. - 0360-3016. ; 71:4, s. 1196-1203
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Adjuvant radiotherapy has during the past decades become increasingly used in the treatment of localized soft tissue sarcoma. We evaluated the effect of radiotherapy (RT) on local recurrence rates (LRRs) in Scandinavia between 1986 and 2005. METHODS AND MATERIALS: A total of 1,093 adult patients with extremity or trunk wall soft tissue sarcoma treated at four Scandinavian sarcoma centers were stratified according to the treatment period (1986-1991, 1992-1997, and 1998-2005). The use of adjuvant RT, quality of the surgical margin, interval between surgery and RT, and LRR were analyzed. The median follow-up was 5 years. RESULTS: The use of RT (77% treated postoperatively) increased from 28% to 53%, and the 5-year LRR decreased from 27% to 15%. The rate of wide surgical margins did not increase. The risk factors for local recurrence were histologic high-grade malignancy (hazard ratio [HR], 5), an intralesional (HR, 6) or marginal (HR, 3) surgical margin, and no RT (HR, 3). The effect of RT on the LRR was also significant after a wide margin resection and in low-grade malignant tumors. The LRR was the same after preoperative and postoperative RT. The median interval from surgery to the start of RT was 7 weeks, and 98% started RT within 4 months. The LRR was the same in patients who started treatment before and after 7 weeks. CONCLUSION: The results of our study have shown that adjuvant RT effectively prevents local recurrence in soft tissue sarcoma, irrespective of the tumor depth, malignancy grade, and surgical margin status. The effect was most pronounced in deep-seated, high-grade tumors, even when removed with a wide surgical margin.
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| 7. |
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| 8. |
- Sancho Pelluz, Javier, et al.
(författare)
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Sialoadhesin Expression in Intact Degenerating Retinas and Following Transplantation.
- 2008
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Ingår i: Investigative Ophthalmology & Visual Science. - : Association for Research in Vision and Ophthalmology (ARVO). - 1552-5783. ; 49, s. 5602-5610
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Resident microglial cells normally do not express sialoadhesin (a sialic acid binding receptor), whereas recruited inflammatory macrophages have been shown to do so. The expression of sialoadhesin was examined here in the course of photoreceptor cell degeneration and following transplantation. Methods: Sialoadhesin expression was analyzed in retinas of rd1 and rds mice. For transplantation studies, neonatal (P2) retinal cells derived from GFP mice were injected intraocularly in adult rd1 mice and controls. Antibodies recognizing different sialoadhesin epitopes, CD11b, and MHC-II were used to identify activated microglial cells in intact retinas and 21 days post-transplantation. Results: In rd1 mice, a few CD11b-positive cells were observed in the outer nuclear layer in the central retina at postnatal day (P) 11 and in increasing numbers between P12 21. In rds mice, CD11b-expressing cells were found from P16 and onwards. No sialoadhesin expressing cells were observed within the rd1 or rds mouse retinas at any of the ages examined (up to P150). Specific staining was only observed in cells found in the vitreal margin of the retina and in surrounding tissues (sclera, cornea, ciliary body, choroid). Following transplantation to normal and rd1 mice, a variable number of sialoadhesin-positive cells were detected within the grafts, in the graft-host interface, and in the subretinal space. Conclusions: The significant activation of microglia/macrophages observed in the various stages of degeneration in rd1 and rds mouse retinas is not accompanied by sialoadhesin expression. However, sialoadhesin-expressing cells are observed following transplantation. The occurrence of such cells could be of significance for the integration and long term survival of retinal grafts, as expression of sialoadhesin could facilitate other phagocytic receptors.
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| 9. |
- Smeland, Sigbjorn, et al.
(författare)
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Scandinavian experience in classical osteosarcoma Results of the SSG XIV protocol
- 2009
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Ingår i: Acta Orthopaedica. - 1745-3682. ; 80, s. 60-66
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose The Scandinavian Sarcoma Group (SSG) XIV protocol was based upon the organisations experience from 3 previous osteosarcoma trials and was considered best standard of care for patients with extremity localised, non-metastatic osteosarcoma. We report the outcome of this protocol. Patients and methods From March 2001 to April 2005, 63 patients recruited from 10 centres in Finland, Sweden and Norway were included in this analysis. Patients received pre-operative chemotherapy consisting of 2 cycles of paired methotrexate (12 g/m(2)), cisplatin (90 mg/m(2)) and doxorubicin (75 mg/m(2)). Good histological responders continued with 3 cycles postoperatively whilst poor responders were salvaged with the addition of 3 cycles of ifusfamide (10-12 g/m(2)). Outcome data was compared to previous SSG osteosarcoma trials. Results With a median follow-up of 64 months for survivors, the projected metastasis-free and sarcoma-related survivals at 5 years were 69% and 77%, respectively. 84% of the patients were treated with limb salvage surgery (49 patients) or rotationplasty (4 patients). 3 toxic deaths (5%) were recorded, all related to acute chemotherapy toxicity. The 5-year metastasis-free survival of patients receiving salvage therapy was 47% compared to 89% for good histological responders that only received the 3 drug combination postoperatively. Interpretation Outcome in the SSG XIV protocol compares favourably to previous SSG osteosarcoma trials and other published trials. The addition of ifosfamide to poor responders as an add on treatment did not improve outcome for poor responders to a similar level as for good responders. In a multi-institutional setting limb salvage surgery can safely be used in more than 80% of the patients.
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| 10. |
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