| 381. |
- Li, Bo, et al.
(författare)
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Therapeutic rationale to target highly expressed CDK7 conferring poor outcomes in triple-negative breast cancer
- 2017
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Ingår i: Cancer Research. - 0008-5472. ; 77:14, s. 3834-3845
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Tidskriftsartikel (refereegranskat)abstract
- Triple-negative breast cancer (TNBC) patients commonly exhibit poor prognosis and high relapse after treatment, but there remains a lack of biomarkers and effective targeted therapies for this disease. Here, we report evidence highlighting the cell-cycle–related kinase CDK7 as a driver and candidate therapeutic target in TNBC. Using publicly available transcriptomic data from a collated set of TNBC patients (n ¼ 383) and the METABRIC TNBC dataset (n ¼ 217), we found CDK7 mRNA levels to be correlated with patient prognosis. High CDK7 protein expression was associated with poor prognosis within the RATHER TNBC cohort (n ¼ 109) and the METABRIC TNBC cohort (n ¼ 203). The highly specific CDK7 kinase inhibitors, BS-181 and THZ1, each downregulated CDK7-mediated phosphorylation of RNA polymerase II, indicative of transcriptional inhibition, with THZ1 exhibiting 500-fold greater potency than BS-181. Mechanistic investigations revealed that the survival of MDA-MB-231 TNBC cells relied heavily on the BCL-2/BCL-XL signaling axes in cells. Accordingly, we found that combining the BCL-2/BCL-XL inhibitors ABT-263/ABT199 with the CDK7 inhibitor THZ1 synergized in producing growth inhibition and apoptosis of human TNBC cells. Collectively, our results highlight elevated CDK7 expression as a candidate biomarker of poor prognosis in TNBC, and they offer a preclinical proof of concept for combining CDK7 and BCL-2/BCL-XL inhibitors as a mechanism-based therapeutic strategy to improve TNBC treatment.
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| 382. |
- Locatelli, F, et al.
(författare)
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The relationship of NT-proBNP and dialysis parameters with outcome of incident haemodialysis patients: results from the membrane permeability outcome study
- 2013
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Ingår i: Blood purification. - : S. Karger AG. - 1421-9735 .- 0253-5068. ; 35:1-3, s. 216-223
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Tidskriftsartikel (refereegranskat)abstract
- <b><i>Background/Aims:</i></b> The association of raised levels of natriuretic peptides with elevated risk of mortality was investigated in the present analysis of the Membrane Permeability Outcome study. <b><i>Methods:</i></b> N-terminal probrain type natriuretic peptide (NT-proBNP) was measured in 618 incident haemodialysis patients, randomised to either high-flux or low-flux. Characteristics of patients with NT-proBNP levels below or above the median were descriptively analysed and survival analysis was performed. <b><i>Results:</i></b> Median NT-proBNP value was 2,124 pg/ml, with 1,854 pg/ml in the high-flux and 2,919 pg/ml in the low-flux group. Survival probability was lowest in patients with both a history of cardiovascular disease and NT-proBNP values above the median (p < 0.001). A multivariate Cox proportional hazard model showed interaction between presence of cardiovascular diseases and NT-proBNP levels above the median. <b><i>Conclusions:</i></b> NT-proBNP is an independent predictor of mortality also in incident haemodialysis patients. Lower concentrations associated with high-flux dialysis suggest a possible biological link to improved survival in this group.
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| 383. |
- Magnusson, Kristina, et al.
(författare)
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SATB2 in Combination With Cytokeratin 20 Identifies Over 95% of all Colorectal Carcinomas
- 2011
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Ingår i: American Journal of Surgical Pathology. - 0147-5185 .- 1532-0979. ; 35:7, s. 937-948
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Tidskriftsartikel (refereegranskat)abstract
- The special AT-rich sequence-binding protein 2 (SATB2), a nuclear matrix-associated transcription factor and epigenetic regulator, was identified as a tissue type-specific protein when screening protein expression patterns in human normal and cancer tissues using an antibody-based proteomics approach. In this respect, the SATB2 protein shows a selective pattern of expression and, within cells of epithelial lineages, SATB2 expression is restricted to glandular cells lining the lower gastrointestinal tract. The expression of SATB2 protein is primarily preserved in cancer cells of colorectal origin, indicating that SATB2 could function as a clinically useful diagnostic marker to distinguish colorectal cancer (CRC) from other types of cancer. The aim of this study was to further explore and validate the specific expression pattern of SATB2 as a clinical biomarker and to compare SATB2 with the well-known cytokeratin 20 (CK20). Immunohistochemistry was used to analyze the extent of SATB2 expression in tissue microarrays with tumors from 9 independent cohorts of patients with primary and metastatic CRCs (n = 1882). Our results show that SATB2 is a sensitive and highly specific marker for CRC with distinct positivity in 85% of all CRCs, and that SATB2 and/or CK20 was positive in 97% of CRCs. In conclusion, the specific expression of SATB2 in a large majority of CRCs suggests that SATB2 can be used as an important complementary tool for the differential diagnosis of carcinoma of unknown primary origin.
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| 384. |
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| 385. |
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| 386. |
- Wagner, I, et al.
(författare)
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Preliminary evaluation of cytosine-phosphate-guanine oligodeoxynucleotides bound to gelatine nanoparticles as immunotherapy for canine atopic dermatitis.
- 2017
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Ingår i: The Veterinary Record. - : Wiley. - 0042-4900 .- 2042-7670. ; 181:5
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Tidskriftsartikel (refereegranskat)abstract
- Cytosine-phosphate-guanine oligodeoxynucleotides (CpG ODN) are a promising new immunotherapeutic treatment option for canine atopic dermatitis (AD). The aim of this uncontrolled pilot study was to evaluate clinical and immunological effects of gelatine nanoparticle (GNP)-bound CpG ODN (CpG GNP) on atopic dogs. Eighteen dogs with AD were treated for 8 weeks (group 1, n=8) or 18 weeks (group 2, n=10). Before inclusion and after 2 weeks, 4 weeks, 6 weeks (group 1+2), 8 weeks, 12 weeks and 16 weeks (group 2) 75 µg CpG ODN/dog (bound to 1.5 mg GNP) were injected subcutaneously. Pruritus was evaluated daily by the owner. Lesions were evaluated and serum concentrations and mRNA expressions of interferon-γ, tumour necrosis factor-α, transforming growth factor-β, interleukin (IL) 10 and IL-4 (only mRNA expression) were determined at inclusion and after 8 weeks (group 1+2) and 18 weeks (group 2). Lesions and pruritus improved significantly from baseline to week 8. Mean improvements from baseline to week 18 were 23 per cent and 44 per cent for lesions and pruritus, respectively, an improvement of ≥50 per cent was seen in six out of nine and three out of six dogs, respectively. IL-4 mRNA expression decreased significantly. The results of this study show a clinical improvement of canine AD with CpG GNP comparable to allergen immunotherapy. Controlled studies are needed to confirm these findings.
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| 387. |
- Wendt, M., et al.
(författare)
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Localization of the High Frequency Field in a Beam-Plasma Diode Due to Density Gradients
- 2001
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Ingår i: Physica Scripta. - 0281-1847. ; 63, s. 62-69
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Tidskriftsartikel (refereegranskat)abstract
- An experimental study of the high frequency (hf) interaction of a strong, warm electron beam with an inhomogeneous, bounded plasma is presented and compared with particle-in-cell simulations. The density is highest in the center of the diode and decreases towards the boundaries. The electric field in the center is dominated by the unstable slow-space-charge wave, but experimental evidence is found, that reflected waves are present near the beam injection grid, where the oscillation frequency f is higher than the local plasma frequency f(pe)(x). The strong field at the resonance point (f = f(pe)(x)) is proposed to excite the unstable beam mode. Simulations confirm this picture by showing a concentration of the spectral power of the beam waves to the frequencies of the trapped Langmuir waves. Linear growth and Landau damping concentrate the beam wave to a 1.5-2 wavelengths wide region. Trapped Langmuir waves can accordingly determine the frequencies and position of the hf-field even for moderate density gradients and field strengths below the threshold for Langmuir collapse.
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| 388. |
- Åström, E., et al.
(författare)
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Precision measurements of linear scattering density using muon tomography
- 2016
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Ingår i: Journal of Instrumentation. - : Institute of Physics Publishing. - 1748-0221 .- 1748-0221. ; 11:7
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Tidskriftsartikel (refereegranskat)abstract
- We demonstrate that muon tomography can be used to precisely measure the properties of various materials. The materials which have been considered have been extracted from an experimental blast furnace, including carbon (coke) and iron oxides, for which measurements of the linear scattering density relative to the mass density have been performed with an absolute precision of 10%. We report the procedures that are used in order to obtain such precision, and a discussion is presented to address the expected performance of the technique when applied to heavier materials. The results we obtain do not depend on the specific type of material considered and therefore they can be extended to any application.
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