| 1. |
- Kobelt-Nguyen, Gisela, et al.
(författare)
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Cost-utility analysis of interferon beta-1B in secondary progressive multiple sclerosis using natural history disease data
- 2002
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Ingår i: International journal of technology assessment in health care. - 1471-6348 .- 0266-4623. ; 18:1, s. 127-138
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Tidskriftsartikel (refereegranskat)abstract
- Different cost-effectiveness analyses have been presented for interferon beta-1b (IFNB) in the treatment of secondary progressive multiple sclerosis (SPMS). All studies have used modeling techniques since any effect on progression of disability achieved during a clinical trial will last beyond the trial. Different approaches to extrapolation have been taken, but generally they have been based on disease progression and relapse rates in clinical trials. The problem with this approach is that the population in clinical trials is a selected group of patients, which has the potential to bias results. A better method for extrapolation is to use epidemiologic data. The objective of this study is to incorporate natural history data for MS into a previously presented cost-utility model and to compare the two methods of extrapolation. Clinical trial data were used to model disease progression during the first 3 years in the model. To extrapolate beyond the trial (10 years), data on progression of disability were available from a geographically based epidemiologic study of the natural history of MS in Canada. There were 568 patients who had converted to SPMS during the follow-up that were included in the data set. Mean costs and utilities for each Markov state were calculated from a population-based cross-sectional study in Sweden. The extrapolation using clinical trial data appears to have underestimated the progression of disability in the long term and thus also the potential benefit of treatment. Using the epidemiologic data, the incremental cost per QALY is SEK 257,000 (US $25,700; US $1 = SEK 10; November 2000) when all costs (direct, informal care, and indirect) are included (discounted 3%). This compares to SEK 342,000 in the previous model. The lower cost-effectiveness ratio is mostly due to a larger QALY gain with treatment than in the previous model (0.217 compared with 0.162). Cost-effectiveness analysis in SPMS requires that the effect of treatment beyond clinical trials be included. The method of extrapolation clearly affects the results, and when available, epidemiologic data should be used. Using the longitudinal data from Canada, the cost-utility ratios for IFNB-1b in the treatment of SPMS appear well within the acceptable range.
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| 2. |
- Bahrampour, Shahrzad, et al.
(författare)
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Brain expansion promoted by polycomb-mediated anterior enhancement of a neural stem cell proliferation program
- 2019
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Ingår i: PLoS biology. - : PUBLIC LIBRARY SCIENCE. - 1544-9173 .- 1545-7885. ; 17:2
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Tidskriftsartikel (refereegranskat)abstract
- During central nervous system (CNS) development, genetic programs establish neural stem cells and drive both stem and daughter cell proliferation. However, the prominent anterior expansion of the CNS implies anterior-posterior (A-P) modulation of these programs. In Drosophila, a set of neural stem cell factors acts along the entire A-P axis to establish neural stem cells. Brain expansion results from enhanced stem and daughter cell proliferation, promoted by a Polycomb Group (PcG)-amp;gt;Homeobox (Hox) homeotic network. But how does PcG-amp;gt;Hox modulate neural-stem-cell-factor activity along the A-P axis? We find that the PcG-amp;gt;Hox network creates an A-P expression gradient of neural stem cell factors, thereby driving a gradient of proliferation. PcG mutants can be rescued by misexpression of the neural stem cell factors or by mutation of one single Hox gene. Hence, brain expansion results from anterior enhancement of core neural-stem-cell-factor expression, mediated by PcG repression of brain Hox expression.
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| 3. |
- Bahrampour, Shahrzad, et al.
(författare)
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Neural Lineage Progression Controlled by a Temporal Proliferation Program.
- 2017
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Ingår i: Developmental Cell. - : Cell Press. - 1534-5807 .- 1878-1551. ; 43:3, s. 332-348
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Tidskriftsartikel (refereegranskat)abstract
- Great progress has been made in identifying transcriptional programs that establish stem cell identity. In contrast, we have limited insight into how these programs are down-graded in a timely manner to halt proliferation and allow for cellular differentiation. Drosophila embryonic neuroblasts undergo such a temporal progression, initially dividing to bud off daughters that divide once (type I), then switching to generating non-dividing daughters (type 0), and finally exiting the cell cycle. We identify six early transcription factors that drive neuroblast and type I daughter proliferation. Early factors are gradually replaced by three late factors, acting to trigger the type I→0 daughter proliferation switch and eventually to stop neuroblasts. Early and late factors regulate each other and four key cell-cycle genes, providing a logical genetic pathway for these transitions. The identification of this extensive driver-stopper temporal program controlling neuroblast lineage progression may have implications for studies in many other systems.less thanbr /greater than (Copyright © 2017 Elsevier Inc. All rights reserved.)
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| 4. |
- Beyerlein, Kenneth R., et al.
(författare)
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Mix-and-diffuse serial synchrotron crystallography
- 2017
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Ingår i: IUCrJ. - : INT UNION CRYSTALLOGRAPHY. - 2052-2525. ; 4:6, s. 769-777
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Tidskriftsartikel (refereegranskat)abstract
- Unravelling the interaction of biological macromolecules with ligands and substrates at high spatial and temporal resolution remains a major challenge in structural biology. The development of serial crystallography methods at X-ray free-electron lasers and subsequently at synchrotron light sources allows new approaches to tackle this challenge. Here, a new polyimide tape drive designed for mix-and-diffuse serial crystallography experiments is reported. The structure of lysozyme bound by the competitive inhibitor chitotriose was determined using this device in combination with microfluidic mixers. The electron densities obtained from mixing times of 2 and 50 s show clear binding of chitotriose to the enzyme at a high level of detail. The success of this approach shows the potential for high-throughput drug screening and even structural enzymology on short timescales at bright synchrotron light sources.
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| 5. |
- Pousette, Jenny, et al.
(författare)
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Prognostic and Predictive Significance of Stromal Tumor-Infiltrating Lymphocytes (sTILs) in ER-Positive/HER2-Negative Postmenopausal Breast Cancer Patients
- 2022
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 14:19
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Tidskriftsartikel (refereegranskat)abstract
- The clinical impact of tumor-infiltrating lymphocytes (TILs) is less known for breast cancer patients with the estrogen receptor-positive (ER+)/human epidermal growth factor receptor-negative (HER−) subtype. Here, we explored the prognostic and predictive value of TILs regarding distant recurrence-free interval (DRFI) and breast cancer-specific survival (BCSS) in 763 postmenopausal patients randomized to receive tamoxifen vs. no systemic treatment. TILs were assessed in whole section tumor samples stained with H&E and divided into low (<10%), intermediate (10–39%), or high (≥40%). High TILs were associated with poor prognostic variables and good prognoses for all patients, but not within the ER+/HER2− group. Within the ER+/HER2− group, high gene expression of CD19 and PD-L1 and high IMMUNE1 score indicated good prognosis in multivariable analysis while high CD8 and CD19 gene expression and high IMMUNE1 score were associated with less tamoxifen benefit. These results indicate that within the ER+/HER2− subtype there could be subsets of patients where expression of specific TIL markers might be used to reveal candidates for immune therapy interventions upon failure of the endocrine therapy.
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| 6. |
- Skånberg, Robin, et al.
(författare)
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VIA-MD : Visual Interactive Analysis of Molecular Dynamics
- 2018
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Ingår i: MolVA 2018 - Workshop on Molecular Graphics and Visual Analysis of Molecular Data. - : The Eurographics Association. - 9783038680819 ; , s. 19-27
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Konferensbidrag (refereegranskat)abstract
- We present a visual exploration environment tailored for large-scale spatio-temporal molecular dynamics simulation data. The environment is referred to as VIA-MD (visual interactive analysis of molecular dynamics) and has been developed in a participatory design process with domain experts on molecular dynamics simulations of complex molecular systems. A key feature of our approach is the support for linked interactive 3D exploration of geometry and statistical analysis using dynamic temporal windowing and animation. Based on semantic level descriptions and hierarchical aggregation of molecular properties we enable interactive filtering, which enables the user to effectively find spatial, temporal and statistical patterns. The VIA-MD environment provides an unprecedented tool for analysis of complex microscopic interactions hidden in large data volumes. We demonstrate the utility of the VIA-MD environment with four use cases. The first two deal with simulation of amyloid plaque associated with development of Alzheimer's, and we study an aqueous solution of 100 probes and an amyloid fibril. The identification of interaction "hotspots" is achieved with the use of combined filter parameters connected with probe molecular planarity and probe-fibril interaction energetics. The third and fourth examples show the wide applicability of the environment by applying it to analysis of molecular properties in material design.
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| 7. |
- Xie, Xuqin, et al.
(författare)
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APR-246 Enhances Colorectal Cancer Sensitivity to Radiotherapy
- 2023
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Ingår i: Molecular Cancer Therapeutics. - : AMER ASSOC CANCER RESEARCH. - 1535-7163 .- 1538-8514. ; 22:8, s. 947-961
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Tidskriftsartikel (refereegranskat)abstract
- p53 mutation is common and highly related to radiotherapy resistance in rectal cancer. APR-246, asa small molecule, can restore the tumor-suppressor function to mutant p53. As there is currently no existing study on combining APR-246 with radiation in rectal cancer, our objective was to investigate whether APR-246 could enhance the sensitivity of colorectal cancer cells, regardless of their p53 status, to radiation treatment. The combination treatment had synergistic effects on HCT116p53-R248W/- (p53Mut) cells, followed by HCT116p53+/+ [wild-type p53 (p53WT)] cells, and exhibited an additive effect on HCT116p53-/- (p53Null) cells through inhibiting proliferation, enhancing reactive oxygen species, and apoptosis. The results were confirmed in zebrafish xenografts. Mechanistically, p53Mut and p53WT cells shared more activated pathways and differentially expressed genes following the combination treat-ment, compared with p53Null cells, although the combination treatment regulated individual pathways in the different cell lines. APR-246 mediated radiosensitization effects through p53-dependent and-independent ways. The results may provide evidence for a clinical trial of the combination in patients with rectal cancer.
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| 8. |
- Øra, Ingrid, et al.
(författare)
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Arsenic trioxide inhibits neuroblastoma growth in vivo and promotes apoptotic cell death in vitro
- 2000
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Ingår i: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 1090-2104 .- 0006-291X. ; 277:1, s. 179-185
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Tidskriftsartikel (refereegranskat)abstract
- Recent clinical studies have shown that inorganic arsenic trioxide (As(2)O(3)) at low concentrations induces complete remission with minimal toxicity in patients with refractory acute promyelocytic leukemia (APL). Preclinical studies suggest that As(2)O(3) induces apoptosis and possibly differentiation in APL cells. Like APL cells, neuroblastoma (NB) cells are thought to be arrested at an early stage of differentiation, and cells of highly malignant tumors fail to undergo spontaneous maturation. Both APL and NB cells can respond with differentiation to retinoic acid (RA) treatment in vitro and probably also in vivo. For that reason we investigated the effect of As(2)O(3) alone and in combination with RA on NB cell lines. In vitro, the number of viable NB cells was reduced at As(2)O(3) concentrations around 1 microM after 72 h exposure. The IC50 in six different cell lines treated for 3 days was in the 1.5 to 5 microM concentration interval, the most sensitive being SK-N-BE(2) cells derived from a chemotherapy resistant tumor. The combined treatment with RA (1 and 3 microM) showed no consistent additional effect with regard to induced cell death. The effect of As(2)O(3) on NB cell number involved As(2)O(3)-induced apoptotic pathways (decreased expression of Bcl-2 and stimulation of caspase-3 activity) with no clear evidence of induced differentiation. The in vivo effect of As(2)O(3) on NB growth was also investigated in nude mice bearing tumors of xenografted NB cells. Although tumor growth was reduced by As(2)O(3) treatment, complete remission was not achieved at the concentrations tested. We suggest that As(2)O(3), in combination with existing treatment modalities, might be a treatment approach for high risk NB patients.
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