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- Abe, O, et al.
(författare)
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Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials
- 2005
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Ingår i: The Lancet. - 1474-547X. ; 365:9472, s. 1687-1717
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Tidskriftsartikel (refereegranskat)abstract
- Background Quinquennial overviews (1985-2000) of the randomised trials in early breast cancer have assessed the 5-year and 10-year effects of various systemic adjuvant therapies on breast cancer recurrence and survival. Here, we report the 10-year and 15-year effects. Methods Collaborative meta-analyses were undertaken of 194 unconfounded randomised trials of adjuvant chemotherapy or hormonal therapy that began by 1995. Many trials involved CMF (cyclophosphamide, methotrexate, fluorouracil), anthracycline-based combinations such as FAC (fluorouracil, doxombicin, cyclophosphamide) or FEC (fluorouracil, epirubicin, cyclophosphamide), tamoxifen, or ovarian suppression: none involved taxanes, trastuzumab, raloxifene, or modem aromatase inhibitors. Findings Allocation to about 6 months of anthracycline-based polychemotherapy (eg, with FAC or FEC) reduces the annual breast cancer death rate by about 38% (SE 5) for women younger than 50 years of age when diagnosed and by about 20% (SE 4) for those of age 50-69 years when diagnosed, largely irrespective of the use of tamoxifen and of oestrogen receptor (ER) status, nodal status, or other tumour characteristics. Such regimens are significantly (2p=0 . 0001 for recurrence, 2p<0 . 00001 for breast cancer mortality) more effective than CMF chemotherapy. Few women of age 70 years or older entered these chemotherapy trials. For ER-positive disease only, allocation to about 5 years of adjuvant tamoxifen reduces the annual breast cancer death rate by 31% (SE 3), largely irrespective of the use of chemotherapy and of age (<50, 50-69, &GE; 70 years), progesterone receptor status, or other tumour characteristics. 5 years is significantly (2p<0 . 00001 for recurrence, 2p=0 . 01 for breast cancer mortality) more effective than just 1-2 years of tamoxifen. For ER-positive tumours, the annual breast cancer mortality rates are similar during years 0-4 and 5-14, as are the proportional reductions in them by 5 years of tamoxifen, so the cumulative reduction in mortality is more than twice as big at 15 years as at 5 years after diagnosis. These results combine six meta-analyses: anthracycline-based versus no chemotherapy (8000 women); CMF-based versus no chemotherapy (14 000); anthracycline-based versus CMF-based chemotherapy (14 000); about 5 years of tamoxifen versus none (15 000); about 1-2 years of tamoxifen versus none (33 000); and about 5 years versus 1-2 years of tamoxifen (18 000). Finally, allocation to ovarian ablation or suppression (8000 women) also significantly reduces breast cancer mortality, but appears to do so only in the absence of other systemic treatments. For middle-aged women with ER-positive disease (the commonest type of breast cancer), the breast cancer mortality rate throughout the next 15 years would be approximately halved by 6 months of anthracycline-based chemotherapy (with a combination such as FAC or FEC) followed by 5 years of adjuvant tamoxifen. For, if mortality reductions of 38% (age <50 years) and 20% (age 50-69 years) from such chemotherapy were followed by a further reduction of 31% from tamoxifen in the risks that remain, the final mortality reductions would be 57% and 45%, respectively (and, the trial results could well have been somewhat stronger if there had been full compliance with the allocated treatments). Overall survival would be comparably improved, since these treatments have relatively small effects on mortality from the aggregate of all other causes. Interpretation Some of the widely practicable adjuvant drug treatments that were being tested in the 1980s, which substantially reduced 5-year recurrence rates (but had somewhat less effect on 5-year mortality rates), also substantially reduce 15-year mortality rates. Further improvements in long-term survival could well be available from newer drugs, or better use of older drugs.
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- Erdelyi, Mate, 1975, et al.
(författare)
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The Binding Mode of Side Chain- and C3-Modified Epothilones to Tubulin
- 2010
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Ingår i: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 5:6, s. 911-920
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Tidskriftsartikel (refereegranskat)abstract
- The tubulin-binding mode of C3- and C15-modified analogues of epothilone A (Epo A) was determined by NMR spectroscopy and computational methods and compared with the existing structural models of tubulin-bound natural Epo A. Only minor differences were observed in the conformation of the macrocycle between Epo A and the C3-modified analogues investigated. In particular, 3-deoxy- (compound 2) and 3-deoxy-2,3-didehydro-Epo A (3) were found to adopt similar conformations in the tubulin-binding cleft as Epo A, thus indicating that the 3-OH group is not essential for epothilones to assume their bioactive conformation. None of the available models of the tubulin-epothilone complex is able to fully recapitulate the differences in tubulin-polymerizing activity and microtubule-binding affinity between C20-modified epothilones 6 (C20-propyl), 7 (C20-butyl), and 8 (C20-hydroxypropyl). Based on the results of transferred NOE experiments in the presence of tubulin, the isomeric C15 quinoline-based Epo B analogues 4 and 5 show very similar orientations of the side chain, irrespective of the position of the nitrogen atom in the quinoline ring. The quinoline side chain stacks on the imidazole moiety of -His227 with equal efficiency in both cases, thus suggesting that the aromatic side chain moiety in epothilones contributes to tubulin binding through strong van der Waals interactions with the protein rather than hydrogen bonding involving the heteroaromatic nitrogen atom. These conclusions are in line with existing tubulin polymerization and microtubule-binding data for 4, 5, and Epo B.
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- Reggiani, M, et al.
(författare)
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Discovery of a point-like source and a third spiral arm in the transition disk around the Herbig Ae star MWC 758
- 2018
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 611
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Tidskriftsartikel (refereegranskat)abstract
- Context. Transition disks offer the extraordinary opportunity to look for newly born planets and to investigate the early stages of planet formation. Aims. In this context we observed the Herbig A5 star MWC 758 with the L'-band vector vortex coronagraph installed in the near-infrared camera and spectrograph NIRC2 at the Keck II telescope, with the aim of unveiling the nature of the spiral structure by constraining the presence of planetary companions in the system. Methods. Our high-contrast imaging observations show a bright (Delta L' = 7.0 +/- 0.3 mag) point-like emission south of MWC 758 at a deprojected separation of similar to 20 au (r = 0 ''.111 +/- 0 ''.004) from the central star. We also recover the two spiral arms (southeast and northwest), already imaged by previous studies in polarized light, and discover a third arm to the southwest of the star. No additional companions were detected in the system down to 5 Jupiter masses beyond 0 ''.6 from the star. Results. We propose that the bright L'-band emission could be caused by the presence of an embedded and accreting protoplanet, although the possibility of it being an asymmetric disk feature cannot be excluded. The spiral structure is probably not related to the protoplanet candidate, unless on an inclined and eccentric orbit, and it could be due to one (or more) yet undetected planetary companions at the edge of or outside the spiral pattern. Future observations and additional simulations will be needed to shed light on the true nature of the point-like source and its link with the spiral arms.
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- Serabyn, E, et al.
(författare)
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The W. M. Keck Observatory infrared vortex coronagraph and a first image of HIP79124 B
- 2017
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Ingår i: Astronomical Journal. - : American Astronomical Society. - 0004-6256 .- 1538-3881. ; 153:1, s. 1-7
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Tidskriftsartikel (refereegranskat)abstract
- An optical vortex coronagraph has been implemented within the NIRC2 camera on the Keck II telescope and used to carry out on-sky tests and observations. The development of this new L′-band observational mode is described, and an initial demonstration of the new capability is presented: a resolved image of the low-mass companion to HIP 79124, which had previously been detected by means of interferometry. With HIP 79124 B at a projected separation of 186.5 mas, both the small inner working angle of the vortex coronagraph and the related imaging improvements were crucial in imaging this close companion directly. Due to higher Strehl ratios and more relaxed contrasts in L′ band versus H band, this new coronagraphic capability will enable high-contrast, small-angle observations of nearby young exoplanets and disks on a par with those of shorter-wavelength extreme adaptive optics coronagraphs.
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| 8. |
- Carlomagno, F, et al.
(författare)
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Comparison of DNA repair protein expression and activities between human fibroblast cell lines with different radiosensitivities.
- 2000
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Ingår i: International journal of cancer. Journal international du cancer. - 0020-7136. ; 85:6, s. 845-9
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Tidskriftsartikel (refereegranskat)abstract
- In order to investigate the molecular basis of variation in response to ionising radiation (IR) in radiotherapy patients, we have studied the expression of several genes involved in DNA double-strand break repair pathways in fibroblast cell lines. Ten lines were established from skin biopsies of cancer patients with different normal-tissue reactions to IR, and 3 from a control individual. For all 10 test cell lines, the cellular radiosensitivity was also known. Using Western blots we measured, in non-irradiated cells, the basal expression levels of ATM, Rad1 and Hus1, involved in the control of cellular DNA damage checkpoints, together with DNA-PKcs, Ku70, Ku80; XRCC4, ligaseIV and Rad51, involved in radiation- induced DSB repair. We also analysed the in vitro enzymatic activities, under non-irradiated conditions, of the DNA-PK and XRCC4/ligaseIV complexes. The levels of expression of the different proteins were similar in all the cell lines, but the activities of the DNA-PK and XRCC4/ligaseIV complexes showed some differences. These differences did not correlate with either the normal tissue response of the patient in vivo or with cellular radiation sensitivity in vitro. The activity differences of these enzyme complexes, therefore, do not account for the variation of responses seen between patients.
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| 9. |
- Erdelyi, Mate, 1975, et al.
(författare)
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The Conformational Preferences of Natural and C3-Modified Epothilones in Aqueous Solution
- 2008
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Ingår i: J. Med. Chem.. - : American Chemical Society (ACS). ; 51:5, s. 1469-73
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Tidskriftsartikel (refereegranskat)abstract
- The conformational properties of the microtubule-stabilizing agent epothilone A (1a) and its 3-deoxy and 3-deoxy-2,3-didehydro derivatives 2 and 3 have been investigated in aqueous solution by a combination of NMR spectroscopic methods, Monte Carlo conformational searches, and NAMFIS calculations. The tubulinbound conformation of epothilone A (1a), as previously proposed on the basis of solution NMR data, was found to represent a significant fraction of the ensemble of conformations present for the free ligands in aqueous solution.
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| 10. |
- Kasper, M., et al.
(författare)
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NEAR: : Low-mass Planets in α Cen with VISIR
- 2017
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Ingår i: The Messenger. ; 169, s. 16-20
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Tidskriftsartikel (refereegranskat)abstract
- ESO, in collaboration with the Breakthrough Initiatives, is working to modify the Very Large Telescope mid-IR imager (VISIR) to greatly enhance its ability to search for potentially habitable planets around both components of the binary Alpha Centauri, part of the closest stellar system to the Earth. Much of the funding for the NEAR (New Earths in the Alpha Cen Region) project is provided by the Breakthrough Initiatives, and ESO mostly provides staff and observing time. The concept combines adaptive optics using the deformable secondary mirror at Unit Telescope 4, a new annular groove phase mask (AGPM) coronagraph optimised for the most sensitive spectral bandpass in the N-band, and a novel internal chopper system for noise filtering based on a concept for longer wavelengths invented by the microwave pioneer Robert Dicke. The NEAR experiment is relevant to the mid-infrared METIS instrument on the Extremely Large Telescope, as the knowledge gained and proof of concept will be transferable.
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