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- Tutt, A. N. J., et al.
(författare)
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Adjuvant Olaparib for Patients with BRCA1- or BRCA2-Mutated Breast Cancer
- 2021
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Ingår i: New England Journal of Medicine. - 0028-4793. ; 384:25, s. 2394-2405
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Poly(adenosine diphosphate-ribose) polymerase inhibitors target cancers with defects in homologous recombination repair by synthetic lethality. New therapies are needed to reduce recurrence in patients with BRCA1 or BRCA2 germline mutation-associated early breast cancer. METHODS We conducted a phase 3, double-blind, randomized trial involving patients with human epidermal growth factor receptor 2 (HER2)-negative early breast cancer with BRCA1 or BRCA2 germline pathogenic or likely pathogenic variants and high-risk clinicopathological factors who had received local treatment and neoadjuvant or adjuvant chemotherapy. Patients were randomly assigned (in a 1:1 ratio) to 1 year of oral olaparib or placebo. The primary end point was invasive disease-free survival. RESULTS A total of 1836 patients underwent randomization. At a prespecified event-driven interim analysis with a median follow-up of 2.5 years, the 3-year invasive disease-free survival was 85.9% in the olaparib group and 77.1% in the placebo group (difference, 8.8 percentage points; 95% confidence interval [CI], 4.5 to 13.0; hazard ratio for invasive disease or death, 0.58; 99.5% CI, 0.41 to 0.82; P<0.001). The 3-year distant disease-free survival was 87.5% in the olaparib group and 80.4% in the placebo group (difference, 7.1 percentage points; 95% CI, 3.0 to 11.1; hazard ratio for distant disease or death, 0.57; 99.5% CI, 0.39 to 0.83; P<0.001). Olaparib was associated with fewer deaths than placebo (59 and 86, respectively) (hazard ratio, 0.68; 99% CI, 0.44 to 1.05; P=0.02); however, the between-group difference was not significant at an interim-analysis boundary of a P value of less than 0.01. Safety data were consistent with known side effects of olaparib, with no excess serious adverse events or adverse events of special interest. CONCLUSIONS Among patients with high-risk, HER2-negative early breast cancer and germline BRCA1 or BRCA2 pathogenic or likely pathogenic variants, adjuvant olaparib after completion of local treatment and neoadjuvant or adjuvant chemotherapy was associated with significantly longer survival free of invasive or distant disease than was placebo. Olaparib had limited effects on global patient-reported quality of life.
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- Gottardo, A., et al.
(författare)
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Isomers in Neutron-rich Lead Isotopes Populated via the Fragmentation of 238U at 1 GeV A
- 2011
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Ingår i: Journal of Physics: Conference Series. - : IOP Publishing. - 1742-6596 .- 1742-6588. ; 312
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Tidskriftsartikel (refereegranskat)abstract
- Neutron-rich nuclei beyond N = 126 in the lead region were populated by fragmenting a 238U beam at 1 GeV A on a Be target and then separated by the Fragment Separator (FRS) at GSI. Their isomeric decays were observed, enabling study of the shell structure of neutron-rich nuclei around the Z=82 shell closure. Some preliminary results are reported in this paper.
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- Cazzaniga, Marina E., et al.
(författare)
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Metastatic or locally advanced breast cancer patients : towards an expert consensus on nab-paclitaxel treatment in HER2-negative tumoursthe MACBETH project
- 2019
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Ingår i: Cancer Chemotherapy and Pharmacology. - : Springer Science and Business Media LLC. - 0344-5704 .- 1432-0843. ; 83:2, s. 301-318
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Despite the large use of nab-paclitaxel as a treatment option in metastatic breast cancer (MBC) across different countries, no definitive data are available in particular clinical situations.Areas covered: Efficacy, safety and schedule issues concerning available literature on nab-paclitaxel in advanced breast cancer and in specific subgroups of patients have been discussed and voted during an International Expert Meeting. Ten expert specialists in oncology, with extensive clinical experience on Nab-P and publications in the field of MBC have been identified. Six scientific areas of interest have been covered, generating 13 specific Statements for Nab-P, after literature review. For efficacy issues, a summary of research quality was performed adopting the GRADE algorithm for evidence scoring. The panel members were invited to express their opinion on the statements, in case of disagreement all the controversial opinions and the relative motivations have been made public.Expert opinion: Consensus was reached in 30.8% of the Nab-P statements, mainly those regarding safety issues, whereas ones regarding efficacy and schedule still remain controversial areas, requiring further data originated by the literature.
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- Krebs, Alice, et al.
(författare)
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Template for the Description of Cell-Based Toxicological Test Methods to Allow Evaluation and Regulatory Use of the Data
- 2019
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Ingår i: Altex. - : ALTEX Edition. - 1868-596X .- 1868-8551. ; 36:4, s. 682-699
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Only few cell-based test methods are described by Organisation for Economic Co-operation and Development (OECD) test guidelines or other regulatory references (e.g., the European Pharmacopoeia). The majority of toxicity tests still falls into the category of non-guideline methods. Data from these tests may nevertheless be used to support regulatory decisions or to guide strategies to assess compounds (e.g., drugs, agrochemicals) during research and development if they fulfill basic requirements concerning their relevance, reproducibility and predictivity. Only a method description of sufficient clarity and detail allows interpretation and use of the data. To guide regulators faced with increasing amounts of data from non-guideline studies, the OECD formulated Guidance Document 211 (GD211) on method documentation for the purpose of safety assessment. As GD211 is targeted mainly at regulators, it leaves scientists less familiar with regulation uncertain as to what level of detail is required and how individual questions should be answered. Moreover, little attention was given to the description of the test system (i.e., cell culture) and the steps leading to it being established in the guidance. To address these issues, an annotated toxicity test method template (ToxTemp) was developed (i) to fulfill all requirements of GD211, (ii) to guide the user concerning the types of answers and detail of information required, (iii) to include acceptance criteria for test elements, and (iv) to define the cells sufficiently and transparently. The fully annotated ToxTemp is provided here, together with reference to a database containing exemplary descriptions of more than 20 cell-based tests.
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- Repsilber, Dirk, 1971-, et al.
(författare)
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Formation of metastable RNA structures by sequential folding during transcription : time-resolved structural analysis of potato spindle tuber viroid (-)-stranded RNA by temperature-gradient gel electrophoresis
- 1999
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Ingår i: RNA. - New York, USA : Cambridge University Press. - 1355-8382 .- 1469-9001. ; 5:4, s. 574-84
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Tidskriftsartikel (refereegranskat)abstract
- A model of functional elements critical for replication and infectivity of the potato spindle tuber viroid (PSTVd) was proposed earlier: a thermodynamically metastable structure containing a specific hairpin (HP II) in the (-)-strand replication intermediate is essential for template activity during (+)-strand synthesis. We present here a detailed kinetic analysis on how PSTVd (-)-strands fold during synthesis by sequential folding into a variety of metastable structures that rearrange only slowly into the structure distribution of the thermodynamic equilibrium. Synthesis of PSTVd (-)-strands was performed by T7-RNA-polymerase; the rate of synthesis was varied by altering the concentration of nucleoside triphosphates to mimic the in vivo synthesis rate of DNA-dependent RNA polymerase II. With dependence on rate and duration of the synthesis, the structure distributions were analyzed by temperature-gradient gel electrophoresis (TGGE). Metastable structures are generated preferentially at low transcription rates--similar to in vivo rates--or at short transcription times at higher rates. Higher transcription rates or longer transcription times lead to metastable structures in low or undetectable amounts. Instead different structures do gradually appear having a more rod-like shape and higher thermodynamic stability, and the thermodynamically optimal rod-like structure dominates finally. It is concluded that viroids are able to use metastable as well as stable structures for their biological functions.
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- Silverwood, H., et al.
(författare)
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A non-parametric method for measuring the local dark matter density
- 2016
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 459:4, s. 4191-4208
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Tidskriftsartikel (refereegranskat)abstract
- We present a new method for determining the local dark matter density using kinematic data for a population of tracer stars. The Jeans equation in the z-direction is integrated to yield an equation that gives the velocity dispersion as a function of the total mass density, tracer density, and the 'tilt' term that describes the coupling of vertical and radial motions. We then fit a dark matter mass profile to tracer density and velocity dispersion data to derive credible regions on the vertical dark matter density profile. Our method avoids numerical differentiation, leading to lower numerical noise, and is able to deal with the tilt term while remaining one dimensional. In this study we present the method and perform initial tests on idealized mock data. We also demonstrate the importance of dealing with the tilt term for tracers that sample a parts per thousand(3)1 kpc above the disc plane. If ignored, this results in a systematic underestimation of the dark matter density.
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- Sivertsson, Sofia, et al.
(författare)
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The local dark matter density from SDSS-SEGUE G-dwarfs
- 2018
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 478:2, s. 1677-1693
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Tidskriftsartikel (refereegranskat)abstract
- We derive the local dark matter density by applying the integrated Jeans equation method from Silverwood et al. to SDSS-SEGUE G-dwarf data processed and presented by Budenbender et al. We use the MULTINEST Bayesian nested sampling software to fit a model for the baryon distribution, dark matter, and tracer stars, including a model for the 'tilt term' that couples the vertical and radial motions, to the data. The alpha-young population from Budenbender et al. yields the most reliable result of rho(dm) = 0.46(-0.08)(+ 0.07) GeV cm(-3) = 0.012(-0.002)(+ 0.002) M-circle dot pc(-3). Our analyses yield inconsistent results for the alpha-young and alpha-old data, pointing to problems in the tilt term and its modelling, the data itself, the assumption of a flat rotation curve, or the effects of disequilibria.
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