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- Burdett, S., et al.
(author)
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Adjuvant chemotherapy for resected early-stage non-small cell lung cancer
- 2015
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In: Cochrane Database of Systematic Reviews. - 1469-493X. ; :3
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Research review (peer-reviewed)abstract
- Background To evaluate the effects of administering chemotherapy following surgery, or following surgery plus radiotherapy (known as adjuvant chemotherapy) in patients with early stage non-small cell lung cancer (NSCLC), we performed two systematic reviews andmeta-analyses of all randomised controlled trials using individual participant data. Results were first published in The Lancet in 2010. Objectives To compare, in terms of overall survival, time to locoregional recurrence, time to distant recurrence and recurrence-free survival: A. Surgery versus surgery plus adjuvant chemotherapy B. Surgery plus radiotherapy versus surgery plus radiotherapy plus adjuvant chemotherapy in patients with histologically diagnosed early stage NSCLC. (2) To investigate whether or not predefined patient subgroups benefit more or less from cisplatin-based chemotherapy in terms of survival. Search methods We supplemented MEDLINE and CANCERLIT searches (1995 to December 2013) with information from trial registers, hand-searching relevant meeting proceedings and by discussion with trialists and organisations. Selection criteria We included trials of a) surgery versus surgery plus adjuvant chemotherapy; and b) surgery plus radiotherapy versus surgery plus radiotherapy plus adjuvant chemotherapy, provided that they randomised NSCLC patients using a method which precluded prior knowledge of treatment assignment. Data collection and analysis We carried out a quantitative meta-analysis using updated information from individual participants from all randomised trials. Data from all patients were sought from those responsible for the trial. We obtained updated individual participant data (IPD) on survival, and date of last follow-up, as well as details of treatment allocated, date of randomisation, age, sex, histological cell type, stage, and performance status. To avoid potential bias, we requested information for all randomised patients, including those excluded from the investigators' original analyses. We conducted all analyses on intention-to-treat on the endpoint of survival. For trials using cisplatin-based regimens, we carried out subgroup analyses by age, sex, histological cell type, tumour stage, and performance status. Main results We identified 35 trials evaluating surgery plus adjuvant chemotherapy versus surgery alone. IPD were available for 26 of these trials and our analyses are based on 8447 participants (3323 deaths) in 34 trial comparisons. There was clear evidence of a benefit of adding chemotherapy after surgery (hazard ratio (HR)= 0.86, 95% confidence interval (CI)= 0.81 to 0.92, p< 0.0001), with an absolute increase in survival of 4% at five years. We identified 15 trials evaluating surgery plus radiotherapy plus chemotherapy versus surgery plus radiotherapy alone. IPD were available for 12 of these trials and our analyses are based on 2660 participants (1909 deaths) in 13 trial comparisons. There was also evidence of a benefit of adding chemotherapy to surgery plus radiotherapy (HR= 0.88, 95% CI= 0.81 to 0.97, p= 0.009). This represents an absolute improvement in survival of 4% at five years. For both meta-analyses, we found similar benefits for recurrence outcomes and there was little variation in effect according to the type of chemotherapy, other trial characteristics or patient subgroup. We did not undertake analysis of the effects of adjuvant chemotherapy on quality of life and adverse events. Quality of life information was not routinely collected during the trials, but where toxicity was assessed and mentioned in the publications, it was thought to be manageable. We considered the risk of bias in the included trials to be low. Authors' conclusions Results from 47 trial comparisons and 11,107 patients demonstrate the clear benefit of adjuvant chemotherapy for these patients, irrespective of whether chemotherapy was given in addition to surgery or surgery plus radiotherapy. This is the most up-to-date and complete systematic review and individual participant data (IPD) meta-analysis that has been carried out.
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| 2. |
- Emonts, B., et al.
(author)
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A CO-rich merger shaping a powerful and hyperluminous infrared radio galaxy at z=2: the Dragonfly Galaxy
- 2015
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In: Monthly Notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 451:1, s. 1025-1035
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Journal article (peer-reviewed)abstract
- In the low-redshift Universe, the most powerful radio sources are often associated with gasrich galaxy mergers or interactions. We here present evidence for an advanced, gas-rich ('wet') merger associated with a powerful radio galaxy at a redshift of z similar to 2. This radio galaxy, MRC 0152-209, is the most infrared-luminous high-redshift radio galaxy known in the Southern hemisphere. Using the Australia Telescope Compact Array, we obtained highresolution CO(1-0) data of cold molecular gas, which we complement with Hubble Space Telescope (HS7)IWide Field Planetaiy Camera 2 (WFPC2) imaging and William Herschel Telescope long-slit spectroscopy. We find that, while roughly M-H2 x 10(10) Me of molecular gas coincides with the central host galaxy, another M-H2 similar to 3 x 10(10) Me is spread across a total extent of'-60 kpc. Most of this widespread CO(1-0) appears to follow prominent tidal features visible in the rest-frame near-UV HSTIWFPC2 imaging. Lya emission shows an excess over He II, but a deficiency over LIR, which is likely the result of photoionization by enhanced but very obscured star formation that was triggered by the merger. In terms of feedback, the radio source is aligned with widespread CO(1-0) emission, which suggests that there is a physical link between the propagating radio jets and the presence of cold molecular gas on scales of the galaxy's halo. Its optical appearance, combined with the transformational stage at which we witness the evolution of MRC 0152-209, leads us to adopt the name 'Dragonfly Galaxy'.
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| 5. |
- Ferreira, Silvia A, et al.
(author)
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Bi-directional cell-pericellular matrix interactions direct stem cell fate
- 2018
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In: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 9:1
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Journal article (peer-reviewed)abstract
- Modifiable hydrogels have revealed tremendous insight into how physical characteristics of cells' 3D environment drive stem cell lineage specification. However, in native tissues, cells do not passively receive signals from their niche. Instead they actively probe and modify their pericellular space to suit their needs, yet the dynamics of cells' reciprocal interactions with their pericellular environment when encapsulated within hydrogels remains relatively unexplored. Here, we show that human bone marrow stromal cells (hMSC) encapsulated within hyaluronic acid-based hydrogels modify their surroundings by synthesizing, secreting and arranging proteins pericellularly or by degrading the hydrogel. hMSC's interactions with this local environment have a role in regulating hMSC fate, with a secreted proteinaceous pericellular matrix associated with adipogenesis, and degradation with osteogenesis. Our observations suggest that hMSC participate in a bi-directional interplay between the properties of their 3D milieu and their own secreted pericellular matrix, and that this combination of interactions drives fate.
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| 6. |
- Liu, Ka‐Cheuk, et al.
(author)
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Inhibition of Cdk5 Promotes β-Cell Differentiation From Ductal Progenitors
- 2017
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In: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 67:1, s. 58-70
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Journal article (peer-reviewed)abstract
- Inhibition of notch signaling is known to induce differentiation of endocrine cells in zebrafish and mouse. After performing an unbiased in vivo screen of ∼2,200 small molecules in zebrafish, we identified an inhibitor of Cdk5 (roscovitine), which potentiated the formation of β-cells along the intrapancreatic duct during concurrent inhibition of notch signaling. We confirmed and characterized the effect with a more selective Cdk5 inhibitor, (R)-DRF053, which specifically increased the number of duct-derived β-cells without affecting their proliferation. By duct-specific overexpression of the endogenous Cdk5 inhibitors Cdk5rap1 or Cdkal1 (which previously have been linked to diabetes in genome-wide association studies), as well as deleting cdk5, we validated the role of chemical Cdk5 inhibition in β-cell differentiation by genetic means. Moreover, the cdk5 mutant zebrafish displayed an increased number of β-cells independently of inhibition of notch signaling, in both the basal state and during β-cell regeneration. Importantly, the effect of Cdk5 inhibition to promote β-cell formation was conserved in mouse embryonic pancreatic explants, adult mice with pancreatic ductal ligation injury, and human induced pluripotent stem (iPS) cells. Thus, we have revealed a previously unknown role of Cdk5 as an endogenous suppressor of β-cell differentiation and thereby further highlighted its importance in diabetes.
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| 7. |
- Pennekamp, Frank, et al.
(author)
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Biodiversity increases and decreases ecosystem stability
- 2018
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In: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 563:7729, s. 109-
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Journal article (peer-reviewed)abstract
- Losses and gains in species diversity affect ecological stability(1-7) and the sustainability of ecosystem functions and services(8-13). Experiments and models have revealed positive, negative and no effects of diversity on individual components of stability, such as temporal variability, resistance and resilience(2,3,6,11,12,14). How these stability components covary remains poorly understood(15). Similarly, the effects of diversity on overall ecosystem stability(16), which is conceptually akin to ecosystem multifunctionality(17,18), remain unknown. Here we studied communities of aquatic ciliates to understand how temporal variability, resistance and overall ecosystem stability responded to diversity (that is, species richness) in a large experiment involving 690 micro-ecosystems sampled 19 times over 40 days, resulting in 12,939 samplings. Species richness increased temporal stability but decreased resistance to warming. Thus, two stability components covaried negatively along the diversity gradient. Previous biodiversity manipulation studies rarely reported such negative covariation despite general predictions of the negative effects of diversity on individual stability components(3). Integrating our findings with the ecosystem multifunctionality concept revealed hump- and U-shaped effects of diversity on overall ecosystem stability. That is, biodiversity can increase overall ecosystem stability when biodiversity is low, and decrease it when biodiversity is high, or the opposite with a U-shaped relationship. The effects of diversity on ecosystem multifunctionality would also be hump- or U-shaped if diversity had positive effects on some functions and negative effects on others. Linking the ecosystem multifunctionality concept and ecosystem stability can transform the perceived effects of diversity on ecological stability and may help to translate this science into policy-relevant information.
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