Summary Background Anaplastic lymphoma kinase ( ALK ) gene rearrangements are oncogenic drivers of non-small-cell lung cancer (NSCLC). Brigatinib (AP26113) is an investigational ALK inhibitor with ...potent preclinical activity against ALK mutants resistant to crizotinib and other ALK inhibitors. We aimed to assess brigatinib in patients with advanced malignancies, particularly ALK -rearranged NSCLC. Methods In this ongoing, single-arm, open-label, phase 1/2 trial, we recruited patients from nine academic hospitals or cancer centres in the USA and Spain. Eligible patients were at least 18 years of age and had advanced malignancies, including ALK -rearranged NSCLC, and disease that was refractory to available therapies or for which no curative treatments existed. In the initial dose-escalation phase 1 stage of the trial, patients received oral brigatinib at total daily doses of 30–300 mg (according to a standard 3 + 3 design). The phase 1 primary endpoint was establishment of the recommended phase 2 dose. In the phase 2 expansion stage, we assessed three oral once-daily regimens: 90 mg, 180 mg, and 180 mg with a 7 day lead-in at 90 mg; one patient received 90 mg twice daily. We enrolled patients in phase 2 into five cohorts: ALK inhibitor-naive ALK -rearranged NSCLC (cohort 1), crizotinib-treated ALK -rearranged NSCLC (cohort 2), EGFRT790M -positive NSCLC and resistance to one previous EGFR tyrosine kinase inhibitor (cohort 3), other cancers with abnormalities in brigatinib targets (cohort 4), and crizotinib-naive or crizotinib-treated ALK -rearranged NSCLC with active, measurable, intracranial CNS metastases (cohort 5). The phase 2 primary endpoint was the proportion of patients with an objective response. Safety and activity of brigatinib were analysed in all patients in both phases of the trial who had received at least one dose of treatment. This trial is registered with ClinicalTrials.gov , number NCT01449461. Findings Between Sept 20, 2011, and July 8, 2014, we enrolled 137 patients (79 58% with ALK -rearranged NSCLC), all of whom were treated. Dose-limiting toxicities observed during dose escalation included grade 3 increased alanine aminotransferase (240 mg daily) and grade 4 dyspnoea (300 mg daily). We initially chose a dose of 180 mg once daily as the recommended phase 2 dose; however, we also assessed two additional regimens (90 mg once daily and 180 mg once daily with a 7 day lead-in at 90 mg) in the phase 2 stage. four (100% 95% CI 40–100) of four patients in cohort 1 had an objective response, 31 (74% 58–86) of 42 did in cohort 2, none (of one) did in cohort 3, three (17% 4–41) of 18 did in cohort 4, and five (83% 36–100) of six did in cohort 5. 51 (72% 60–82) of 71 patients with ALK -rearranged NSCLC with previous crizotinib treatment had an objective response (44 62% (50–73) had a confirmed objective response). All eight crizotinib-naive patients with ALK -rearranged NSCLC had a confirmed objective response (100% 63–100). Three (50% 95% CI 12–88) of six patients in cohort 5 had an intracranial response. The most common grade 3–4 treatment-emergent adverse events across all doses were increased lipase concentration (12 9% of 137), dyspnoea (eight 6%), and hypertension (seven 5%). Serious treatment-emergent adverse events (excluding neoplasm progression) reported in at least 5% of all patients were dyspnoea (ten 7%), pneumonia (nine 7%), and hypoxia (seven 5%). 16 (12%) patients died during treatment or within 31 days of the last dose of brigatinib, including eight patients who died from neoplasm progression. Interpretation Brigatinib shows promising clinical activity and has an acceptable safety profile in patients with crizotinib-treated and crizotinib-naive ALK -rearranged NSCLC. These results support its further development as a potential new treatment option for patients with advanced ALK -rearranged NSCLC. A randomised phase 2 trial in patients with crizotinib-resistant ALK -rearranged NSCLC is prospectively assessing the safety and efficacy of two regimens assessed in the phase 2 portion of this trial (90 mg once daily and 180 mg once daily with a 7 day lead-in at 90 mg). Funding ARIAD Pharmaceuticals.
Rhinoviruses (RVs), which are the most common cause of virally induced asthma exacerbations, account for much of the burden of asthma in terms of morbidity, mortality, and associated cost. ...Interleukin-25 (IL-25) activates type 2-driven inflammation and is therefore potentially important in virally induced asthma exacerbations. To investigate this, we examined whether RV-induced IL-25 could contribute to asthma exacerbations. RV-infected cultured asthmatic bronchial epithelial cells exhibited a heightened intrinsic capacity for IL-25 expression, which correlated with donor atopic status. In vivo human IL-25 expression was greater in asthmatics at baseline and during experimental RV infection. In addition, in mice, RV infection induced IL-25 expression and augmented allergen-induced IL-25. Blockade of the IL-25 receptor reduced many RV-induced exacerbation-specific responses including type 2 cytokine expression, mucus production, and recruitment of eosinophils, neutrophils, basophils, and T and non-T type 2 cells. Therefore, asthmatic epithelial cells have an increased intrinsic capacity for expression of a pro-type 2 cytokine in response to a viral infection, and IL-25 is a key mediator of RV-induced exacerbations of pulmonary inflammation.
Tree-ring records can provide valuable information to advance our understanding of contemporary terrestrial carbon cycling and to reconstruct key metrics in the decades preceding monitoring data. The ...growing use of tree rings in carbon-cycle research is being facilitated by increasing recognition of reciprocal benefits among research communities. Yet, basic questions persist regarding what tree rings represent at the ecosystem level, how to optimally integrate them with other data streams, and what related challenges need to be overcome. It is also apparent that considerable unexplored potential exists for tree rings to refine assessments of terrestrial carbon cycling across a range of temporal and spatial domains. Here, we summarize recent advances and highlight promising paths of investigation with respect to (1) growth phenology, (2) forest productivity trends and variability, (3) CO₂ fertilization and water-use efficiency, (4) forest disturbances, and (5) comparisons between observational and computational forest productivity estimates. We encourage the integration of tree-ring data: with eddy-covariance measurements to investigate carbon allocation patterns and water-use efficiency; with remotely sensed observations to distinguish the timing of cambial growth and leaf phenology; and with forest inventories to develop continuous, annually-resolved and long-term carbon budgets. In addition, we note the potential of tree-ring records and derivatives thereof to help evaluate the performance of earth system models regarding the simulated magnitude and dynamics of forest carbon uptake, and inform these models about growth responses to (non-)climatic drivers. Such efforts are expected to improve our understanding of forest carbon cycling and place current developments into a long-term perspective.
We present distance scale measurements from the baryon acoustic oscillation signal in the constant stellar mass and low-redshift sample samples from the Data Release 12 of the Baryon Oscillation ...Spectroscopic Survey. The total volume probed is 14.5 Gpc3, a 10 per cent increment from Data Release 11. From an analysis of the spherically averaged correlation function, we infer a distance to z = 0.57 of
$D_V(z)r^{\rm fid}_{\rm d}/r_{\rm d} = 2028\pm 21$
Mpc and a distance to z = 0.32 of
$D_V(z)r^{\rm fid}_{\rm d}/r_{\rm d} = 1264\pm 22$
Mpc assuming a cosmology in which
$r^{\rm fid}_{\rm d} = 147.10$
Mpc. From the anisotropic analysis, we find an angular diameter distance to z = 0.57 of
$D_{\rm A}(z)r^{\rm fid}_{\rm d}/r_{\rm d} = 1401\pm 21$
Mpc and a distance to z = 0.32 of 981 ± 20 Mpc, a 1.5 and 2.0 per cent measurement, respectively. The Hubble parameter at z = 0.57 is
$H(z)r_{\rm d}/r^{\rm fid}_{\rm d} = 100.3\pm 3.7$
km s−1 Mpc−1 and its value at z = 0.32 is 79.2 ± 5.6 km s−1 Mpc−1, a 3.7 and 7.1 per cent measurement, respectively. These cosmic distance scale constraints are in excellent agreement with a Λ cold dark matter model with cosmological parameters released by the recent Planck 2015 results.
Dynamic changes in 5-methylcytosine (5mC) have been implicated in the regulation of gene expression critical for consolidation of memory. However, little is known about how these changes in 5mC are ...regulated in the adult brain. The enzyme methylcytosine dioxygenase TET1 (TET1) has been shown to promote active DNA demethylation in the nervous system. Therefore, we took a viral-mediated approach to overexpress the protein in the hippocampus and examine its potential involvement in memory formation. We found that Tet1 is a neuronal activity-regulated gene and that its overexpression leads to global changes in modified cytosine levels. Furthermore, expression of TET1 or a catalytically inactive mutant (TET1m) resulted in the upregulation of several neuronal memory-associated genes and impaired contextual fear memory. In summary, we show that neuronal Tet1 regulates DNA methylation levels and that its expression, independent of its catalytic activity, regulates the expression of CNS activity-dependent genes and memory formation.
•Transcription of the Tet1 gene is regulated by neuronal activity•Tet1 expression causes global changes in cytosine methylation and hydroxymethylation•Tet1 positively regulates the expression of memory-related genes•Tet1 overexpression impairs memory formation independent of its catalytic activity
Kaas et al. explore the role of the 5-methylcytosine dioxygenase Tet1 in cognition using a viral-mediated approach to overexpress the enzyme in the hippocampus and demonstrate that Tet1 regulates 5mC hydroxylation, active DNA demethylation, gene transcription, and memory formation.
The apical complex is the instrument of invasion used by apicomplexan parasites, and the conoid is a conspicuous feature of this apparatus found throughout this phylum. The conoid, however, is ...believed to be heavily reduced or missing from Plasmodium species and other members of the class Aconoidasida. Relatively few conoid proteins have previously been identified, making it difficult to address how conserved this feature is throughout the phylum, and whether it is genuinely missing from some major groups. Moreover, parasites such as Plasmodium species cycle through 3 invasive forms, and there is the possibility of differential presence of the conoid between these stages. We have applied spatial proteomics and high-resolution microscopy to develop a more complete molecular inventory and understanding of the organisation of conoid-associated proteins in the model apicomplexan Toxoplasma gondii. These data revealed molecular conservation of all conoid substructures throughout Apicomplexa, including Plasmodium, and even in allied Myzozoa such as Chromera and dinoflagellates. We reporter-tagged and observed the expression and location of several conoid complex proteins in the malaria model P. berghei and revealed equivalent structures in all of its zoite forms, as well as evidence of molecular differentiation between blood-stage merozoites and the ookinetes and sporozoites of the mosquito vector. Collectively, we show that the conoid is a conserved apicomplexan element at the heart of the invasion mechanisms of these highly successful and often devastating parasites.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Surface mining for coal has taken place in the Central Appalachian region of the United States for well over a century, with a notable increase since the 1970s. Researchers have quantified the ...ecosystem and health impacts stemming from mining, relying in part on a geospatial dataset defining surface mining's extent at a decadal interval. This dataset, however, does not deliver the temporal resolution necessary to support research that could establish causal links between mining activity and environmental or public health and safety outcomes, nor has it been updated since 2005. Here we use Google Earth Engine and Landsat imagery to map the yearly extent of surface coal mining in Central Appalachia from 1985 through 2015, making our processing models and output data publicly available. We find that 2,900 km2 of land has been newly mined over this 31-year period. Adding this more-recent mining to surface mines constructed prior to 1985, we calculate a cumulative mining footprint of 5,900 km2. Over the study period, correlating active mine area with historical surface mine coal production shows that each metric ton of coal is associated with 12 m2 of actively mined land. Our automated, open-source model can be regularly updated as new surface mining occurs in the region and can be refined to capture mining reclamation activity into the future. We freely and openly offer the data for use in a range of environmental, health, and economic studies; moreover, we demonstrate the capability of using tools like Earth Engine to analyze years of remotely sensed imagery over spatially large areas to quantify land use change.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We explore the cosmological implications of the angle-averaged correlation function, ...(s), and the clustering wedges, ...(s) and ...(s), of the LOWZ and CMASS galaxy samples from Data Releases 10 ...and 11 of the Sloan Digital Sky Survey III (SDSS-III) Baryon Oscillation Spectroscopic Survey. Our results show no significant evidence for a deviation from the standard ... cold dark matter model. The combination of the information from our clustering measurements with recent data from the cosmic microwave background is sufficient to constrain the curvature of the Universe to ...k = 0.0010 ± 0.0029, the total neutrino mass to ... < 0.23 eV (95 per cent confidence level), the effective number of relativistic species to Neff = 3.31 ± 0.27 and the dark energy equation of state to wDE = -1.051 ± 0.076. These limits are further improved by adding information from Type Ia supernovae and baryon acoustic oscillations from other samples. In particular, this data set combination is completely consistent with a time-independent dark energy equation of state, in which case we find wDE = -1.024 ± 0.052. We explore the constraints on the growth rate of cosmic structures assuming f(z) = ... and obtain ... = 0.69 ± 0.15, consistent with the predictions of general relativity of ... = 0.55. (ProQuest: ... denotes formulae/symbols omitted.)
ATP-dependent severing of microtubules was first reported in Xenopus laevis egg extracts in 1991. Two years later this observation led to the purification of the first known microtubule-severing ...enzyme, katanin. Katanin homologs have now been identified throughout the animal kingdom and in plants. Moreover, members of two closely related enzyme subfamilies, spastin and fidgetin, have been found to sever microtubules and might act alongside katanins in some contexts (Roll-Mecak and McNally, 2010; Yu et al., 2008; Zhang et al., 2007). Over the past few years, it has become clear that microtubule-severing enzymes contribute to a wide range of cellular activities including mitosis and meiosis, morphogenesis, cilia biogenesis and disassembly, and migration. Thus, this group of enzymes is revealing itself to be among the most important of the microtubule regulators. This Commentary focuses on our growing understanding of how microtubule-severing enzymes contribute to the organization and dynamics of diverse microtubule arrays, as well as the structural and biophysical characteristics that afford them the unique capacity to catalyze the removal of tubulin from the interior microtubule lattice. Our goal is to provide a broader perspective, focusing on a limited number of particularly informative, representative and/or timely findings.
Rhinoviruses are the major cause of asthma exacerbations; however, its underlying mechanisms are poorly understood. We hypothesized that the epithelial cell-derived cytokine IL-33 plays a central ...role in exacerbation pathogenesis through augmentation of type 2 inflammation.
To assess whether rhinovirus induces a type 2 inflammatory response in asthma in vivo and to define a role for IL-33 in this pathway.
We used a human experimental model of rhinovirus infection and novel airway sampling techniques to measure IL-4, IL-5, IL-13, and IL-33 levels in the asthmatic and healthy airways during a rhinovirus infection. Additionally, we cultured human T cells and type 2 innate lymphoid cells (ILC2s) with the supernatants of rhinovirus-infected bronchial epithelial cells (BECs) to assess type 2 cytokine production in the presence or absence of IL-33 receptor blockade.
IL-4, IL-5, IL-13, and IL-33 are all induced by rhinovirus in the asthmatic airway in vivo and relate to exacerbation severity. Further, induction of IL-33 correlates with viral load and IL-5 and IL-13 levels. Rhinovirus infection of human primary BECs induced IL-33, and culture of human T cells and ILC2s with supernatants of rhinovirus-infected BECs strongly induced type 2 cytokines. This induction was entirely dependent on IL-33.
IL-33 and type 2 cytokines are induced during a rhinovirus-induced asthma exacerbation in vivo. Virus-induced IL-33 and IL-33-responsive T cells and ILC2s are key mechanistic links between viral infection and exacerbation of asthma. IL-33 inhibition is a novel therapeutic approach for asthma exacerbations.
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