Aluminum is an experimentally demonstrated neurotoxin and the most commonly used vaccine adjuvant. Despite almost 90 years of widespread use of aluminum adjuvants, medical science's understanding ...about their mechanisms of action is still remarkably poor. There is also a concerning scarcity of data on toxicology and pharmacokinetics of these compounds. In spite of this, the notion that aluminum in vaccines is safe appears to be widely accepted. Experimental research, however, clearly shows that aluminum adjuvants have a potential to induce serious immunological disorders in humans. In particular, aluminum in adjuvant form carries a risk for autoimmunity, long-term brain inflammation and associated neurological complications and may thus have profound and widespread adverse health consequences. In our opinion, the possibility that vaccine benefits may have been overrated and the risk of potential adverse effects underestimated, has not been rigorously evaluated in the medical and scientific community. We hope that the present paper will provide a framework for a much needed and long overdue assessment of this highly contentious medical issue.
Gene targeting is a challenge in organisms where non-homologous end-joining is the predominant form of recombination. We show that cell division cycle synchronization can be applied to significantly ...increase the rate of homologous recombination during transformation. Using hydroxyurea-mediated cell cycle arrest, we obtained improved gene targeting rates in Yarrowia lipolytica, Arxula adeninivorans, Saccharomyces cerevisiae, Kluyveromyces lactis and Pichia pastoris demonstrating the broad applicability of the method. Hydroxyurea treatment enriches for S-phase cells that are active in homologous recombination and enables previously unattainable genomic modifications.
Abstract
On time scales that are long compared to the phase relaxation time, a quasi-steady supersaturation sqs is expected to exist in clouds. On shorter time scales, however, turbulent fluctuations ...of temperature and water vapor concentration should generate fluctuations in supersaturation. The variability of temperature, water vapor, and supersaturation has been measured in situ with submeter resolution in warm, continental, shallow cumulus clouds. Several cumuli with horizontal extents of order 100 m were sampled during their first appearance and development to depths of ~100 m in a growing boundary layer. Fluctuations of the saturation ratio are observed to be approximately normally distributed with standard deviations on the order of 1%. This variability is almost one order of magnitude larger than sqs calculated using simultaneous measurements of the vertical velocity component and the droplet size distribution. It is argued that, depending on the ratio of the phase relaxation and the turbulent mixing time, substantial fluctuations in the supersaturation field can exist on small spatial scales, centered on sqs for the mean state. The observations also suggest that, on larger scales, fluctuations of the supersaturation field are damped by cloud droplet growth. Droplets with diameters of up to 20 μm were observed in the shallow cumulus clouds, whereas the adiabatic diameter was less than 10 μm. Such large droplets may be explained by a few droplets experiencing the highest observed supersaturations for a certain time. Consequences for aerosol activation and droplet size dispersion in a highly fluctuating supersaturation field are briefly discussed.
Highlights • Postzygotic mutation is a common occurrence. • The developmental stage and timing of new mutations influence their phenotypic effects and likelihood of transmission. • All major classes ...of mutations are observed in the mosaic state. • Mathematical modeling of mosaicism can inform estimates of recurrence risk for new mutations.
In the ongoing phase I PROFILE 1001 study, crizotinib showed antitumor activity in patients with ROS1-rearranged advanced non-small-cell lung cancer (NSCLC). Here, we present updated antitumor ...activity, overall survival (OS) and safety data (additional 46.2months follow-up) for patients with ROS1-rearranged advanced NSCLC from PROFILE 1001.
ROS1 status was determined by FISH or reverse transcriptase–polymerase chain reaction. All patients received crizotinib at a starting dose of 250mg twice daily.
Fifty-three patients received crizotinib, with a median duration of treatment of 22.4months. At data cut-off, treatment was ongoing in 12 patients (23%). The objective response rate (ORR) was 72% 95% confidence interval (CI), 58% to 83%, including six confirmed complete responses and 32 confirmed partial responses; 10 patients had stable disease. Responses were durable (median duration of response 24.7months; 95% CI, 15.2–45.3). ORRs were consistent across different patient subgroups. Median progression-free survival was 19.3months (95% CI, 15.2–39.1). A total of 26 deaths (49%) occurred (median follow-up period of 62.6months), and of the remaining 27 patients (51%), 14 (26%) were in follow-up at data cut-off. Median OS was 51.4months (95% CI, 29.3 to not reached) and survival probabilities at 12, 24, 36, and 48months were 79%, 67%, 53%, and 51%, respectively. No correlation was observed between OS and specific ROS1 fusion partner. Treatment-related adverse events (TRAEs) were mainly grade 1 or 2, per CTCAE v3.0. There were no grade ≥4 TRAEs and no TRAEs associated with permanent discontinuation. No new safety signals were reported with long-term crizotinib treatment.
These findings serve as a new benchmark for OS in ROS1-rearranged advanced NSCLC, and continue to show the clinically meaningful benefit and safety of crizotinib in this molecular subgroup.
ClinicalTrials.gov identifier NCT00585195
Sphagnum-dominated peatlands contain approx. 30 % of the terrestrial carbon pool in the form of partially decomposed plant material (peat), and, as a consequence, Sphagnum is currently a focus of ...studies on biogeochemistry and control of global climate. Sphagnum species differ in ecologically important traits that scale up to impact ecosystem function, and sequencing of the genome from selected Sphagnum species is currently underway. As an emerging model system, these resources for Sphagnum will facilitate linking nucleotide variation to plant functional traits, and through those traits to ecosystem processes. A solid phylogenetic framework for Sphagnum is crucial to comparative analyses of species-specific traits, but relationships among major clades within Sphagnum have been recalcitrant to resolution because the genus underwent a rapid radiation. Herein a well-supported hypothesis for phylogenetic relationships among major clades within Sphagnum based on organellar genome sequences (plastid, mitochondrial) is provided.
We obtained nucleotide sequences (273 753 nucleotides in total) from the two organellar genomes from 38 species (including three outgroups). Phylogenetic analyses were conducted using a variety of methods applied to nucleotide and amino acid sequences. The Sphagnum phylogeny was rooted with sequences from the related Sphagnopsida genera, Eosphagnum and Flatbergium
Phylogenetic analyses of the data converge on the following subgeneric relationships: (Rigida (((Subsecunda) (Cuspidata)) ((Sphagnum) (Acutifolia))). All relationships were strongly supported. Species in the two major clades (i.e. Subsecunda + Cuspidata and Sphagnum + Acutifolia), which include >90 % of all Sphagnum species, differ in ecological niches and these differences correlate with other functional traits that impact biogeochemical cycling. Mitochondrial intron presence/absence are variable among species and genera of the Sphagnopsida. Two new nomenclatural combinations are made, in the genera Eosphagnum and Flatbergium
Newly resolved relationships now permit phylogenetic analyses of morphological, biochemical and ecological traits among Sphagnum species. The results clarify long-standing disagreements about subgeneric relationships and intrageneric classification.
Climate models robustly project that global warming will lead to a poleward shift of the annual-mean zonal-mean extratropical jet streams. The magnitude of such shifts remains uncertain, however, and ...recent work has indicated a potentially important role of cloud radiative interactions. The model spread found in realistic simulations with interactive sea surface temperatures (SSTs) is captured in aquaplanet simulations with prescribed SSTs, because of which the latter setup is adapted here to study the impact of regional atmospheric cloud radiative changes on the jet position. Simulations with two CMIP5 models and prescribed regional cloud changes show that the rise of tropical high-level clouds and the upward and poleward movement of midlatitude high-level clouds lead to poleward jet shifts. High-latitude low-level cloud changes shift the jet poleward in one model but not in the other. The impact of clouds on the jet operates via the atmospheric radiative forcing that is created by the cloud changes and is qualitatively reproduced in a dry model, although the latter is too sensitive because of its simplified treatment of diabatic processes. The 10-model CMIP5 aquaplanet ensemble of global warming exhibits correlations between jet shifts, regional temperature changes, and regional cloud changes that are consistent with the prescribed cloud simulations. This provides evidence that the atmospheric radiative forcing from tropical and midlatitude high-level cloud changes contributes to model uncertainty in future jet shifts, in addition to the surface radiative forcing from extratropical cloud changes highlighted by previous studies.
•Investigator-assessed PFS data in the ALEX study are now mature (53% of events in the alectinib arm).•Alectinib significantly prolonged PFS vs crizotinib (stratified HR 0.43, 95% CI 0.32–0.58; ...median 34.8 vs 10.9 months).•OS data are immature (37% of events); median NR alectinib vs 57.4 months crizotinib (stratified HR 0.67, 95% CI 0.46–0.98).•5-year OS rate of 62.5% with alectinib and 45.5% with crizotinib.•Median treatment duration was longer with alectinib (28.1 vs 10.8 months crizotinib), with no new safety signals seen.
The ALEX study demonstrated significantly improved progression-free survival (PFS) with alectinib versus crizotinib in treatment-naive ALK-positive non-small-cell lung cancer (NSCLC) at the primary data cut-off (9 February 2017). We report mature PFS (cut-off: 30 November 2018) and overall survival (OS) data up to 5 years (cut-off: 29 November 2019).
Patients with stage III/IV ALK-positive NSCLC were randomized to receive twice-daily alectinib 600 mg (n = 152) or crizotinib 250 mg (n = 151) until disease progression, toxicity, withdrawal or death. Primary end point: investigator-assessed PFS. Secondary end points included objective response rate, OS and safety.
Mature PFS data showed significantly prolonged investigator-assessed PFS with alectinib hazard ratio (HR) 0.43, 95% confidence interval (CI) 0.32–0.58; median PFS 34.8 versus 10.9 months crizotinib. Median duration of OS follow-up: 48.2 months alectinib, 23.3 months crizotinib. OS data remain immature (37% of events). Median OS was not reached with alectinib versus 57.4 months with crizotinib (stratified HR 0.67, 95% CI 0.46–0.98). The 5-year OS rate was 62.5% (95% CI 54.3–70.8) with alectinib and 45.5% (95% CI 33.6–57.4) with crizotinib, with 34.9% and 8.6% of patients still on study treatment, respectively. The OS benefit of alectinib was seen in patients with central nervous system metastases at baseline HR 0.58 (95% CI 0.34–1.00) and those without HR 0.76 (95% CI 0.45–1.26). Median treatment duration was longer with alectinib (28.1 versus 10.8 months), and no new safety signals were observed.
Mature PFS data from ALEX confirmed significant improvement in PFS for alectinib over crizotinib in ALK-positive NSCLC. OS data remain immature, with a higher 5-year OS rate with alectinib versus crizotinib. This is the first global randomized study to show clinically meaningful improvement in OS for a next-generation tyrosine kinase inhibitor versus crizotinib in treatment-naive ALK-positive NSCLC.
NCT02075840.
For right-censored data perhaps the most commonly used tests are weighted logrank tests, such as the logrank and Wilcoxon-type tests. In this paper we review several generalizations of those weighted ...logrank tests to interval-censored data and present an R package,
, to implement many of them. The
package depends on the
package, also presented here, which performs exact and asymptotic linear permutation tests. The
package performs many of the tests included in the already available
package, and provides an independent validation of
. We review analysis methods for interval-censored data, and we describe and show how to use the
and
packages.
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