The M-type stars

The papers in this volume cover the following topics: (1) basic properties and photometric variability of M and related stars; (2) spectroscopy and nonthermal processes; (3) circumstellar radio molecular lines; (4) circumstellar shells, the formation of grains, and radiation transfer; (5) mass loss; (6) circumstellar chemistry; (7) thermal atmospheric models; (8) quasi-thermal models; (9) observations on the atmospheres of M dwarfs; and (1) theoretical work on M dwarfs

Exhumation of the Sierra de Cameros (Iberian Range, Spain): constraints from low-temperature thermochronology

We present new fission-track and (U–Th)/He data from apatite and zircon in order to reconstruct the exhumation of the Sierra de Cameros, in the northwestern part of Iberian Range, Spain. Zircon fission-track ages from samples from the depocentre of the basin were reset during the metamorphic peak at approximately 100 Ma. Detrital apatites from the uppermost sediments retain fission-track age information that is older than the sediment deposition age, indicating that these rocks have not exceeded 110 8C. Apatites from deeper in the stratigraphic sequence of the central part of the basin have fission-track ages of around 40 Ma, significantly younger than the stratigraphic age, recording the time of cooling after peak metamorphic conditions. Apatite (U–Th)/He ages in samples from these sediments are 31–40 Ma and record the last period of cooling during Alpine compression. The modelled thermal history derived from the uppermost sediments indicates that the thermal pulse associated with peak metamorphism was rapid, and that the region has cooled continuously to the present. The estimated palaeogeothermal gradient is around 86 8C km21 and supports a tectonic model with a thick sedimentary fill (c. 8 km) and explains the origin of the low-grade metamorphism observed in the oldest sediments

Assessing Ozone-Related Health Impacts under a Changing Climate

Climate change may increase the frequency and intensity of ozone episodes in future summers in the United States. However, only recently have models become available that can assess the impact of climate change on O(3) concentrations and health effects at regional and local scales that are relevant to adaptive planning. We developed and applied an integrated modeling framework to assess potential O(3)-related health impacts in future decades under a changing climate. The National Aeronautics and Space Administration–Goddard Institute for Space Studies global climate model at 4° × 5° resolution was linked to the Penn State/National Center for Atmospheric Research Mesoscale Model 5 and the Community Multiscale Air Quality atmospheric chemistry model at 36 km horizontal grid resolution to simulate hourly regional meteorology and O(3) in five summers of the 2050s decade across the 31-county New York metropolitan region. We assessed changes in O(3)-related impacts on summer mortality resulting from climate change alone and with climate change superimposed on changes in O(3) precursor emissions and population growth. Considering climate change alone, there was a median 4.5% increase in O(3)-related acute mortality across the 31 counties. Incorporating O(3) precursor emission increases along with climate change yielded similar results. When population growth was factored into the projections, absolute impacts increased substantially. Counties with the highest percent increases in projected O(3) mortality spread beyond the urban core into less densely populated suburban counties. This modeling framework provides a potentially useful new tool for assessing the health risks of climate change

Relationship between the lipid composition of maternal plasma and infant plasma through breast milk

Abstract: Introduction: This study was motivated by the report that infant development correlates with particular lipids in infant plasma. Objective: The hypothesis was that the abundance of these candidate biomarkers is influenced by the dietary intake of the infant. Methods: A cohort of 30 exclusively-breastfeeding mother–infant pairs from a small region of West Africa was used for this observational study. Plasma and milk from the mother and plasma from her infant were collected within 24 h, 3 months post partum. The lipid, sterol and glyceride composition was surveyed using direct infusion MS in positive and negative ion modes. Analysis employed a combination of univariate and multivariate tests. Results: The lipid profiles of mother and infant plasma samples are similar but distinguishable, and both are distinct from milk. Phosphatidylcholines (PC), cholesteryl esters (CEs) and cholesterol were more abundant in mothers with respect to their infants, e.g. PC(34:1) was 5.66% in mothers but 3.61% in infants (p = 3.60 × 10−10), CE(18:2) was 8.05% in mothers but 5.18% in infants (p = 1.37 × 10−11) whilst TGs were lower in mothers with respect to their infants, e.g. TG(52:2) was 2.74% in mothers and 4.23% in infants (p = 1.63 × 10−05). A latent structure model showed that four lipids in infant plasma previously shown to be biomarkers clustered with cholesteryl esters in the maternal circulation. Conclusion: This study found evidence that the abundance of individual lipid isoforms associated with infant development are associated with the abundance of individual molecular species in the mother’s circulation

Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study.

BackgroundInternal tandem duplication mutations in FLT3 are common in acute myeloid leukaemia and are associated with rapid relapse and short overall survival. The clinical benefit of FLT3 inhibitors in patients with acute myeloid leukaemia has been limited by rapid generation of resistance mutations, particularly in codon Asp835 (D835). We aimed to assess the highly selective oral FLT3 inhibitor gilteritinib in patients with relapsed or refractory acute myeloid leukaemia.MethodsIn this phase 1-2 trial, we enrolled patients aged 18 years or older with acute myeloid leukaemia who either were refractory to induction therapy or had relapsed after achieving remission with previous treatment. Patients were enrolled into one of seven dose-escalation or dose-expansion cohorts assigned to receive once-daily doses of oral gilteritinib (20 mg, 40 mg, 80 mg, 120 mg, 200 mg, 300 mg, or 450 mg). Cohort expansion was based on safety and tolerability, FLT3 inhibition in correlative assays, and antileukaemic activity. Although the presence of an FLT3 mutation was not an inclusion criterion, we required ten or more patients with locally confirmed FLT3 mutations (FLT3mut+) to be enrolled in expansion cohorts at each dose level. On the basis of emerging findings, we further expanded the 120 mg and 200 mg dose cohorts to include FLT3mut+ patients only. The primary endpoints were the safety, tolerability, and pharmacokinetics of gilteritinib. Safety and tolerability were assessed in the safety analysis set (all patients who received at least one dose of gilteritinib). Responses were assessed in the full analysis set (all patients who received at least one dose of study drug and who had at least one datapoint post-treatment). Pharmacokinetics were assessed in a subset of the safety analysis set for which sufficient data for concentrations of gilteritinib in plasma were available to enable derivation of one or more pharmacokinetic variables. This study is registered with ClinicalTrials.gov, number NCT02014558, and is ongoing.FindingsBetween Oct 15, 2013, and Aug 27, 2015, 252 adults with relapsed or refractory acute myeloid leukaemia received oral gilteritinib once daily in one of seven dose-escalation (n=23) or dose-expansion (n=229) cohorts. Gilteritinib was well tolerated; the maximum tolerated dose was established as 300 mg/day when two of three patients enrolled in the 450 mg dose-escalation cohort had two dose-limiting toxicities (grade 3 diarrhoea and grade 3 elevated aspartate aminotransferase). The most common grade 3-4 adverse events irrespective of relation to treatment were febrile neutropenia (97 [39%] of 252), anaemia (61 [24%]), thrombocytopenia (33 [13%]), sepsis (28 [11%]), and pneumonia (27 [11%]). Commonly reported treatment-related adverse events were diarrhoea (92 [37%] of 252]), anaemia (86 [34%]), fatigue (83 [33%]), elevated aspartate aminotransferase (65 [26%]), and increased alanine aminotransferase (47 [19%]). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (98 [39%] of 252; five related to treatment), progressive disease (43 [17%]), sepsis (36 [14%]; two related to treatment), pneumonia (27 [11%]), acute renal failure (25 [10%]; five related to treatment), pyrexia (21 [8%]; three related to treatment), bacteraemia (14 [6%]; one related to treatment), and respiratory failure (14 [6%]). 95 people died in the safety analysis set, of which seven deaths were judged possibly or probably related to treatment (pulmonary embolism [200 mg/day], respiratory failure [120 mg/day], haemoptysis [80 mg/day], intracranial haemorrhage [20 mg/day], ventricular fibrillation [120 mg/day], septic shock [80 mg/day], and neutropenia [120 mg/day]). An exposure-related increase in inhibition of FLT3 phosphorylation was noted with increasing concentrations in plasma of gilteritinib. In-vivo inhibition of FLT3 phosphorylation occurred at all dose levels. At least 90% of FLT3 phosphorylation inhibition was seen by day 8 in most patients receiving a daily dose of 80 mg or higher. 100 (40%) of 249 patients in the full analysis set achieved a response, with 19 (8%) achieving complete remission, ten (4%) complete remission with incomplete platelet recovery, 46 (18%) complete remission with incomplete haematological recovery, and 25 (10%) partial remission INTERPRETATION: Gilteritinib had a favourable safety profile and showed consistent FLT3 inhibition in patients with relapsed or refractory acute myeloid leukaemia. These findings confirm that FLT3 is a high-value target for treatment of relapsed or refractory acute myeloid leukaemia; based on activity data, gilteritinib at 120 mg/day is being tested in phase 3 trials.FundingAstellas Pharma, National Cancer Institute (Leukemia Specialized Program of Research Excellence grant), Associazione Italiana Ricerca sul Cancro

Poincare Semigroup Symmetry as an Emergent Property of Unstable Systems

The notion that elementary systems correspond to irreducible representations of the Poincare group is the starting point for this paper, which then goes on to discuss how a semigroup for the time evolution of unstable states and resonances could emerge from the underlying Poincare symmetry. Important tools in this analysis are the Clebsch-Gordan coefficients for the Poincare group.Comment: 17 pages, 1 figur

A phase 1 clinical trial of vorinostat in combination with decitabine in patients with acute myeloid leukaemia or myelodysplastic syndrome

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/108599/1/bjh13016.pd