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Phosphoinositide 3-kinase δ (PI3Kδ) has a key role in lymphocytes, and inhibitors that target this PI3K have been approved for treatment of B cell malignancies1-3. Although studies in mouse models of solid tumours have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumour immunity4,5, its effect on solid tumours in humans remains unclear. Here we assessed the effects of the PI3Kδi AMG319 in human patients with head and neck cancer in a neoadjuvant, double-blind, placebo-controlled randomized phase II trial (EudraCT no. 2014-004388-20). PI3Kδ inhibition decreased the number of tumour-infiltrating regulatory T (Treg) cells and enhanced the cytotoxic potential of tumour-infiltrating T cells. At the tested doses of AMG319, immune-related adverse events (irAEs) required treatment to be discontinued in 12 out of 21 of patients treated with AMG319, suggestive of systemic effects on Treg cells. Accordingly, in mouse models, PI3Kδi decreased the number of Treg cells systemically and caused colitis. Single-cell RNA-sequencing analysis revealed a PI3Kδi-driven loss of tissue-resident colonic ST2 Treg cells, accompanied by expansion of pathogenic T helper 17 (TH17) and type 17 CD8+ T (TC17) cells, which probably contributed to toxicity; this points towards a specific mode of action for the emergence of irAEs. A modified treatment regimen with intermittent dosing of PI3Kδi in mouse models led to a significant decrease in tumour growth without inducing pathogenic T cells in colonic tissue, indicating that alternative dosing regimens might limit toxicity.

Increases in temperature and pressure caused by rapid burial of sediments seaward of the Sumatra subduction zone have been hypothesized to trigger dehydration reactions that diagenetically strengthen sediments and contribute to the formation of an over‐pressured pre‐décollement, which together facilitate the occurrence of large shallow earthquakes. We present paleomagnetic, rock magnetic, and electron microscopic analyses from drill cores collected offshore Sumatra at Site U1480 during IODP Expedition 362 that support this hypothesis. The older pre‐fan units (Late Cretaceous to early Paleocene) were deposited when Site U1480 was moving rapidly northward with the Indian plate from a paleolatitude of 50° to 30°S, which would equate to expected absolute paleomagnetic inclinations of 70°–43°. Most of the older pre‐fan sediments, however, have shallow observed inclinations (shallower than ±20°), indicating that the sediments were overprinted when Site U1480 was located near the paleoequator, as it has been since the early Oligocene. Electron microscopic observations reveal that the pre‐existing detrital magnetite grains have undergone pervasive dissolution and alteration by hydrothermal fluids. The diagenesis observed is consistent with mineral dehydration, possibly driven by rapid burial of pelagic sediments by the ∼1250 m thick Nicobar Fan sequence. In addition, the elevated burial temperature also facilitated the smectite to illite conversion reaction. We hypothesize that chemical reactions resulted in the formation of fine‐grained magnetite that records a chemical remanent magnetization overprint. This overprint is consistent with the alteration occurring after burial by the thick Nicobar Fan sequence sometime in the past few million years. Plain Language Summary: Sediments and rocks commonly contain magnetic minerals that record the direction and intensity of Earth's magnetic field as they are being emplaced, thus preserving an ancient record of the geomagnetic field. Subsequent alteration of the magnetic minerals caused by heating and/or fluid circulation can result in the acquisition of secondary magnetizations (i.e., remagnetization) that may overprint or completely reset the primary ancient magnetization. Such remagnetization provides evidence of the physical and chemical changes that have occurred. Here through paleomagnetic, rock magnetic, and microscopic analyses of the deeper older (pre‐fan) stratigraphic sequence cored offshore Sumatra, we find that hydrothermal fluids, resulting from mineral dehydration driven by rapid burial of this sequence by younger, thick Nicobar Fan sediments, led to pervasive secondary remagnetization. Consequently, the newly formed magnetite recorded a much younger paleomagnetic field, leaving a shallow overprint that probably occurred sometime in the past few million years. The dehydration reactions also increased the strength of the sediments entering the subduction zone and aided in the formation of slip surfaces (called décollements), possibly contributing to the shallow, large earthquakes that have generated tsunamis off Sumatra. Key Points: The 60–67 Ma pre‐fan sediments offshore Sumatra were most likely remagnetized since deposition of the Nicobar Fan sediments, which began at ∼9 MaRemagnetization of pre‐fan sediments caused by mineral dehydration may be linked to shallow seismogenic slip off SumatraMagnetic properties of input sediments in the subduction margin record conditions that may have facilitated the generation of earthquakes [ABSTRACT FROM AUTHOR]

Geological records from the Antarctic margin offer direct evidence of environmental variability at high southern latitudes and provide insight regarding ice sheet sensitivity to past climate change. The early to mid-Miocene (23-14 Mya) is a compelling interval to study as global temperatures and atmospheric CO2 concentrations were similar to those projected for coming centuries. Importantly, this time interval includes the Miocene Climatic Optimum, a period of global warmth during which average surface temperatures were 3-4 °C higher than today. Miocene sediments in the ANDRILL-2A drill core from the Western Ross Sea, Antarctica, indicate that the Antarctic ice sheet (AIS) was highly variable through this key time interval. A multiproxy dataset derived from the core identifies four distinct environmental motifs based on changes in sedimentary facies, fossil assemblages, geochemistry, and paleotemperature. Four major disconformities in the drill core coincide with regional seismic discontinuities and reflect transient expansion of grounded ice across the Ross Sea. They correlate with major positive shifts in benthic oxygen isotope records and generally coincide with intervals when atmospheric CO2 concentrations were at or below preindustrial levels (∼280 ppm). Five intervals reflect ice sheet minima and air temperatures warm enough for substantial ice mass loss during episodes of high (∼500 ppm) atmospheric CO2 These new drill core data and associated ice sheet modeling experiments indicate that polar climate and the AIS were highly sensitive to relatively small changes in atmospheric CO2 during the early to mid-Miocene.

BackgroundSafe and effective treatments are urgently needed for patients with relapsed or refractory acute myeloid leukaemia. We investigated the efficacy and safety of vosaroxin, a first-in-class anticancer quinolone derivative, plus cytarabine in patients with relapsed or refractory acute myeloid leukaemia.MethodsThis phase 3, double-blind, placebo-controlled trial was undertaken at 101 international sites. Eligible patients with acute myeloid leukaemia were aged 18 years of age or older and had refractory disease or were in first relapse after one or two cycles of previous induction chemotherapy, including at least one cycle of anthracycline (or anthracenedione) plus cytarabine. Patients were randomly assigned 1:1 to vosaroxin (90 mg/m(2) intravenously on days 1 and 4 in a first cycle; 70 mg/m(2) in subsequent cycles) plus cytarabine (1 g/m(2) intravenously on days 1-5) or placebo plus cytarabine through a central interactive voice system with a permuted block procedure stratified by disease status, age, and geographical location. All participants were masked to treatment assignment. The primary efficacy endpoint was overall survival and the primary safety endpoint was 30-day and 60-day all-cause mortality. Efficacy analyses were done by intention to treat; safety analyses included all treated patients. This study is registered with ClinicalTrials.gov, number NCT01191801.FindingsBetween Dec 17, 2010, and Sept 25, 2013, 711 patients were randomly assigned to vosaroxin plus cytarabine (n=356) or placebo plus cytarabine (n=355). At the final analysis, median overall survival was 7·5 months (95% CI 6·4-8·5) in the vosaroxin plus cytarabine group and 6·1 months (5·2-7·1) in the placebo plus cytarabine group (hazard ratio 0·87, 95% CI 0·73-1·02; unstratified log-rank p=0·061; stratified p=0·024). A higher proportion of patients achieved complete remission in the vosaroxin plus cytarabine group than in the placebo plus cytarabine group (107 [30%] of 356 patients vs 58 [16%] of 355 patients, p

Palaeomagnetic secular variation (PSV) and excursion data obtained across MIS 8 (243–300 ka) from the western North Atlantic Ocean ODP (Ocean Drilling Program) sites 1060–1063 show composite high-resolution PSV records (both directions and relative palaeointensity) developed for each site and intercompared. Two methods of chronostratigraphy allow us to date these records. First, we used published results that compared the calcium carbonate records of ODP Leg 172 sediments and tuned them with Milankovich cyclicity. We also compared our palaeointensity records with the PISO-1500 global palaeointensity record that was dated with oxygen isotope stratigraphy. We prefer the PISO-1500 record to date our cores. Two excursions are preserved in our PSV records—Excursions 8α and 9α. Our revised age estimates for both excursions are 8α (236.7–239.8 ka) and 9α (283.7–286.9 ka). We have compared shipboard measurements of the two excursions with u-channel measurements of selected excursion intervals. Excursion 8α is interpreted as a 'Class II' excursion (local reversal) with in-phase inclination and declination changes; Excursion 9α is a 'Class I' excursion with 90° out-of-phase inclination and declination changes. Averaged directions (after removal of true excursional directions) and relative palaeointensity in 3 and 9 ka overlapping intervals show significant PSV directional variability over 104 yr timescales that is regionally correlatable among the four sites. A notable pattern of angular dispersion variability involves most time spent with low (∼10°) dispersion, with three shorter intervals of high (∼25°) dispersion. The relative palaeointensity variability also shows significant variability over 104 yr timescales with three notable intervals of low palaeointensity in all four records and a direct correspondence between the three low-palaeointensity intervals and the three intervals of high angular dispersion. The two magnetic field excursions occur in two of the three low-palaeointensity/high-dispersion intervals. This suggests that the geomagnetic field operates in two states between reversals, one with regular to high palaeointensity and low directional variability and one with low palaeointensity and significantly higher directional variability and excursions. [ABSTRACT FROM AUTHOR]