Sedimentological constraints on the late Silurian history of the Highland Boundary Fault, Scotland : Implications for Midland Valley Basin development

Peer reviewedPostprin

Constraints on synrift intrabasinal horst development from alluvial fan and aeolian deposits (Triassic, Fundy Basin, Nova Scotia)

The authors would like to acknowledge Shell E and P for funding this study, Rob Raeside at the Acadia University and Liz Kosters for their support during the field seasons. We also would like to thank Brian P. J. Williams for enthusiastic discussions in the field.Peer reviewedPostprintPostprin

Bipolar HII regions - Morphology and star formation in their vicinity - I - G319.88++00.79 and G010.32−-00.15

Our goal is to identify bipolar HII regions and to understand their morphology, their evolution, and the role they play in the formation of new generations of stars. We use the Spitzer and Herschel Hi-GAL surveys to identify bipolar HII regions. We search for their exciting star(s) and estimate their distances using near-IR data. Dense clumps are detected using Herschel-SPIRE data. MALT90 observations allow us to ascertain their association with the central HII region. We identify Class 0/I YSOs using their Spitzer and Herschel-PACS emissions. These methods will be applied to the entire sample of candidate bipolar HII regions. This paper focuses on two bipolar HII regions, one interesting in terms of its morphology, G319.88$+$00.79, and one in terms of its star formation, G010.32$-$00.15. Their exciting clusters are identified and their photometric distances estimated to be 2.6 kpc and 1.75 kpc, respectively. We suggest that these regions formed in dense and flat structures that contain filaments. They have a central ionized region and ionized lobes perpendicular to the parental cloud. The remains of the parental cloud appear as dense (more than 10^4 per cm^3) and cold (14-17 K) condensations. The dust in the PDR is warm (19-25 K). Dense massive clumps are present around the central ionized region. G010.32-00.14 is especially remarkable because five clumps of several hundred solar masses surround the central HII region; their peak column density is a few 10^23 per cm^2, and the mean density in their central regions reaches several 10^5 per cm^3. Four of them contain at least one massive YSO; these clumps also contain extended green objects and Class II methanol masers. This morphology suggests that the formation of a second generation of massive stars has been triggered by the central bipolar HII region. It occurs in the compressed material of the parental cloud.Comment: 32 pages, 28 figures, to be published in A&

An overview of treatment options for patients with relapsed/refractory multiple myeloma and renal impairment

Renal impairment (RI) is a relatively common complication of multiple myeloma, which increases in frequency as disease becomes more advanced and recovery of renal function becomes less likely as patients progress through lines of therapy. Clinical trials in the relapsed/refractory multiple myeloma (RRMM) setting have not uniformly included patients with RI or robustly reported their outcomes. Here, we review existing data among patients with RI and RRMM across drug classes (including immunomodulatory agents, proteasome inhibitors, monoclonal antibodies, antibody-drug conjugates, chimeric antigen receptor T-cell therapies, and exportin-1 inhibitor) to provide an improved understanding of available treatment options for this important population. We highlight data from pivotal clinical trials, including data relating to renal response (as defined by the International Myeloma Working Group) and discuss real-world experiences in patients with RI, where applicable. Despite substantial advances in RRMM treatment, the presence of RI remains associated with reduced overall survival. Consistent inclusion of patients with RI, and uniform reporting of their outcomes, should be encouraged in future prospective trials of treatments for RRMM

Unbiasing the density of TTV-characterised sub-Neptunes: Update of the mass-radius relationship of 34 Kepler planets

Transit Timing Variations (TTVs) can provide useful information on compact multi-planetary systems observed by transits, by putting constraints on the masses and eccentricities of the observed planets. This is especially helpful when the host star is not bright enough for radial velocity follow-up. However, in the past decades, numerous works have shown that TTV-characterised planets tend to have a lower densities than RV-characterised planets. Re-analysing 34 Kepler planets in the super-Earth to sub-Neptunes range using the RIVERS approach, we show that at least part of these discrepancies was due to the way transit timings were extracted from the light curve, which had a tendency to under-estimate the TTV amplitudes. We recover robust mass estimates (i.e. low prior dependency) for 23 of the planets. We compare these planets the RV-characterised population. A large fraction of these previously had a surprisingly low density now occupy a place of the mass-radius diagram much closer to the bulk of the known planets, although a slight shift toward lower densities remains, which could indicate that the compact multi-planetary systems characterised by TTVs are indeed composed of planets which are different from the bulk of the RV-characterised population. These results are especially important for obtaining an unbiased view of the compact multi-planetary systems detected by Kepler, TESS, and the upcoming PLATO mission

Synthesis and biological evaluation of ferrocene-based cannabinoid receptor 2 ligands

Ferrocene analogues of known fatty acid amide hydrolase inhibitors and CB2 ligands have been synthesized and characterized spectroscopically and crystallographically. The resulting bioorganometallic isoxazoles were assayed for their effects on CB1 and CB2 receptors as well as on FAAH. None had any FAAH activity but compound 3, 5-(2-(pentyloxy)phenyl)-N-ferrocenylisoxazole- 3-carboxamide, was found to be a potent CB2 ligand (Ki = 32.5 nM)

O415 Efficacy and safety of 48-week maintenance with QD ATV vs ATV/r (both + 2NRTIs) in patients with VL <50 c/mL after induction with ATV/r + 2NRTIs: study AI424136

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Refining the properties of the TOI-178 system with CHEOPS and TESS

Context. The TOI-178 system consists of a nearby late K-dwarf transited by six planets in the super-Earth to mini-Neptune regime, with radii ranging from ~1.1 to 2.9 R⊕ and orbital periods between 1.9 and 20.7 days. All planets but the innermost one form a chain of Laplace resonances. Mass estimates derived from a preliminary radial velocity (RV) dataset suggest that the planetary densities do not decrease in a monotonic way with the orbital distance to the star, contrary to what one would expect based on simple formation and evolution models. Aims. To improve the characterisation of this key system and prepare for future studies (in particular with JWST), we performed a detailed photometric study based on 40 new CHEOPS visits, one new TESS sector, and previously published CHEOPS, TESS, and NGTS data. Methods. First we updated the parameters of the host star using the new parallax from Gaia EDR3. We then performed a global analysis of the 100 transits contained in our data to refine the physical and orbital parameters of the six planets and study their transit timing variations (TTVs). We also used our extensive dataset to place constraints on the radii and orbital periods of potential additional transiting planets in the system. Results. Our analysis significantly refines the transit parameters of the six planets, most notably their radii, for which we now obtain relative precisions of ≲3%, with the exception of the smallest planet, b, for which the precision is 5.1%. Combined with the RV mass estimates, the measured TTVs allow us to constrain the eccentricities of planets c to g, which are found to be all below 0.02, as expected from stability requirements. Taken alone, the TTVs also suggest a higher mass for planet d than that estimated from the RVs, which had been found to yield a surprisingly low density for this planet. However, the masses derived from the current TTV dataset are very prior-dependent, and further observations, over a longer temporal baseline, are needed to deepen our understanding of this iconic planetary system

Inhibiting the oncogenic translation program is an effective therapeutic strategy in multiple myeloma

Published in final edited form as: Sci Transl Med. 2017 May 10; 9(389). https://doi.org/10.1126/scitranslmed.aal2668.Multiple myeloma (MM) is a frequently incurable hematological cancer in which overactivity of MYC plays a central role, notably through up-regulation of ribosome biogenesis and translation. To better understand the oncogenic program driven by MYC and investigate its potential as a therapeutic target, we screened a chemically diverse small-molecule library for anti-MM activity. The most potent hits identified were rocaglate scaffold inhibitors of translation initiation. Expression profiling of MM cells revealed reversion of the oncogenic MYC-driven transcriptional program by CMLD010509, the most promising rocaglate. Proteome-wide reversion correlated with selective depletion of short-lived proteins that are key to MM growth and survival, most notably MYC, MDM2, CCND1, MAF, and MCL-1. The efficacy of CMLD010509 in mouse models of MM confirmed the therapeutic relevance of these findings in vivo and supports the feasibility of targeting the oncogenic MYC-driven translation program in MM with rocaglates

Melflufen for relapsed and refractory multiple myeloma

Introduction: The overall survival of patients with multiple myeloma has improved with the advent of novel agents; however, multiple myeloma remains incurable. Combinations of standard-of-care agents such as immunomodulators, proteasome inhibitors, and anti-CD38 monoclonal antibodies are increasingly used in earlier lines of therapy. Patients with disease that is refractory to multiple novel agents represent a population with high unmet medical need and for whom therapies with new mechanisms of action could be beneficial. Melphalan flufenamide (melflufen) has demonstrated encouraging activity in patients with relapsed and refractory multiple myeloma. Areas covered: This review provides an overview of the mechanism of action of melflufen, a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly delivers alkylating agents into tumor cells. It reviews key Phase I and II clinical trial data for melflufen in combination with dexamethasone as well as in triplet combinations with daratumumab or bortezomib. The safety profile of melflufen, which is characterized primarily by clinically manageable hematologic adverse events, is described. Expert opinion: Melflufen has potential to fill a gap in the myeloma treatment landscape by providing a new mechanism of action with clinically meaningful efficacy and a favorable safety profile in patients refractory to multiple novel agents