Brown dwarfs and very low mass stars in the Hyades cluster : a dynamically evolved mass function

We conducted a search for brown dwarfs (BDs) and very low mass (VLM) stars in the 625 Myr-old Hyades cluster in order to derive the cluster's mass function across the stellar-substellar boundary. We performed a deep (I=23, z=22.5) photometric survey over 16 sq.deg. around the cluster center, followed up with K-band photometry to measure the proper motion of candidate members, and optical and near-IR spectroscopy of probable BD and VLM members. We report the discovery of the first 2 brown dwarfs in the Hyades cluster. The 2 objects have a spectral type early-T and their optical and near-IR photometry as well as their proper motion are consistent with them being cluster members. According to models, their mass is 50 Jupiter masses at an age of 625 Myr. We also report the discovery of 3 new very low mass stellar members of the cluster, and confirm the membership of 16 others. We combine these results with a list of previously known cluster members to build the present-day mass function (PDMF) of the Hyades cluster from 50 Jupiter masses to 3Mo. We find the Hyades PDMF to be strongly deficient in very low mass objects and brown dwarfs compared to the IMF of younger open clusters such as the Pleiades. We interpret this deficiency as the result of dynamical evolution over the past few 100 Myr, i.e., the preferential evaporation of low mass cluster members due to weak gravitational encounters. We thus estimate that the Hyades cluster currently hosts about 10-15 brown dwarfs, while its initial substellar population may have amounted up to 150-200 members.Comment: 16 page

Cancer-specific production of n-acetylaspartate via NAT8L overexpression in non-small cell lung cancer and its potential as a circulating biomarker

In order to identify new cancer-associated metabolites that may be useful for early detection of lung cancer, we performed a global metabolite profiling of a non-small cell lung cancer (NSCLC) line and immortalized normal lung epithelial cells from the same patient. Among several metabolites with significant cancer/normal differences, we identified a unique metabolic compound, N-acetylaspartate (NAA), in cancer cells-undetectable in normal lung epithelium. NAA's cancer-specific detection was validated in additional cancer and control lung cells as well as selected NSCLC patient tumors and control tissues. NAA's cancer specificity was further supported in our analysis of NAA synthetase (gene symbol: NAT8L) gene expression levels in The Cancer Genome Atlas: elevated NAT8L expression in approximately 40% of adenocarcinoma and squamous cell carcinoma cases (N = 577), with minimal expression in all nonmalignant lung tissues (N = 74). We then showed that NAT8L is functionally involved in NAA production of NSCLC cells through siRNA-mediated suppression of NAT8L, which caused selective reduction of intracellular and secreted NAA. Our cell culture experiments also indicated that NAA biosynthesis in NSCLC cells depends on glutamine availability. For preliminary evaluation of NAA's clinical potential as a circulating biomarker, we developed a sensitive NAA blood assay and found that NAA blood levels were elevated in 46% of NSCLC patients (N = 13) in comparison with age-matched healthy controls (N = 21) among individuals aged 55 years or younger. Taken together, these results indicate that NAA is produced specifically in NSCLC tumors through NAT8L overexpression, and its extracellular secretion can be detected in blood. (C) 2015 AACR

XPO1-dependent nuclear export is a druggable vulnerability in KRAS-mutant lung cancer

The common participation of oncogenic KRAS proteins in many of the most lethal human cancers, together with the ease of detecting somatic KRAS mutant alleles in patient samples, has spurred persistent and intensive efforts to develop drugs that inhibit KRAS activity. However, advances have been hindered by the pervasive inter- and intra-lineage diversity in the targetable mechanisms that underlie KRAS-driven cancers, limited pharmacological accessibility of many candidate synthetic-lethal interactions and the swift emergence of unanticipated resistance mechanisms to otherwise effective targeted therapies. Here we demonstrate the acute and specific cell-autonomous addiction of KRAS-mutant non-small-cell lung cancer cells to receptor-dependent nuclear export. A multi-genomic, data-driven approach, utilizing 106 human non-small-cell lung cancer cell lines, was used to interrogate 4,725 biological processes with 39,760 short interfering RNA pools for those selectively required for the survival of KRAS-mutant cells that harbour a broad spectrum of phenotypic variation. Nuclear transport machinery was the sole process-level discriminator of statistical significance. Chemical perturbation of the nuclear export receptor XPO1 (also known as CRM1), with a clinically available drug, revealed a robust synthetic-lethal interaction with native or engineered oncogenic KRAS both in vitro and in vivo. The primary mechanism underpinning XPO1 inhibitor sensitivity was intolerance to the accumulation of nuclear IκBα (also known as NFKBIA), with consequent inhibition of NFκB transcription factor activity. Intrinsic resistance associated with concurrent FSTL5 mutations was detected and determined to be a consequence of YAP1 activation via a previously unappreciated FSTL5-Hippo pathway regulatory axis. This occurs in approximately 17% of KRAS-mutant lung cancers, and can be overcome with the co-administration of a YAP1-TEAD inhibitor. These findings indicate that clinically available XPO1 inhibitors are a promising therapeutic strategy for a considerable cohort of patients with lung cancer when coupled to genomics-guided patient selection and observation.status: publishe