Determination of complex subclonal structures of hematological malignancies by multiplexed genotyping of blood progenitor colonies.

Current next-generation sequencing (NGS) technologies allow unprecedented insights into the mutational profiles of tumors. Recent studies in myeloproliferative neoplasms have further demonstrated that, not only the mutational profile, but also the order in which these mutations are acquired is relevant for our understanding of the disease. Our ability to assign mutation order from NGS data alone is, however, limited. Here, we present a strategy of highly multiplexed genotyping of burst forming unit-erythroid colonies based on NGS results to assess subclonal tumor structure. This allowed for the generation of complex clonal hierarchies and determination of order of mutation acquisition far more accurately than was possible from NGS data alone.Work in ARG lab has been supported by the Leukemia and Lymphoma Society (grant 7001-12), the National Institute of Health Research (grant NF-SI-0512-10079) and core support grants by the MRC and Wellcome Trust to the Cambridge Institute for Medical Research (100140/Z/12/Z) and Wellcome Trust-MRC Cambridge Stem Cell Institute (097922/Z/11/Z). Work in ARG's laboratory has in addition been supported by Cancer Research UK (grants C1163/A12765 and C1163/A21762), Bloodwise (grant 13003) and the Wellcome Trust (grant 104710/Z/14/Z

The promise and peril of intensive-site-based ecological research: insights from the Hubbard Brook ecosystem study

Abstract. Ecological research is increasingly concentrated at particular locations or sites. This trend reflects a variety of advantages of intensive, site-based research, but also raises important questions about the nature of such spatially delimited research: how well does site based research represent broader areas, and does it constrain scientific discovery?We provide an overview of these issues with a particular focus on one prominent intensive research site: the Hubbard Brook Experimental Forest (HBEF), New Hampshire, USA. Among the key features of intensive sites are: long-term, archived data sets that provide a context for new discoveries and the elucidation of ecological mechanisms; the capacity to constrain inputs and parameters, and to validate models of complex ecological processes; and the intellectual cross-fertilization among disciplines in ecological and environmental sciences. The feasibility of scaling up ecological observations from intensive sites depends upon both the phenomenon of interest and the characteristics of the site. An evaluation of deviation metrics for the HBEF illustrates that, in some respects, including sensitivity and recovery of streams and trees from acid deposition, this site is representative of the Northern Forest region, of which HBEF is a part. However, the mountainous terrain and lack of significant agricultural legacy make the HBEF among the least disturbed sites in the Northern Forest region. Its relatively cool, wet climate contributes to high stream flow compared to other sites. These similarities and differences between the HBEF and the region can profoundly influence ecological patterns and processes and potentially limit the generality of observations at this and other intensive sites. Indeed, the difficulty of scaling up may be greatest for ecological phenomena that are sensitive to historical disturbance and that exhibit the greatest spatiotemporal variation, such as denitrification in soils and the dynamics of bird communities. Our research shows that end member sites for some processes often provide important insights into the behavior of inherently heterogeneous ecological processes. In the current era of rapid environmental and biological change, key ecological responses at intensive sites will reflect both specific local drivers and regional trends

HST STIS spectroscopy of the triple nucleus of M31: two nested disks in Keplerian rotation around a Supermassive Black Hole

We present HST spectroscopy of the nucleus of M31 obtained with STIS. Spectra taken around the CaT lines at 8500 see only the red giants in the double bright- ness peaks P1 and P2. In contrast, spectra taken at 3600-5100 A are sensitive to the tiny blue nucleus embedded in P2, the lower surface brightness red nucleus. P2 has a K-type spectrum, but the embedded blue nucleus has an A-type spectrum with strong Balmer absorption lines. Given the small likelihood for stellar collisions, a 200 Myr old starburst appears to be the most plausible origin of the blue nucleus. In stellar population, size, and velocity dispersion, the blue nucleus is so different from P1 and P2 that we call it P3. The line-of-sight velocity distributions of the red stars in P1+P2 strengthen the support for Tremaine s eccentric disk model. The kinematics of P3 is consistent with a circular stellar disk in Keplerian rotation around a super-massive black hole with M_bh = 1.4 x 10^8 M_sun. The P3 and the P1+P2 disks rotate in the same sense and are almost coplanar. The observed velocity dispersion of P3 is due to blurred rotation and has a maximum value of sigma = 1183+-201 km/s. The observed peak rotation velocity of P3 is V = 618+-81 km/s at radius 0.05" = 0.19 pc corresponding to a circular rotation velocity at this radius of ~1700 km/s. Any dark star cluster alternative to a black hole must have a half-mass radius <= 0.03" = 0.11 pc. We show that this excludes clusters of brown dwarfs or dead stars on astrophysical grounds.Comment: Astrophysical Journal, Sep 20, 2005, 21 pages including 20 figure

U.S. prevalence of endocrine therapy-naive locally advanced or metastatic breast cancer

Background: Variations in treatment choice, or late stage at first diagnosis, mean that, despite guideline recommendations, not all patients with hormone receptor (hr)-positive locally advanced or metastatic breast cancer (la/mbca) will have received endocrine therapy before disease progression. In the present study, we aimed to estimate the proportion of women with postmenopausal hr-positive la/mbca in the United States who are endocrine therapy-naive. Methods: Women in the Optum Electronic Health Record (ehr) database with a breast cancer (bca) diagnosis (January 2008-March 2015) were included. Patient and malignancy characteristics were identified using structured data fields and natural-language processing of free-text clinical notes. The proportion of women with postmenopausal hr-positive, human epidermal growth factor 2 (her2)-negative (or unknown) la/mbca who had not received prior endocrine therapy was determined. Results were extrapolated to the entire U.S. population using the U.S. National Cancer Institute\u27s Surveillance, Epidemiology, and End Results database. Results are presented descriptively. Results: In the ehr database, 11,831 women with bca had discernible information on postmenopausal status, hr status, and disease stage. Of those women, 1923 (16.3%) had postmenopausal hr-positive, her2-negative (or unknown) la/mbca, and 70.7% of those 1923 patients (n = 1360) had not received prior endocrine therapy, accounting for 11.5% of the overall population. Extrapolating those estimates nationally suggests an annual incidence of 14,784 cases, and a 5-year limited duration prevalence of 50,638 cases. Conclusions: A substantial proportion of women with postmenopausal hr-positive la/mbca in the United States could be endocrine therapy-naive

Why is low waist-to-chest ratio attractive in males? The mediating roles of perceived dominance, fitness, and protection ability

Past research suggests that a lower waist-to-chest ratio (WCR) in men (i.e., narrower waist and broader chest) is viewed as attractive by women. However, little work has directly examined why low WCRs are preferred. The current work merged insights from theory and past research to develop a model examining perceived dominance, fitness, and protection ability as mediators of to WCR-attractiveness relationship. These mediators and their link to both short-term (sexual) and long-term (relational) attractiveness were simultaneously tested by having 151 women rate one of 15 avatars, created from 3D body scans. Men with lower WCR were perceived as more physically dominant, physically fit, and better able to protect loved ones; these characteristics differentially mediated the effect of WCR on short-term, long-term, and general attractiveness ratings. Greater understanding of the judgments women form regarding WCR may yield insights into motivations by men to manipulate their body image

Hypothalamic CaMKK2 Contributes to the Regulation of Energy Balance

SummaryDetailed knowledge of the pathways by which ghrelin and leptin signal to AMPK in hypothalamic neurons and lead to regulation of appetite and glucose homeostasis is central to the development of effective means to combat obesity. Here we identify CaMKK2 as a component of one of these pathways, show that it regulates hypothalamic production of the orexigenic hormone NPY, provide evidence that it functions as an AMPKα kinase in the hypothalamus, and demonstrate that it forms a unique signaling complex with AMPKα and β. Acute pharmacologic inhibition of CaMKK2 in wild-type mice, but not CaMKK2 null mice, inhibits appetite and promotes weight loss consistent with decreased NPY and AgRP mRNAs. Moreover, the loss of CaMKK2 protects mice from high-fat diet-induced obesity, insulin resistance, and glucose intolerance. These data underscore the potential of targeting CaMKK2 as a therapeutic intervention

AMI observations of unmatched Planck ERCSC LFI sources at 15.75 GHz

The Planck Early Release Compact Source Catalogue includes 26 sources with no obvious matches in other radio catalogues (of primarily extragalactic sources). Here we present observations made with the Arcminute Microkelvin Imager Small Array (AMI SA) at 15.75 GHz of the eight of the unmatched sources at declination > +10 degrees. Of the eight, four are detected and are associated with known objects. The other four are not detected with the AMI SA, and are thought to be spurious.Comment: 6 pages, 5 figures, 4 table

Microwave observations of spinning dust emission in NGC6946

We report new cm-wave measurements at five frequencies between 15 and 18GHz of the continuum emission from the reportedly anomalous "region 4" of the nearby galaxy NGC6946. We find that the emission in this frequency range is significantly in excess of that measured at 8.5GHz, but has a spectrum from 15-18GHz consistent with optically thin free-free emission from a compact HII region. In combination with previously published data we fit four emission models containing different continuum components using the Bayesian spectrum analysis package radiospec. These fits show that, in combination with data at other frequencies, a model with a spinning dust component is slightly preferred to those that possess better-established emission mechanisms.Comment: submitted MNRA

AMI observations of Lynds Dark Nebulae: further evidence for anomalous cm-wave emission

Observations at 14.2 to 17.9 GHz made with the AMI Small Array towards fourteen Lynds Dark Nebulae with a resolution of 2' are reported. These sources are selected from the SCUBA observations of Visser et al. (2001) as small angular diameter clouds well matched to the synthesized beam of the AMI Small Array. Comparison of the AMI observations with radio observations at lower frequencies with matched uv-plane coverage is made, in order to search for any anomalous excess emission which can be attributed to spinning dust. Possible emission from spinning dust is identified as a source within a 2' radius of the Scuba position of the Lynds dark nebula, exhibiting an excess with respect to lower frequency radio emission. We find five sources which show a possible spinning dust component in their spectra. These sources have rising spectral indices in the frequency range 14.2--17.9 GHz. Of these five one has already been reported, L1111, we report one new definite detection, L675, and three new probable detections (L944, L1103 and L1246). The relative certainty of these detections is assessed on the basis of three criteria: the extent of the emission, the coincidence of the emission with the Scuba position and the likelihood of alternative explanations for the excess. Extended microwave emission makes the likelihood of the anomalous emission arising as a consequence of a radio counterpart to a protostar or a proto-planetary disk unlikely. We use a 2' radius in order to be consistent with the IRAS identifications of dark nebulae (Parker 1988), and our third criterion is used in the case of L1103 where a high flux density at 850 microns relative to the FIR data suggests a more complicated emission spectrum.Comment: submitted MNRA