Telegram from Ida M. Snowden

Telegram concerning visit to Logan

Letters between Ida M. Snowden and W. J. Kerr, as well as letters of recommendation from Thomas H. Smith, Allan M. Fleming, J. L. Kendall, and W. W. Maughan

Letters concerning Mrs. Ida M. Snowden

No germline mutations in the histone acetyltransferase gene EP300 in BRCA1 and BRCA2 negative families with breast cancer and gastric, pancreatic, or colorectal cancer

INTRODUCTION: Mutations in BRCA1, BRCA2, ATM, TP53, CHK2 and PTEN account for many, but not all, multiple-case breast and ovarian cancer families. The histone acetyltransferase gene EP300 may function as a tumour suppressor gene because it is sometimes somatically mutated in breast, colorectal, gastric and pancreatic cancers, and is located on a region of chromosome 22 that frequently undergoes loss of heterozygosity in many cancer types. We hypothesized that germline mutations in EP300 may account for some breast cancer families that include cases of gastric, pancreatic and/or colorectal cancer. METHODS: We screened the entire coding region of EP300 for mutations in the youngest affected members of 23 non-BRCA1/BRCA2 breast cancer families with at least one confirmed case of gastric, pancreatic and/or colorectal cancer. These families were ascertained in Australia through the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer. RESULTS: Denaturing HPLC analysis identified a heterozygous alteration at codon 211, specifically a GGC to AGC (glycine to serine) alteration, in two individuals. This conservative amino acid change was not within any known functional domains of EP300. The frequency of the Ser211 variant did not differ significanlty between a series of 352 breast cancer patients (4.0%) and 254 control individuals (2.8%; P = 0.5). CONCLUSION: The present study does not support a major role for EP300 mutations in breast and ovarian cancer families with a history of gastric, pancreatic and/or colorectal cancer

Retired A Stars and Their Companions. III. Comparing the Mass-Period Distributions of Planets Around A-Type Stars and Sun-Like Stars

We present an analysis of ~5 years of Lick Observatory radial velocity measurements targeting a uniform sample of 31 intermediate-mass subgiants (1.5 < M*/Msun < 2.0) with the goal of measuring the occurrence rate of Jovian planets around (evolved) A-type stars and comparing the distributions of their orbital and physical characteristics to those of planets around Sun-like stars. We provide updated orbital solutions incorporating new radial velocity measurements for five known planet-hosting stars in our sample; uncertainties in the fitted parameters are assessed using a Markov Chain Monte Carlo method. The frequency of Jovian planets interior to 3 AU is 26 (+9,-8)%, which is significantly higher than the ~5-10% frequency observed around solar-mass stars. The median detection threshold for our sample includes minimum masses down to {0.2, 0.3, 0.5, 0.6, 1.3} MJup within {0.1, 0.3, 0.6, 1.0, 3.0} AU. To compare the properties of planets around intermediate-mass stars to those around solar-mass stars we synthesize a population of planets based on the parametric relationship dN ~ M^{alpha}P^{beta} dlnM dlnP, the observed planet frequency, and the detection limits we derived. We find that the values of alpha and beta for planets around solar-type stars from Cumming et al. fail to reproduce the observed properties of planets in our sample at the 4 sigma level, even when accounting for the different planet occurrence rates. Thus, the properties of planets around A stars are markedly different than those around Sun-like stars, suggesting that only a small (~ 50%) increase in stellar mass has a large influence on the formation and orbital evolution of planets.Comment: Accepted by the Astrophysical Journal; 15 pages, 15 figure

The Case for a Directional Dark Matter Detector and the Status of Current Experimental Efforts

We present the case for a dark matter detector with directional sensitivity. This document was developed at the 2009 CYGNUS workshop on directional dark matter detection, and contains contributions from theorists and experimental groups in the field. We describe the need for a dark matter detector with directional sensitivity; each directional dark matter experiment presents their project\u27s status; and we close with a feasibility study for scaling up to a one ton directional detector, which would cost around $150M

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

THE CASE FOR A DIRECTIONAL DARK MATTER DETECTOR AND THE STATUS OF CURRENT EXPERIMENTAL EFFORTS

We present the case for a dark matter detector with directional sensitivity. This document was developed at the 2009 CYGNUS workshop on directional dark matter detection, and contains contributions from theorists and experimental groups in the field. We describe the need for a dark matter detector with directional sensitivity; each directional dark matter experiment presents their project's status; and we close with a feasibility study for scaling up to a one ton directional detector, which would cost around $150M