Remodelling of the natural product fumagillol employing a reaction discovery approach

In the search for new biologically active molecules, diversity-oriented synthetic strategies break through the limitation of traditional library synthesis by sampling new chemical space. Many natural products can be regarded as intriguing starting points for diversity-oriented synthesis, wherein stereochemically rich core structures may be reorganized into chemotypes that are distinctly different from the parent structure. Ideally, to be suited to library applications, such transformations should be general and involve few steps. With this objective in mind, the highly oxygenated natural product fumagillol has been successfully remodelled in several ways using a reaction-discovery-based approach. In reactions with amines, excellent regiocontrol in a bis-epoxide opening/cyclization sequence can be obtained by size-dependent interaction of an appropriate catalyst with the parent molecule, forming either perhydroisoindole or perhydroisoquinoline products. Perhydroisoindoles can be further remodelled by cascade processes to afford either morpholinone or bridged 4,1-benzoxazepine-containing structures.P50 GM067041 - NIGMS NIH HHS; P50 GM067041-07 - NIGMS NIH HHS; P50 GM067041-08 - NIGMS NIH HHS; P50 GM067041-09 - NIGMS NIH HH

Limiting Behaviour of the Mean Residual Life

In survival or reliability studies, the mean residual life or life expectancy is an important characteristic of the model. Here, we study the limiting behaviour of the mean residual life, and derive an asymptotic expansion which can be used to obtain a good approximation for large values of the time variable. The asymptotic expansion is valid for a quite general class of failure rate distributions--perhaps the largest class that can be expected given that the terms depend only on the failure rate and its derivatives.Comment: 19 page

Impact of lung cancer screening results on participant health-related quality of life and state anxiety in the National Lung Screening Trial

BACKGROUND Low-dose computed tomography (LDCT) lung screening has been associated with a 20% reduction in lung cancer mortality. A major barrier to the adoption of lung screening is the potential negative psychological impact of a false-positive (FP) screen, occurring in 20% to 50% of those screened. The objective of this study was to assess the impact of abnormal findings on health-related quality of life (HRQoL) and anxiety in the American College of Radiology (ACRIN)/National Lung Screening Trial (NLST). METHODS The NLST was a randomized screening trial comparing LDCT with chest X-ray screening (CXR). This study was part of the original protocol. A total of 2812 participants at 16 of 23 ACRIN sites who had baseline HRQoL assessments were asked to complete the Short Form-36 and the State Trait Anxiety Inventory (form Y-1) questionnaires to assess short-term (1 month) and long-term (6 months) effects of screening. FP were lung cancer–free at 1 year, and true-positives (TP) were not. RESULTS Of the total participants, 1024 (36.4%) participants were FP, 63 (2.2%) were TP, 344 (12.2%) had significant incidental findings (SIFs), and 1381 (49.1%) had negative screens. Participants had been randomized to LDCT (n = 1947) and CXR (n = 865). Short-term and long-term HRQoL and state anxiety did not differ across participants with FP, SIF, or negative screens. Short-term and long-term HRQoL were lower and anxiety was higher for TP participants compared to participants with FP, SIF, and negative screens. CONCLUSIONS In a large multicenter lung screening trial, participants receiving a false-positive or SIF screen result experienced no significant difference in HRQoL or state anxiety at 1 or at 6 months after screening relative to those receiving a negative result. Cancer 2014;120:3401–3409. © 2014 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. In a large multi-center lung screening trial, participants receiving a false positive or significant incidental finding screen result experienced no significant difference in health related quality of life or state anxiety at 1 or at 6 months after screening relative to those receiving a negative result

Arterial properties as determinants of left ventricular mass and fibrosis in severe aortic Stenosis : findings from ACRIN PA 4008

Background-The role of arterial load in severe aortic stenosis is increasingly recognized. However, patterns of pulsatile load and their implications in this population are unknown. We aimed to assess the relationship between the arterial properties and both (1) left ventricular remodeling and fibrosis and (2) the clinical course of patients with severe aortic stenosis undergoing aortic valve replacement (AVR). Methods and Results-We enrolled 38 participants with symptomatic severe aortic stenosis scheduled to undergo surgical AVR. Aortic root characteristic impedance, wave reflections parameters (reflection magnitude, reflected wave transit time), and myocardial extracellular mass were measured with cardiac magnetic resonance imaging and arterial tonometry Cardiac magnetic resonance imaging was repeated at 6 months in 30 participants. A reduction in cellular mass (133.6 versus 113.9 g; P=0.002) but not extracellular mass (42.3 versus 40.6 g; P=0.67) was seen after AVR. Participants with higher extracellular mass exhibited greater reflection magnitude (0.68 versus 0.54; P=0.006) and lower aortic root characteristic impedance (56.3 versus 96.9 dynes/s per cm(5); P=0.006). Reflection magnitude was a significant predictor of smaller improvement in the quality of life (Kansas City Cardiomyopathy Questionnaire score) after AVR (R=-0.51; P=0.0026). The 6-minute walk distance at 6 months after AVR was positively correlated with the reflected wave transit time (R=0.52; P=0.01). Conclusions-Consistent with animal studies, arterial wave reflections are associated with interstitial volume expansion in severe aortic stenosis and predict a smaller improvement in quality of life following AVR. Future trials should assess whether wave reflections represent a potential therapeutic target to mitigate myocardial interstitial remodeling and to improve the clinical status of this patient population

WHOI Hawaii Ocean Timeseries Station (WHOTS) : WHOTS-6 2009 mooring turnaround cruise report

The Woods Hole Oceanographic Institution (WHOI) Hawaii Ocean Timeseries Site (WHOTS), 100 km north of Oahu, Hawaii, is intended to provide long-term, high-quality air-sea fluxes as a part of the NOAA Climate Observation Program. The WHOTS mooring also serves as a coordinated part of the Hawaiian Ocean Timeseries (HOT) program, contributing to the goals of observing heat, fresh water and chemical fluxes at a site representative of the oligotrophic North Pacific Ocean. The approach is to maintain a surface mooring outfitted for meteorological and oceanographic measurements at a site near 22.75°N, 158°W by successive mooring turnarounds. These observations will be used to investigate air–sea interaction processes related to climate variability. The first WHOTS mooring (WHOTS-1) was deployed in August 2004. Turnaround cruises for successive moorings (WHOTS-2 through WHOTS-5) have typically been in either June or July. This report documents recovery of the WHOTS-5 mooring and deployment of the sixth mooring (WHOTS-6). The moorings utilize Surlyn foam buoys as the surface element and are outfitted with two Air–Sea Interaction Meteorology (ASIMET) systems. Each ASIMET system measures, records, and transmits via Argos satellite the surface meteorological variables necessary to compute air–sea fluxes of heat, moisture and momentum. The upper 155 m of the mooring is outfitted with oceanographic sensors for the measurement of temperature, conductivity and velocity in a cooperative effort with R. Lukas of the University of Hawaii (UH). A pCO2 system is installed on the buoy in a cooperative effort with Chris Sabine at the Pacific Marine Environmental Laboratory. Dr. Frank Bradley, CSIRO, Australia, assisted with meteorological sensor comparisons. A NOAA “Teacher at Sea” and a NOAA “Teacher in the Lab” participated in the cruise. The WHOTS mooring turnaround was done on the University of Hawaii research vessel Kilo Moana, Cruise KM-09-16, by the Upper Ocean Processes Group of the Woods Hole Oceanographic Institution in cooperation with UH and NOAA’s Earth System Research Laboratory, Physical Sciences Division (ESRL/PSD). The cruise took place between 9 and 17 July 2009. Operations began with deployment of the WHOTS-6 mooring on 10 July at approximately 22°40.0'N, 157°57.0'W in 4758 m of water. This was followed by meteorological intercomparisons and CTDs at the WHOTS-6 and WHOTS-5 sites. The WHOTS-5 mooring was recovered on 15 July 2009. The Kilo Moana then moved to the HOT central site (22°45.0'N, 158°00.0'W) for CTD casts. This report describes the cruise operations in more detail, as well as some of the in-port operations and pre-cruise buoy preparations.Funding was provided by the National Oceanic and Atmospheric Administration under Grant No. NA17RJ1223 for the Cooperative Institute for Climate and Ocean Research (CICOR)

Low Background Signal Readout Electronics for the MAJORANA DEMONSTRATOR

The MAJORANA DEMONSTRATOR is a planned 40 kg array of Germanium detectors intended to demonstrate the feasibility of constructing a tonne-scale experiment that will seek neutrinoless double beta decay ($0\nu\beta\beta$) in $^{76}\mathrm{Ge}$. Such an experiment would require backgrounds of less than 1 count/tonne-year in the 4 keV region of interest around the 2039 keV Q-value of the $\beta\beta$ decay. Designing low-noise electronics, which must be placed in close proximity to the detectors, presents a challenge to reaching this background target. This paper will discuss the MAJORANA collaboration's solutions to some of these challenges