ALBERT

Description: Author Posting. © American Meteorological Society, 2009. This article is posted here by permission of The UK–SOLAS projects were funded by the Natural Environment Research Council Grants NE/C001826/1 (HiWASE), NE/C001842/1 (SEASAW), NE/C001702/1 (DOGEE), and NE/E011489/1 (DMS Fluxes); and by NSF Grants ATM05-26341 (Hawaii), OCE-0623450 (Miami), and NSF-OCE 0549887/0834340/0550000 (APL-UW). for personal use, not for redistribution. The definitive version was published in Bulletin of the American Meteorological Society 90 (2009): 629-644, doi:10.1175/2008BAMS2578.1.

Description: As part of the U.K. contribution to the international Surface Ocean–Lower Atmosphere Study, a series of three related projects—DOGEE, SEASAW, and HiWASE—undertook experimental studies of the processes controlling the physical exchange of gases and sea spray aerosol at the sea surface. The studies share a common goal: to reduce the high degree of uncertainty in current parameterization schemes. The wide variety of measurements made during the studies, which incorporated tracer and surfactant release experiments, included direct eddy correlation fluxes, detailed wave spectra, wind history, photographic retrievals of whitecap fraction, aerosol-size spectra and composition, surfactant concentration, and bubble populations in the ocean mixed layer. Measurements were made during three cruises in the northeast Atlantic on the RRS Discovery during 2006 and 2007; a fourth campaign has been making continuous measurements on the Norwegian weather ship Polarfront since September 2006. This paper provides an overview of the three projects and some of the highlights of the measurement campaigns.

Description: As part of the U.K. contribution to the international Surface Ocean–Lower Atmosphere Study, a series of three related projects—DOGEE, SEASAW, and HiWASE—undertook experimental studies of the processes controlling the physical exchange of gases and sea spray aerosol at the sea surface. The studies share a common goal: to reduce the high degree of uncertainty in current parameterization schemes. The wide variety of measurements made during the studies, which incorporated tracer and surfactant release experiments, included direct eddy correlation fluxes, detailed wave spectra, wind history, photographic retrievals of whitecap fraction, aerosol-size spectra and composition, surfactant concentration, and bubble populations in the ocean mixed layer. Measurements were made during three cruises in the northeast Atlantic on the RRS Discovery during 2006 and 2007; a fourth campaign has been making continuous measurements on the Norwegian weather ship Polarfront since September 2006. This paper provides an overview of the three projects and some of the highlights of the measurement campaigns.

Description: Author Posting. © American Meteorological Society, 2009. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Bulletin of the American Meteorological Society 90 (2009): ES9-ES16, doi:10.1175/2008BAMS2578.2.

Description: The Climate Absolute Radiance and Refractivity Observatory (CLARREO) mission will provide a calibration laboratory in orbit for the purpose of accurately measuring and attributing climate change. CLARREO measurements establish new climate change benchmarks with high absolute radiometric accuracy and high statistical confidence across a wide range of essential climate variables. CLARREO's inherently high absolute accuracy will be verified and traceable on orbit to Système Internationale (SI) units. The benchmarks established by CLARREO will be critical for assessing changes in the Earth system and climate model predictive capabilities for decades into the future as society works to meet the challenge of optimizing strategies for mitigating and adapting to climate change. The CLARREO benchmarks are derived from measurements of the Earth's thermal infrared spectrum (5–50 μm), the spectrum of solar radiation reflected by the Earth and its atmosphere (320–2300 nm), and radio occultation refractivity from which accurate temperature profiles are derived. The mission has the ability to provide new spectral fingerprints of climate change, as well as to provide the first orbiting radiometer with accuracy sufficient to serve as the reference transfer standard for other space sensors, in essence serving as a “NIST [National Institute of Standards and Technology] in orbit.” CLARREO will greatly improve the accuracy and relevance of a wide range of space-borne instruments for decadal climate change. Finally, CLARREO has developed new metrics and methods for determining the accuracy requirements of climate observations for a wide range of climate variables and uncertainty sources. These methods should be useful for improving our understanding of observing requirements for most climate change observations.

Description: Ancient blue oak trees are still widespread across the foothills of the Coast Ranges, Cascades, and Sierra Nevada in California. The most extensive tracts of intact old-growth blue oak woodland appear to survive on rugged and remote terrain in the southern Coast Ranges and on the foothills west and southwest of Mt. Lassen. In the authors' sampling of old-growth stands, most blue oak appear to have recruited to the canopy in the middle to late nineteenth century. The oldest living blue oak tree sampled was over 459 years old, and several dead blue oak logs had over 500 annual rings. Precipitation sensitive tree-ring chronologies up to 700 years long have been developed from old blue oak trees and logs. Annual ring-width chronologies of blue oak are strongly correlated with cool season precipitation totals, streamflow in the major rivers of California, and the estuarine water quality of San Francisco Bay. A new network of 36 blue oak chronologies records spatial anomalies in growth that arise from latitudinal changes in the mean storm track and location of landfalling atmospheric rivers. These long, climate-sensitive blue oak chronologies have been used to reconstruct hydroclimatic history in California and will help to better understand and manage water resources. The environmental history embedded in blue oak growth chronologies may help justify efforts to conserve these authentic old-growth native woodlands.

Description: During Northern Hemisphere winters, the West Coast of North America is battered by extratropical storms. The impact of these storms is of paramount concern to California, where aging water supply and flood protection infrastructures are challenged by increased standards for urban flood protection, an unusually variable weather regime, and projections of climate change. Additionally, there are inherent conflicts between releasing water to provide flood protection and storing water to meet requirements for the water supply, water quality, hydropower generation, water temperature and flow for at-risk species, and recreation. To improve reservoir management and meet the increasing demands on water, improved forecasts of precipitation, especially during extreme events, are required. Here, the authors describe how California is addressing their most important and costliest environmental issue—water management—in part, by installing a state-of-the-art observing system to better track the area’s most severe wintertime storms.

Description: Author Posting. © American Meteorological Society 2006. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Climate 19 (2006): 2122–2143, doi:10.1175/JCLI3761.1.

Description: The Community Climate System Model version 3 (CCSM3) has recently been developed and released to the climate community. CCSM3 is a coupled climate model with components representing the atmosphere, ocean, sea ice, and land surface connected by a flux coupler. CCSM3 is designed to produce realistic simulations over a wide range of spatial resolutions, enabling inexpensive simulations lasting several millennia or detailed studies of continental-scale dynamics, variability, and climate change. This paper will show results from the configuration used for climate-change simulations with a T85 grid for the atmosphere and land and a grid with approximately 1° resolution for the ocean and sea ice. The new system incorporates several significant improvements in the physical parameterizations. The enhancements in the model physics are designed to reduce or eliminate several systematic biases in the mean climate produced by previous editions of CCSM. These include new treatments of cloud processes, aerosol radiative forcing, land–atmosphere fluxes, ocean mixed layer processes, and sea ice dynamics. There are significant improvements in the sea ice thickness, polar radiation budgets, tropical sea surface temperatures, and cloud radiative effects. CCSM3 can produce stable climate simulations of millennial duration without ad hoc adjustments to the fluxes exchanged among the component models. Nonetheless, there are still systematic biases in the ocean–atmosphere fluxes in coastal regions west of continents, the spectrum of ENSO variability, the spatial distribution of precipitation in the tropical oceans, and continental precipitation and surface air temperatures. Work is under way to extend CCSM to a more accurate and comprehensive model of the earth's climate system.

Description: We would like to acknowledge the substantial contributions to and support for the CCSM project from the National Science Foundation (NSF), the Department of Energy (DOE), the National Oceanic and Atmospheric Administration, and the National Aeronautics and Space Administration.

Description: Key Points Complete genome sequence analysis of 40 DLBCL tumors and 13 cell lines reveals novel somatic point mutations, rearrangements, and fusions. Recurrence of mutations in genes involved in B-cell homing were identified in germinal center B-cell DLBCLs.

Description: Abstract 404 To characterize the genomic events associated with distinct subtypes of AML, we used whole genome sequencing to compare 24 tumor/normal sample pairs from patients with normal karyotype (NK) M1-AML (12 cases) and t(15;17)-positive M3-AML (12 cases). All single nucleotide variants (SNVs), small insertions and deletions (indels), and cryptic structural variants (SVs) identified by whole genome sequencing (average coverage 28x) were validated using sample-specific custom Nimblegen capture arrays, followed by Illumina sequencing; an average coverage of 972 reads per somatic variant yielded 10,597 validated somatic variants (average 421/genome). Of these somatic mutations, 308 occurred in 286 unique genes; on average, 9.4 somatic mutations per genome had translational consequences. Several important themes emerged: 1) AML genomes contain a diverse range of recurrent mutations. We assessed the 286 mutated genes for recurrency in an additional 34 NK M1-AML cases and 9 M3-AML cases. We identified 51 recurrently mutated genes, including 37 that had not previously been described in AML; on average, each genome had 3 recurrently mutated genes (M1 = 3.2; M3 = 2.8, p = 0.32). 2) Many recurring mutations cluster in mutually exclusive pathways, suggesting pathophysiologic importance. The most commonly mutated genes were: FLT3 (36%), NPM1 (25%), DNMT3A (21%), IDH1 (18%), IDH2 (10%), TET2 (10%), ASXL1 (6%), NRAS (6%), TTN (6%), and WT1 (6%). In total, 3 genes (excluding PML-RARA) were mutated exclusively in M3 cases. 22 genes were found only in M1 cases (suggestive of alternative initiating mutations which occurred in methylation, signal transduction, and cohesin complex genes). 25 genes were mutated in both M1 and M3 genomes (suggestive of common progression mutations relevant for both subtypes). A single mutation in a cell growth/signaling gene occurred in 38 of 67 cases (FLT3, NRAS, RUNX1, KIT, CACNA1E, CADM2, CSMD1); these mutations were mutually exclusive of one another, and many of them occurred in genomes with PML-RARA, suggesting that they are progression mutations. We also identified a new leukemic pathway: mutations were observed in all four genes that encode members of the cohesin complex (STAG2, SMC1A, SMC3, RAD21), which is involved in mitotic checkpoints and chromatid separation. The cohesin mutations were mutually exclusive of each other, and collectively occur in 10% of non-M3 AML patients. 3) AML genomes also contain hundreds of benign “passenger” mutations. On average 412 somatic mutations per genome were translationally silent or occurred outside of annotated genes. Both M1 and M3 cases had similar total numbers of mutations per genome, similar mutation types (which favored C〉T/G〉A transitions), and a similar random distribution of variants throughout the genome (which was affected neither by coding regions nor expression levels). This is consistent with our recent observations of random “passenger” mutations in hematopoietic stem cell (HSC) clones derived from normal patients (Ley et al manuscript in preparation), and suggests that most AML-associated mutations are not pathologic, but pre-existed in the HSC at the time of initial transformation. In both studies, the total number of SNVs per genome correlated positively with the age of the patient (R2 = 0.48, p = 0.001), providing a possible explanation for the increasing incidence of AML in elderly patients. 4) NK M1 and M3 AML samples are mono- or oligo-clonal. By comparing the frequency of all somatic mutations within each sample, we could identify clusters of mutations with similar frequencies (leukemic clones) and determined that the average number of clones per genome was 1.8 (M1 = 1.5; M3 = 2.2; p = 0.04). 5) t(15;17) is resolved by a non-homologous end-joining repair pathway, since nucleotide resolution of all 12 t(15;17) breakpoints revealed inconsistent micro-homologies (0 – 7 bp). Summary: These data provide a genome-wide overview of NK and t(15;17) AML and provide important new insights into AML pathogenesis. AML genomes typically contain hundreds of random, non-genic mutations, but only a handful of recurring mutated genes that are likely to be pathogenic because they cluster in mutually exclusive pathways; specific combinations of recurring mutations, as well as rare and private mutations, shape the leukemia phenotype in an individual patient, and help to explain the clinical heterogeneity of this disease. Disclosures: Westervelt: Novartis: Speakers Bureau.

Description: Abstract 99 Whole genome sequencing with next generation technologies represents a new, unbiased approach for discovering somatic variations in cancer genomes. Our group recently reported the DNA sequence and analysis of the genomes of two patients with normal karyotype acute myeloid leukemia (AML). Improvements in next generation sequencing technologies (principally, paired-end sequencing) led us to reevaluate the first case (Ley et al, Nature 456:66–72, 2008) with deeper sequence coverage. We discovered a novel frameshift mutation in DNMT3A, one of the three genes in humans (DNMT1, DNMT3A, and DNMT3B) that encodes a DNA methyltransferase that catalyzes the addition of methyl groups to cytosine within CpG dinucleotides. We then sequenced all the coding exons of this gene in 280 additional de novo cases of AML to define recurring mutations. 62/281 de novo AML cases (22%) had mutations with translational effects in the DNMT3A gene. 18 different missense mutations were identified, the most common of which was at amino acid R882 (37 cases). Frameshifts (n=6), nonsense mutations (n=6), splice site mutations (n=3), and a 1.5 Mbp deletion that included the DNMT3A gene were also identified. DNMT3A mutations were highly enriched in cases with intermediate risk cytogenetics (56/166=33.7%; p

Description: Background: Therapy for patients (pts) with high risk and/or relapsed or refractory AML remains unsatisfactory. Retrospective studies have demonstrated activity of fludarabine, cytarabine, granulocyte colony stimulating factor and idarubicin (FLAG-IDA) as salvage therapy in pts with relapsed or refractory AML. Furthermore, a recent randomized trial has indicated high complete remission (CR) rates with improved relapsed-free survival when FLAG-IDA is administered as frontline induction chemotherapy (Burnett et al. J Clin Oncol 2013). Therefore, since January 2011, we have employed FLAG-IDA as first line therapy in pts with high risk AML (i.e. poor risk cytogenetics, antecedent myeloproliferative neoplasm or myelodysplastic syndrome, or therapy-related AML), or as first salvage in pts with primary refractory or relapsed AML, in an attempt to improve CR rates and permit more patients with AML to advance to allogeneic hematopoietic stem cell transplantation (alloSCT). Methods: A retrospective review was conducted of the 62 consecutive patients with high risk AML or primary refractory or relapsed AML treated with FLAG-IDA between January 2011 to December 2013 at the Princess Margaret Cancer Centre to determine the CR rate and overall survival (OS) associated with FLAG-IDA remission induction chemotherapy. Results: Baseline characteristics of the patients are listed in Table 1. Fourteen pts received FLAG-IDA as first induction, whereas 48 pts received FLAG-IDA as salvage (39 as first salvage and 9 as second salvage). The overall CR rate (i.e. CR + CR with incomplete platelet recovery [CRi]) using FLAG-IDA as frontline therapy was assessed in 13 patients, as one pt died during induction therapy and therefore, was not evaluable. Of the 13 evaluable patients, all achieved CR or CRi. The overall CR rate for the salvage induction group was 73% (i.e. 31% CR and 42% CRi). The CR duration was censored at time of transplant. The CR duration for pts receiving FLAG-IDA as first induction was 3 mos (range, 0-15 mos). For pts receiving FLAG-IDA as salvage therapy, the CR1 duration for primary refractory AML pts was 6 mos (range, 2-58 mos) and CR2 duration for relapsed AML pts was 4 mos (range, 1-12 mos). 76% of patients (n=10) who received frontline FLAG-IDA induction chemotherapy, and achieved CR/CRi, had a donor identified, but only 40% of those pts underwent alloSCT. 85% of pts (n=30) who received salvage FLAG-IDA, and achieved CR/CRi, had a donor identified, but only 53% of those pts proceeded to alloSCT. The length of hospital stay during the first FLAG-IDA induction was 33 days (range, 17-96 days), whereas the length of hospital stay for salvage FLAG-IDA induction was 43 days (range, 10-305 days). Fourteen percent of pts in the first induction group were admitted to the ICU during their induction, compared to 17% of pts in the salvage induction group. The median ICU stay was 39.5 days and 14 days, respectively. There was a 14% death rate during FLAG-IDA induction for both groups. The median follow up time from diagnosis for both groups was 15.28 mos (range, 2-70.4 mos). Overall survival at 1 and 2 years in the upfront FLAG-IDA induction group was 65% and 41%, respectively, while OS at 1 and 2 years for the salvage FLAG-IDA group was 60% and 35%, respectively. Conclusions: The toxicities associated with FLAG-IDA induction, including induction death rates and ICU admission rates, are acceptable and similar in the untreated and heavily pre-treated groups. FLAG-IDA induction can result in durable CR rates, permitting patients with high risk AML or patients with primary refractory or relapsed AML to proceed to allogeneic transplantation. Table 1: Patient Characteristics Front-LineN=14 SalvageN=48 Median age, y (range) ≥70y (%) ≥60y (%) 65.5 (21-76) 2 (14%) 10 (71%) 50 (18-76) 2 (4%) 10 (21%) Gender 7M : 7F 22M : 26F Secondary/Therapy-related Prior MDS Prior MPN 14 (100%) 2 (14%) 2 (14%) 17 (35%) 8 (17%) 2 (4%) Cytogenetic risk group Good Intermediate Poor 0 4 (28%) 10 (71%) 3 (6%) 28 (58%) 17 (35%) Molecular abnormalities cKit mutated FLT3-ITD mutated 0 1 (7%) 2 (4%) 5 (10%) Median no. prior treatment regimens (range) 0 1 (1-2) Prior chemotherapy regimen Daunorubicin + cytarabine NOVE-HiDAc Other NA NA NA 43 (90%) 11 (23%) 3 (6%) Disease status Primary refractory Relapsed CR1 duration