Accurate estimation of homologue-specific DNA concentration-ratios in cancer samples allows long-range haplotyping

Interpretation of allelic copy measurements at polymorphic markers in cancer samples presents distinctive challenges and opportunities. Due to frequent gross chromosomal alterations occurring in cancer (aneuploidy), many genomic regions are present at homologous-allele imbalance. Within such regions, the unequal contribution of alleles at heterozygous markers allows for direct phasing of the haplotype derived from each individual parent. In addition, genome-wide estimates of homologue specific copy- ratios (HSCRs) are important for interpretation of the cancer genome in terms of fixed integral copy-numbers. We describe HAPSEG, a probabilistic method to interpret bi- allelic marker data in cancer samples. HAPSEG operates by partitioning the genome into segments of distinct copy number and modeling the four distinct genotypes in each segment. We describe general methods for fitting these models to data which are suit- able for both SNP microarrays and massively parallel sequencing data. In addition, we demonstrate a specially tailored error-model for interpretation of systematic variations arising in microarray platforms. The ability to directly determine haplotypes from cancer samples represents an opportunity to expand reference panels of phased chromosomes, which may have general interest in various population genetic applications. In addition, this property may be exploited to interrogate the relationship between germline risk and cancer phenotype with greater sensitivity than is possible using unphased genotype. Finally, we exploit the statistical dependency of phased genotypes to enable the fitting of more elaborate sample-level error-model parameters, allowing more accurate estimation of HSCRs in cancer samples

Diabetic retinopathy developing in two cases on tolbutamide therapy

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Subtype-specific genomic alterations define new targets for soft tissue sarcoma therapy

2011 February 1Soft-tissue sarcomas, which result in approximately 10,700 diagnoses and 3,800 deaths per year in the United States1, show remarkable histologic diversity, with more than 50 recognized subtypes2. However, knowledge of their genomic alterations is limited. We describe an integrative analysis of DNA sequence, copy number and mRNA expression in 207 samples encompassing seven major subtypes. Frequently mutated genes included TP53 (17% of pleomorphic liposarcomas), NF1 (10.5% of myxofibrosarcomas and 8% of pleomorphic liposarcomas) and PIK3CA (18% of myxoid/round-cell liposarcomas, or MRCs). PIK3CA mutations in MRCs were associated with Akt activation and poor clinical outcomes. In myxofibrosarcomas and pleomorphic liposarcomas, we found both point mutations and genomic deletions affecting the tumor suppressor NF1. Finally, we found that short hairpin RNA (shRNA)-based knockdown of several genes amplified in dedifferentiated liposarcoma, including CDK4 and YEATS4, decreased cell proliferation. Our study yields a detailed map of molecular alterations across diverse sarcoma subtypes and suggests potential subtype-specific targets for therapy.Memorial Sloan-Kettering Cancer Center (Soft Tissue Sarcoma Program Project P01 CA047179

Tidal Flushing Restores the Physiological Condition of Fish Residing in Degraded Salt Marshes

Roads, bridges, and dikes constructed across salt marshes can restrict tidal flow, degrade habitat quality for nekton, and facilitate invasion by non-native plants including Phragmites australis. Introduced P. australis contributes to marsh accretion and eliminates marsh surface pools thereby adversely affecting fish by reducing access to intertidal habitats essential for feeding, reproduction, and refuge. Our study assessed the condition of resident fish populations (Fundulus heteroclitus) at four tidally restricted and four tidally restored marshes in New England invaded by P. australis relative to adjacent reference salt marshes. We used physiological and morphological indicators of fish condition, including proximate body composition (% lipid, % lean dry, % water), recent daily growth rate, age class distributions, parasite prevalence, female gravidity status, length-weight regressions, and a common morphological indicator (Fulton’s K) to assess impacts to fish health. We detected a significant increase in the quantity of parasites infecting fish in tidally restricted marshes but not in those where tidal flow was restored to reduce P. australis cover. Using fish length as a covariate, we found that unparasitized, non-gravid F. heteroclitus in tidally restricted marshes had significantly reduced lipid reserves and increased lean dry (structural) mass relative to fish residing in reference marshes. Fish in tidally restored marshes were equivalent across all metrics relative to those in reference marshes indicating that habitat quality was restored via increased tidal flushing. Reference marshes adjacent to tidally restored sites contained the highest abundance of young fish (ages 0–1) while tidally restricted marshes contained the lowest. Results indicate that F. heteroclitus residing in physically and hydrologically altered marshes are at a disadvantage relative to fish in reference marshes but the effects can be reversed through ecological restoration

The polar expression of ENSO and sea-ice variability as recorded in a South Pole ice core

An annually dated ice core recovered from South Pole (2850 m a.s.l.) in 1995, that covers the period 1487–1992, was analyzed for the marine biogenic sulfur species methanesulfonate (MS). Empirical orthogonal function analysis is used to calibrate the high-resolution MS series with associated environmental series for the period of overlap (1973–92). Utilizing this calibration we present a ~500 year long proxy record of the polar expression of the El Niño–Southern Oscillation (ENSO) and southeastern Pacific sea-ice extent variations. These records reveal short-term periods of increased (1800–50, 1900–40) and decreased sea-ice extent (1550–1610, 1660–1710, 1760–1800). In general, increased (decreased) sea-ice extent is associated with a higher (lower) frequency of El Niño events

Ecology of Phragmites australis and responses to tidal restoration

Tidal Marsh Restoration provides the scientific foundation and practical guidance necessary for coastal zone stewards to initiate salt marsh tidal restoration programs. The book compiles, synthesizes, and interprets the current state of knowledge on the science and practice of salt marsh restoration, bringing together leaders across a range of disciplines in the sciences (hydrology, soils, vegetation, zoology), engineering (hydraulics, modeling), and public policy, with coastal managers who offer an abundance of practical insight and guidance on the development of programs. The book is an essential work for managers, planners, regulators, environmental and engineering consultants, and others engaged in planning, designing, and implementing projects or programs aimed at restoring tidal flow to tide-restricted or diked salt marshes.https://scholarworks.wm.edu/asbookchapters/1065/thumbnail.jp

Online optimization with switching cost

We consider algorithms for "smoothed online convex optimization (SOCO)" problems. SOCO is a variant of the class of "online convex optimization (OCO)" problems that is strongly related to the class of "metrical task systems", each of which have been studied extensively. Prior literature on these problems has focused on two performance metrics: regret and competitive ratio. There exist known algorithms with sublinear regret and known algorithms with constant competitive ratios; however no known algorithms achieve both. In this paper, we show that this is due to a fundamental incompatibility between regret and the competitive ratio -- no algorithm (deterministic or randomized) can achieve sublinear regret and a constant competitive ratio, even in the case when the objective functions are linear

Short-Term Relapse Quantitation as a Fully Surrogate Endpoint for Long-Term Sustained Progression of Disability in RRMS Patients Treated with Natalizumab

Time to sustained worsening in the expanded disability status scale as the standard for evaluating the accumulation of disability has been used as a measure of clinical efficacy in many relapsing-remitting multiple sclerosis (RRMS) clinical trials. However, this measurement usually requires a large sample and long-term study to demonstrate the treatment effect. Annualized relapse rate or time to first relapse is also widely used as alternative measurements of clinical efficacy. A formal statistical validation of short-term relapse activity as a surrogate endpoint for long-term sustained progression of disability could potentially permit smaller, shorter, and less expensive clinical trials in RRMS. Four statistical validation/evaluation approaches consistently showed that relapse activity through one year of treatment serves as statistically valid surrogate endpoint for time to sustained progression of disability. The analysis demonstrates that long-term sustained progression of disability can be predicted by short-term relapse measures with 4 consistent validations of statistical approaches, including a formal statistical hypothesis test. This was demonstrated in a large phase III trial of natalizumab and showed that the beneficial clinical effect of natalizumab on sustained progression of disability at 2 years in patients with RRMS can be predicted by the total number of relapses at 1 year

Phenotopic Plasticity of Leaf Shape Along a Temperature Gradient in \u3cem\u3eAcer Rubrum\u3c/em\u3e

Both phenotypic plasticity and genetic determination can be important for understanding how plants respond to environmental change. However, little is known about the plastic response of leaf teeth and leaf dissection to temperature. This gap is critical because these leaf traits are commonly used to reconstruct paleoclimate from fossils, and such studies tacitly assume that traits measured from fossils reflect the environment at the time of their deposition, even during periods of rapid climate change. We measured leaf size and shape in Acer rubrum derived from four seed sources with a broad temperature range and grown for two years in two gardens with contrasting climates (Rhode Island and Florida). Leaves in the Rhode Island garden have more teeth and are more highly dissected than leaves in Florida from the same seed source. Plasticity in these variables accounts for at least 6–19 % of the total variance, while genetic differences among ecotypes probably account for at most 69–87 %. This study highlights the role of phenotypic plasticity in leaf-climate relationships. We suggest that variables related to tooth count and leaf dissection in A. rubrum can respond quickly to climate change, which increases confidence in paleoclimate methods that use these variables

Somatic retrotransposition in human cancer revealed by whole-genome and exome sequencing

Retrotransposons constitute a major source of genetic variation, and somatic retrotransposon insertions have been reported in cancer. Here, we applied TranspoSeq, a computational framework that identifies retrotransposon insertions from sequencing data, to whole genomes from 200 tumor/normal pairs across 11 tumor types as part of The Cancer Genome Atlas (TCGA) Pan-Cancer Project. In addition to novel germline polymorphisms, we find 810 somatic retrotransposon insertions primarily in lung squamous, head and neck, colorectal, and endometrial carcinomas. Many somatic retrotransposon insertions occur in known cancer genes. We find that high somatic retrotransposition rates in tumors are associated with high rates of genomic rearrangement and somatic mutation. Finally, we developed TranspoSeq-Exome to interrogate an additional 767 tumor samples with hybrid-capture exome data and discovered 35 novel somatic retrotransposon insertions into exonic regions, including an insertion into an exon of the PTEN tumor suppressor gene. The results of this large-scale, comprehensive analysis of retrotransposon movement across tumor types suggest that somatic retrotransposon insertions may represent an important class of structural variation in cancer.National Cancer Institute (U.S.) (grant U24CA143867)National Cancer Institute (U.S.) (grant U24CA126546