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Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract with around 5000 new cases per year. Outcomes for patients with GIST dramatically improved after the development of tyrosine kinase inhibitors targeted against the aberrant signaling pathways that drive GIST oncogenesis. Majority of patients derive benefit from first-line imatinib, and the type of driver mutation is predictive of response. However, almost half of the patients eventually develop resistance to initial targeted therapy and further lines of treatment do not have the same impact. Regorafenib is an oral multi-kinase inhibitor approved as a third-line therapy for advanced GIST and though its efficacy is limited in comparison to imatinib, it has activity across the various driver mutation categories in GIST even in the setting of imatinib resistance. Herein, we describe a case of central retinal vein occlusion (CRVO) secondary to regorafenib and review regorafenib's efficacy and toxicity profile.

Fibrates are commonly prescribed for hypertriglyceridemia, but they also lower LDL cholesterol and increase HDL cholesterol. Large interindividual variations in lipid response suggest that some patients may benefit more than others and genetic studies could help identify such patients.We carried out the first genome-wide association study of lipid response to fenofibrate using data from two well-characterized clinical trials: the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) Study and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Study. Genome-wide association study data from both studies were imputed to the 1000 Genomes CEU reference panel (phase 1). Lipid response was modeled as the log ratio of the post-treatment lipid level to the pretreatment level. Linear mixed models (GOLDN, N=813 from 173 families) and linear regression models (ACCORD, N=781) adjusted for pretreatment lipid level, demographic variables, clinical covariates, and ancestry were used to evaluate the association of genetic markers with lipid response. Among Caucasians, the results were combined using inverse-variance weighted fixed-effects meta-analyses. The main findings from the meta-analyses were examined in other ethnic groups from the HyperTG study (N=267 Hispanics) and ACCORD (N=83 Hispanics, 138 African Americans).A known lipid locus harboring the pre-B-cell leukemia homeobox 4 (PBX4) gene on chromosome 19 is important for LDL cholesterol response to fenofibrate (smallest P=1.5×10). The main results replicated with nominal statistical significance in Hispanics from ACCORD (P0.05).Future research should evaluate the usefulness of this locus to refine clinical strategies for lipid-lowering treatments.

Signaling from the human hematopoietic stem cell (HSC) niche formed by osteoblastic cells regulates hematopoiesis. We previously found that retinoic acid receptor alpha (RARα), a transcription factor activated by retinoic acid (RA), mediates both granulocytic and osteoblastic differentiation. This effect depends on decreased phosphorylation of serine 77 of RARα (RARαS77) by the cyclin-dependent kinase-activating kinase (CAK) complex, a key cell-cycle regulator. In this article, we report that, by suppressing CAK phosphorylation of RARα, RA induces FGF8f to mediate osteosarcoma U2OS cell differentiation in an autocrine manner. By contrast, paracrine FGF8f secreted into osteoblast-conditioned medium by U2OS cells transduced with FGF8f or a phosphorylation-defective RARαS77 mutant, RARαS77A, bypasses RA stimuli to cross-mediate granulocytic differentiation of different types of human leukemic myeloblasts and normal primitive hematopoietic CD34+ cells, possibly through modulating mitogen-activated protein kinase (MAPK) pathways. Further experiments using recombinant human FGF8f (rFGF8f) stimuli, antibody neutralization, and peptide blocking showed that paracrine FGF8f is required for mediating terminal leukemic myeloblast differentiation. These studies indicate a novel regulatory mechanism of granulocytic differentiation instigated by RA from the HSC niche, which links loss of CAK phosphorylation of RARα with paracrine FGF8f-mediated MAPK signaling to mediate leukemic myeloblast differentiation in the absence of RA. Therefore, these findings provide a compelling molecular rationale for further investigation of paracrine FGF8f regulation, with the intent of devising HSC niche-based FGF8f therapeutics for myeloid leukemia, with or without RA-resistance. Mol Cancer Ther; 11(2); 267–76. ©2011 AACR.

We present a novel synthesis in which hemoglobin and Fe(2+) react, in the presence of KNO3 and KOH, to produce protein microgels that contain magnetic iron oxide nanoparticles. The synthesis results in microgels with polymer properties (denaturing and glass transition temperatures) that are consistent with the dried protein. The iron oxide nanoparticles that exhibit an average diameter of 22nm, are ferrimagnetic, and display properties consistent with Fe3O4. The multiple functional capabilities displayed by these materials: biocompatibility, magnetism, dye uptake and controlled release, and other properties archetypal of hydrogels, will make the magnetic hydrogels attractive for a number of biomedical applications.

Aims: Individualization of cancer chemotherapy based on the patient’s genetic makeup holds promise for reducing side effects and improving efficacy. However, the relative contribution of genetics to drug response is unknown. Materials & methods: In this study, we investigated the cytotoxic effect of 29 commonly prescribed chemotherapeutic agents from diverse drug classes on 125 lymphoblastoid cell lines derived from 14 extended families. Results: The results of this systematic study highlight the variable role that genetics plays in response to cytotoxic drugs, ranging from a heritability of 0.60 for epirubicin. Conclusion: Putative quantitative trait loci for cytotoxic response were identified, as well as drug class-specific signatures, which could indicate possible shared genetic mechanisms. In addition to the identification of putative quantitative trait locis, the results of this study inform the prioritization of chemotherapeutic drugs with a sizable genetic response component for future investigation. Original submitted 6 April 2011; Revision submitted 1 July 2011

Warfarin-dosing algorithms incorporating CYP2C9 and VKORC1 −1639G>A improve dose prediction compared with algorithms based solely on clinical and demographic factors. However, these algorithms better capture dose variability among whites than Asians or blacks. Herein, we evaluate whether other VKORC1 polymorphisms and haplotypes explain additional variation in warfarin dose beyond that explained by VKORC1 −1639G>A among Asians (n = 1103), blacks (n = 670), and whites (n = 3113). Participants were recruited from 11 countries as part of the International Warfarin Pharmacogenetics Consortium effort. Evaluation of the effects of individual VKORC1 single nucleotide polymorphisms (SNPs) and haplotypes on warfarin dose used both univariate and multi variable linear regression. VKORC1 −1639G>A and 1173C>T individually explained the greatest variance in dose in all 3 racial groups. Incorporation of additional VKORC1 SNPs or haplotypes did not further improve dose prediction. VKORC1 explained greater variability in dose among whites than blacks and Asians. Differences in the percentage of variance in dose explained by VKORC1 across race were largely accounted for by the frequency of the −1639A (or 1173T) allele. Thus, clinicians should recognize that, although at a population level, the contribution of VKORC1 toward dose requirements is higher in whites than in nonwhites; genotype predicts similar dose requirements across racial groups.

Warfarin is one of the most widely used anticoagulants in the world. Treatment is complicated by a large inter-individual variation in the dose needed to reach adequate levels of anticoagulation i.e. INR 2.0 – 3.0. The objective of this thesis was to evaluate which factors, mainly genetic but also non-genetic, that affect the response to warfarin in terms of required maintenance dose, efficacy and safety with special focus on warfarin dose prediction.Through candidate gene and genome-wide studies, we have shown that the genes CYP2C9 and VKORC1 are the major determinants of warfarin maintenance dose. By combining the SNPs CYP2C9 *2, CYP2C9 *3 and VKORC1 rs9923231 with the clinical factors age, height, weight, ethnicity, amiodarone and use of inducers (carbamazepine, phenytoin or rifampicin) into a prediction model (the IWPC model) we can explain 43 % to 51 % of the variation in warfarin maintenance dose. Patients requiring doses < 29 mg/week and doses ≥ 49 mg/week benefitted the most from pharmacogenetic dosing. Further, we have shown that the difference across ethnicities in percent variance explained by VKORC1 was largely accounted for by the allele frequency of rs9923231. Other novel genes affecting maintenance dose (NEDD4 and DDHD1), as well as the replicated CYP4F2 gene, have small effects on dose predictions and are not likely to be cost-effective, unless inexpensive genotyping is available.Three types of prediction models for warfarin dosing exist: maintenance dose models, loading dose models and dose revision models. The combination of these three models is currently being used in the warfarin treatment arm of the European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) study. Other clinical trials aiming to prove the clinical validity and utility of pharmacogenetic dosing are also underway.The future of pharmacogenetic warfarin dosing relies on results from these ongoing studies, the availability of inexpensive genotyping and the cost-effectiveness of pharmacogenetic driven warfarin dosing compared with new oral anticoagulant drugs.

Co30Fe70 nanocrystallites have been synthesized by alkalide co-reduction of Co2+ and Fe3+. As produced, the material consists of highly pyrophoric 4.0 nm nanocrystals with a narrow ( of ∼20 K prior to removal of the by-products in which they are embedded. Removal of the by-products allows magnetic interactions between the particles with a consequent increase in the transition temperature to greater than 300 K. Annealing at temperatures higher than 300 °C under vacuum resulted in agglomeration and particle growth; annealing above 500 °C resulted in a change in the shape of the particles to largely rectangular prisms with little further growth above 700 °C. Ms increased with increasing annealing temperature reaching values as large as ∼89% of the bulk value (245 emu/g) after annealing at 700 °C while retaining low Mr and Hc. While rapid exposure of the Co30Fe70 nanocrystallites to air resulted in spontaneous combustion, gradual, slow exposure over a period of one week resulted in the formation of a thin surface coating of CoFe2O4, or air stable “core-shell” alloy–oxide nanocrystallites.

Cette recherche en geographie historique, en Guyane Britannique au dix-neuvieme siecle, etudie les raisons qui ont amene un groupe d' immigrants Portugais de Madere a dominer le commerce au detail a la fin de l' esclavage. Un recours a la theorie d' une societe pluraliste nous indique la marche a suivre pour expliquer le ‘pourquoi’ de cette domination. Certains indices orienterent notre recherche. Nous nous sommes demandes ‘pour qui’ cette societe pluraliste etait-elle si necessaire et qui d'autres, en plus de Portugais, beneficiaient de ce controle du commerce au detail. Nous avons la preuve evidente que les Portugais avaient recu l'appui de l'elite europiene, d'autre part les planteurs avaient tout interet a garder les Noirs comme ouvriers sur leurs plantations, les privant ainsi de leurs droits. Une importante immigration de main-d'euvre indienne engagee sous contract et l'appui des planteurs permit a l'elite de maintenir son controle de la colonie en etablissant et en perpetuant les divisions ethniques sur les plans economique, social et geographique. The central questions of this research on the historical geography of nineteenth-century British Guiana are how and why an immigrant group from Madeira (the Portuguese) came to dominate the post-emancipation retail trade of the colony. A recourse to plural-society theory suggested where one should inquire. By asking for ‘whom’ the creation of a plural society was so necessary; and ‘who’ else, besides the Portuguese, benefited from Portuguese control of the retail trade, one received sufficient clues and direction to know where to look. Evidence was uncovered which established that the Portuguese initially received help from the European elite. This support and substantial indentured immigration from India enabled the elite to maintain its control of the colony by establishing and perpetuating ethnic divisions in the colony's economy, society, and geography.

Little is known for certain about the genetics of schizophrenia. The advent of genomewide association has been widely anticipated as a promising means to identify reproducible DNA sequence variation associated with this important and debilitating disorder. A total of 738 cases with DSM-IV schizophrenia (all participants in the CATIE study) and 733 group-matched controls were genotyped for 492,900 single-nucleotide polymorphisms (SNPs) using the Affymetrix 500K two-chip genotyping platform plus a custom 164K fill-in chip. Following multiple quality control steps for both subjects and SNPs, logistic regression analyses were used to assess the evidence for association of all SNPs with schizophrenia. We identified a number of promising SNPs for follow-up studies, although no SNP or multimarker combination of SNPs achieved genomewide statistical significance. Although a few signals coincided with genomic regions previously implicated in schizophrenia, chance could not be excluded. These data do not provide evidence for the involvement of any genomic region with schizophrenia detectable with moderate sample size. However, a planned genomewide association study for response phenotypes and inclusion of individual phenotype and genotype data from this study in meta-analyses hold promise for eventual identification of susceptibility and protective variants.

The Great Lakes Fishery Commission (GLFC) considers the application of sea lamprey pheromones a promising alternative-control method for its sea lamprey management program. Several components of two pheromones that regulate migration and reproduction, respectively, have been identified and synthesized. Potential utility of these pheromone compounds in lamprey management have been demonstrated in a series of field experiments. These discoveries have laid a solid foundation for development of pheromone-based management. In order to identify potential strategies that will be practical, effective, and economical, we propose a hypothesis driven approach that integrates concepts and experimental methods from several disciplines of biological science, such as neurobiology, biochemistry, and behavioral ecology to illustrate the exact function of identified compounds. In the interim, we identify the necessary steps, or issues critical to eventual implementation, to charter a pathway that leads from laboratory research to effective deployment of pheromones. Finally, we highlight a strategy that fosters collaboration among scientists across disciplines, as well as among research institutes and lamprey control agencies, to accomplish this research agenda.

Regardless of the extremely subtle acoustic changes that are perceptible within almost all perception research studies, it is the total overall effect that generally occupies each individual listener. A long line of research indicates that many subtle `music changes' are often not perceived accurately and are actually mistakenly identified. Another line of research indicates that almost everyone is capable of discriminating extremely small acoustic alterations if directed to do so. This study investigated spliced versions of Johann Strauss's Blue Danube Waltz all performed by the Vienna Philharmonic Orchestra with five different conductors demonstrating a wide range of conducting styles recorded across an 18-year period. Four groups of musicians ( N = 108) participated in the study: (1) video-only; (2) audio-video combination; (3) audio-only with verbal cues asking whether there were different conductors, ensembles, or compositions; and (4) audio-only without cues. Results indicated that while several of the audio-only with cues participants indicated differences in conductors, none in the non-cued group did. Not one of the music major participants in the two audio-only groups correctly identified that the stimulus had five different conductors.

Cysteinyl leukotrienes (CYSLTR) are potent biological mediators in the pathophysiology of asthma for which two receptors have been characterized, CYSLTR1 and CYSLTR2. The leukotriene modifying agents currently used to control bronchoconstriction and inflammation in asthmatic patients are CYSLTR1-specific leukotriene receptor antagonists. In this report, we investigated a possible role for therapeutic modulation of CYSLTR2 in asthma by investigating genetic association with asthma and further characterization of the pharmacology of a coding polymorphism.The association of CYSLTR2 polymorphisms with asthma was assessed by transmission disequilibrium test in two family-based collections (359 families from Denmark and Minnesota, USA and 384 families from the Genetics of Asthma International Network).A significant association of the coding polymorphism, 601AG, with asthma was observed (P = 0.003). We replicated these findings in a collection of 384 families from the Genetics of Asthma International Network (P = 0.04). The G allele is significantly under-transmitted to asthmatics, indicating a possible role for this receptor in resistance to asthma. The potency of cysteinyl leukotrienes at the wild-type CYSLTR2 and the coding polymorphism 601AG were assessed using a calcium mobilization assay. The potency of LTC4 and LTE4 was similar for both forms of the receptor and LTB4 was inactive, however, LTD4 was approximately five-fold less potent on 601AG compared to wild-type CYSLTR2.Since 601AG alters the potency of LTD4 and this variant allele may be associated with resistance to asthma, it is possible that modulation of the CYSLTR2 may be useful in asthma pharmacotherapy.

Recent advances in technologies for high-throughout single-nucleotide polymorphism (SNP)–based genotyping have improved efficiency and cost so that it is now becoming reasonable to consider the use of SNPs for genomewide linkage analysis. However, a suitable screening set of SNPs and a corresponding linkage map have yet to be described. The SNP maps described here fill this void and provide a resource for fast genome scanning for disease genes. We have evaluated 6,297 SNPs in a diversity panel composed of European Americans, African Americans, and Asians. The markers were assessed for assay robustness, suitable allele frequencies, and informativeness of multi-SNP clusters. Individuals from 56 Centre d'Etude du Polymorphisme Humain pedigrees, with >770 potentially informative meioses altogether, were genotyped with a subset of 2,988 SNPs, for map construction. Extensive genotyping-error analysis was performed, and the resulting SNP linkage map has an average map resolution of 3.9 cM, with map positions containing either a single SNP or several tightly linked SNPs. The order of markers on this map compares favorably with several other linkage and physical maps. We compared map distances between the SNP linkage map and the interpolated SNP linkage map constructed by the deCode Genetics group. We also evaluated cM/Mb distance ratios in females and males, along each chromosome, showing broadly defined regions of increased and decreased rates of recombination. Evaluations indicate that this SNP screening set is more informative than the Marshfield Clinic’s commonly used microsatellite-based screening set.

The genotyping of closely spaced single-nucleotide polymorphism (SNP) markers frequently yields highly correlated data, owing to extensive linkage disequilibrium (LD) between markers. The extent of LD varies widely across the genome and drives the number of frequent haplotypes observed in small regions. Several studies have illustrated the possibility that LD or haplotype data could be used to select a subset of SNPs that optimize the information retained in a genomic region while reducing the genotyping effort and simplifying the analysis. We propose a method based on the spectral decomposition of the matrices of pairwise LD between markers, and we select markers on the basis of their contributions to the total genetic variation. We also modify Clayton’s “haplotype tagging SNP” selection method, which utilizes haplotype information. For both methods, we propose sliding window–based algorithms that allow the methods to be applied to large chromosomal regions. Our procedures require genotype information about a small number of individuals for an initial set of SNPs and selection of an optimum subset of SNPs that could be efficiently genotyped on larger numbers of samples while retaining most of the genetic variation in samples. We identify suitable parameter combinations for the procedures, and we show that a sample size of 50–100 individuals achieves consistent results in studies of simulated data sets in linkage equilibrium and LD. When applied to experimental data sets, both procedures were similarly effective at reducing the genotyping requirement while maintaining the genetic information content throughout the regions. We also show that haplotype-association results that Hosking et al. obtained near CYP2D6 were almost identical before and after marker selection.

Dy nanoparticles have been produced at subambient temperature by alkalide reduction. In the bulk, Dy is ferromagnetic below 89 K. In contrast, the nanoparticles’ magnetization is blocked below ∼9 and ∼20 K for unheated and samples annealed at 1000 °C for 4 h, respectively. This behavior is consistent with a reduction in Tc due to finite size effects. Magnetization is linearly dependent on field at temperatures higher than ∼6 times TB and shows remanence-free hysteresis at lower temperature. Magnetic entropy curves generated from magnetization data are consistent with that expected for a paramagnet, yielding large values at low temperature due to the high effective moment of Dy.

We conducted a genome scan using a 10-cM map to search for genes linked to type 2 diabetes in 691 individuals from a founder population, the Old Order Amish. We then saturated two regions on chromosomes 1 and 14 showing promising linkage signals with additional markers to produce a ∼2-cM map for fine mapping. Analyses of both discrete traits (type 2 diabetes and the composite trait of type 2 diabetes and/or impaired glucose homeostasis [IGH]), and quantitative traits (glucose levels during a 75-g oral glucose challenge, designated glucose 0–180 and HbA1c) were performed. We obtained significant evidence for linkage to type 2 diabetes in a novel region on chromosome 14q11 (logarithm of odds [LOD] for diabetes = 3.48, P = 0.00005). Furthermore, we observed evidence for the existence of a diabetes-related locus on chromosome 1q21-q24 (LOD for type 2 diabetes/IGH = 2.35, P = 0.0008), a region shown to be linked to diabetes in several other studies. Suggestive evidence for linkage to glucose traits was observed on three other regions: 14q11-q13 (telomeric to that above with LOD = 1.82–1.85 for glucose 150 and 180), 1p31 (LOD = 1.28–2.30 for type 2 diabetes and glucose 120–180), and 18p (LOD = 3.07, P = 0.000085 for HbA1c and LOD = 1.50 for glucose 0). In conclusion, our findings provide evidence that type 2 diabetes susceptibility genes reside on chromosomes 1, 14, and 18.

(Y0.95Eu0.05)2O3 nanoparticles have been synthesized by subambient homogeneous reduction using alkalide solutions and subsequent oxidation. As synthesized, the material consists of free-flowing agg...

Single-crystal conductivity measurements of the electride K+(cryptand[2.2.2])e- show pronounced anisotropy. Conductivity of the sheetlike crystals is 10−30 times greater in the “easy” than in the “hard” in-plane direction and 105−106 times greater than that perpendicular to the plane. The magnetic susceptibility is well-described by the alternating linear chain Heisenberg antiferromagnetic model. Both phenomena are consistent with the structure, which has very open pseudo-1D channels that connect large dumbbell-shaped two-electron cavities to form a chain of coupled electron spins. Slightly smaller channels interconnect these chains to form a 2D network of channels and cavities. The proposed conductivity mechanism is the random 2D hopping of hole defects that are highly mobile down the open 1D chain. They undergo activated transport to adjacent chains as a result of defect sites (such as K-) in the primary chain.

Fe3C, VC, TaC, and TiC nanocrystals have been synthesized by subambient alkalide reduction. The initial products in all cases appear to be either amorphous or sub-nanocrystalline. Annealing between 950 and 1200 °C, depending on the compound, resulted in nanocrystalline materials. Surface areas, measured by the BET method, range between 66 and 164 m2/g and crystallite sizes between ∼2 and 25 nm.

There have been increasing efforts to relate drug efficacy and disease predisposition with genetic polymorphisms. We present statistical tests for association of haplotype frequencies with discrete and continuous traits in samples of unrelated individuals. Haplotype frequencies are estimated through the expectation-maximization algorithm, and each individual in the sample is expanded into all possible haplotype configurations with corresponding probabilities, conditional on their genotype. A regression-based approach is then used to relate inferred haplotype probabilities to the response. The relationship of this technique to commonly used approaches developed for case-control data is discussed. We confirm the proper size of the test under H₀ and find an increase in power under the alternative by comparing test results using inferred haplotypes with single-marker tests using simulated data. More importantly, analysis of real data comprised of a dense map of single nucleotide polymorphisms spaced along a 12-cM chromosomal region allows us to confirm the utility of the haplotype approach as well as the validity and usefulness of the proposed statistical technique. The method appears to be successful in relating data from multiple, correlated markers to response.

Graphite is classified as a strategic and critical mineral by the US and EU. The worldwide market for graphite was ~ $15 billion in 2016. It is used in numerous industries including metallurgy, refractories and dominates the market for active materials in Li-ion battery anodes. Both natural and synthetic graphites are used for Li-ion anodes. Natural graphite is mined but requires large-scale beneficiation and purification with HF, HCl and H2SO4, with a large environmental impact to water, land and air. In addition, attaining the purity levels required for Li-ion application results in as much as ~70% material loss. The production of synthetic graphite is a very long and extremely energy intensive process (heating at ~ 3000 ˚C for weeks) and results in very large scale environmentally deleterious emissions. Predicted growth in the graphite market will be driven by sharp increases in the market for Li-ion batteries, with 12 "mega" factory scheduled to begin production by 2020. Tesla's "giga" factory alone is thought to require the output of 4 - 6 new flake graphite mines or the equivalent quantity of synthetic graphite. However, supplies of natural graphite are under pressure with China recently closing ~ 200 flake graphite mines due to their environmental impact. In addition, shortages in the supply of the high quality needle petcoke necessary for synthetic graphite production are predicted. As a result, graphite price have tripled in the past 10 years, as production has been flat. Here we report the first Li-ion battery grade synthetic graphite made from biomass. The production is carbon negative, rapid, high yield and low cost. We have demonstrated the synthesis from cellulose, lignin and inexpensive whole biomass feedstock including sawdust and corncob. The resulting graphite is extremely high purity and highly crystalline, matching commercial synthetic graphites. Its performance in Li-ion batteries is outstanding, achieving near theoretical capacity with extremely long cycle life (see figure). Details of the synthesis, characterization and performance will be presented. Figure 1

The phenomenon of negative remanent magnetization (NRM) has been observed experimentally in a number of heterogeneous magnetic systems and has been considered anomalous. The existence of NRM in homogenous magnetic materials is still in debate, mainly due to the lack of compelling support from experimental data and a convincing theoretical explanation for its thermodynamic validation. Here we resolve the long-existing controversy by presenting experimental evidence and physical justification that NRM is real in a prototype homogeneous ferromagnetic nanoparticle, an europium sulfide nanoparticle. We provide novel insights into major and minor hysteresis behavior that illuminate the true nature of the observed inverted hysteresis and validate its thermodynamic permissibility and, for the first time, present counterintuitive magnetic aftereffect behavior that is consistent with the mechanism of magnetization reversal, possessing unique capability to identify NRM. The origin and conditions of NRM are explained quantitatively via a wasp-waist model, in combination of energy calculations.

Background Limited clinical data on real-world practice patterns are available for patients with metastatic/relapsed soft tissue sarcomas (STS). The primary objective of this study was to evaluate treatment patterns in patients with metastatic/relapsed STS following failure of prior chemotherapy by examining data collected from 2000 to 2011 from a major tertiary academic cancer center in the United States. Methods Medical records, including community-based referral records, from a tertiary cancer center for adult patients with metastatic/relapsed STS with confirmed disease progression who commenced second-line treatment between January 1, 2000 and February 4, 2011, and with at least 3 months of follow-up data following second-line treatment initiation, were retrospectively reviewed. Overall survival, time to progression, and clinician-reported tumor response were collected. Results A total of 99 patients (leiomyosarcoma, n = 48; synovial cell sarcoma, n = 7; liposarcoma, n = 5; or other histological subtypes, n = 39) received an average of four lines of treatment (maximum of 10). No consistent or dominant regimens were used in each treatment line beyond the second line. Median second-line treatment duration was 4.1 months (95% confidence interval, 3.0–5.0). Overall, 72 of 99 patients (73%) discontinued second-line treatment due to progressive disease. Median progression-free survival from initiation of second-line treatment varied across regimens from 2.0 to 6.6 months (overall median, 5.4 months). Conclusions Wide variations in treatment were evident, with no single standard of care for patients with metastatic/relapsed STS. Most patients discontinued second-line treatment due to progressive disease, often receiving additional systemic therapy with other drugs. These data suggest a high unmet need for more efficacious treatment options and improved data collection to guide practice among patients with relapsed/refractory STS.

Research of advanced power cycles has shown supercritical carbon dioxide power cycles may have thermal efficiency benefits relative to steam cycles at temperatures around 500–700°C. To realize these benefits for CSP, it is necessary to increase the maximum outlet temperature of current tower designs. Research at NREL is investigating a concept that uses high-pressure supercritical carbon dioxide as the heat transfer fluid to achieve a 650°C receiver outlet temperature. At these operating conditions, creep becomes an important factor in the design of a tubular receiver and contemporary design assumptions for both solar and traditional boiler applications must be revisited and revised. This paper discusses lessons learned for high-pressure, high-temperature tubular receiver design. An analysis of a simplified receiver tube is discussed, and the results show the limiting stress mechanisms in the tube and the impact on the maximum allowable flux as design parameters vary. Results of this preliminary analysis indicate an underlying trade-off between tube thickness and the maximum allowable flux on the tube. Future work will expand the scope of design variables considered and attempt to optimize the design based on cost and performance metrics.

Background The goal of this study was to perform candidate gene association with cytotoxicity of chemotherapeutics in cell line models through resequencing and discovery of rare and low frequency variants along with common variations. Here, an association study of cytotoxicity response to 30 FDA approved drugs was conducted and we applied next generation targeted sequencing technology to discover variants from 103 candidate genes in 95 lymphoblastoid cell lines from 14 CEPH pedigrees. In this article, we called variants across 95 cell lines and performed association analysis for cytotoxic response using the Family Based Association Testing method and software. Results We called 2281 variable SNP genotypes across the 103 genes for these cell lines and identified three genes of significant association within this marker set. Specifically, ATP-binding cassette, sub-family C, member 5 (ABCC5), metallothionein 1A (MT1A) and NAD(P)H dehydrogenase quinone1 (NQO1) were significantly associated with oxaliplatin drug response. The significant SNP on NQO1 (rs1800566) has been linked with poor survival rates in patients with non-small cell lung cancer treated with cisplatin (which belongs to the same class of drugs as oxaliplatin). A SNP (rs1846692) near the 5′ region of MT1A was associated with arsenic trioxide. Conclusions The results from this study are promising and this serves as a proof-of-principle demonstration of the use of sequencing data in the cytotoxicity models of human cell lines. With increased sample sizes, such studies will be a fast and powerful way to associate common and rare variants with drug response; while overcoming the cost and time limitations to recruit cohorts for association study.

The production rate and selectivity of a cross-catalytic peptide network are optimized in a simulated continuous reaction process, under a peptide solubility constraint. The steady state of this open process is not the equilibrium state, and the optimal solution employs diverse cooperative components.

To identify the genetic determinants of typical obesity, we performed a genome-wide scan of obesity-related traits using data from the Amish. Multipoint linkage analysis was performed using a variance components procedure on body mass index (BMI), waist circumference, percentage of body fat, and serum leptin concentrations. All 672 individuals were genotyped for 357 markers in 22 autosomes. We observed modest evidence for linkage, with the maximum log odds (lod) scores for linkage for these traits occurring on chromosomes 3p (percentage of body fat: lod = 1.61, near the peroxisome proliferator-activated receptor-α gene), 14q (waist: lod = 1.80), and 16p (leptin: lod = 1.72; BMI: lod = 1.68). We also tested for linkage to BMI-adjusted leptin concentrations and observed suggestive evidence for linkage on chromosome 10p (lod = 2.73), approximately 10–20 cM telomeric from obesity loci previously reported in French and German Caucasians. Two additional linkage signals for this trait were observed on chromosome...

Background —Hypertension is a major risk factor for coronary heart disease, stroke, congestive heart failure, renal insufficiency, and peripheral vascular disease. Although the genetic contribution to variation in blood pressure is well recognized, the specific genes involved are mostly unknown. We carried out a genome-wide scan to identify loci influencing blood pressure in the Old Order Amish population of Lancaster County, Pennsylvania. Methods and Results —Blood pressures were measured in 694 adult participants from families recruited without regard to blood pressure. We performed a quantitative linkage analysis by using 357 microsatellite markers. In multipoint analysis, strong evidence for linkage was observed with both diastolic (lod=3.36; P =0.00004) and to a lesser extent systolic (lod=1.64; P =0.003) blood pressure in the region of chromosome 2q31-34. Peak evidence for linkage occurred at map positions 217 and 221 cM from pter for diastolic and systolic blood pressure, respectively. Conclusions —A gene linked to familial primary pulmonary hypertension has recently been mapped to this same region, suggesting the intriguing hypothesis that other (attenuated) mutations in this same gene may influence variation in systolic and diastolic blood pressure in this population.

Crystalline Cs+(18-crown-6)2e- was found to be a linear chain Heisenberg antiferromagnet (J/kB = −38.3 K). It undergoes a slow, irreversible transition above ∼230 K from a crystalline low temperature (LT) phase to a disordered Curie−Weiss paramagnetic high temperature (HT) phase. A 100 ppm diamagnetic (more shielded) shift of the 133Cs MAS NMR peak accompanies this transition. EPR studies confirm the transition and are in accord with the conversion of the known crystal structure to a disordered phase. This HT phase undergoes an additional first-order reversible transition upon cooling below ∼220 K (ΔH = 0.33 kJ mol-1 upon rewarming) accompanied by the formation of two peaks in the 133Cs NMR spectrum. Variable-temperature powder X-ray diffraction confirms the disordered or microcrystalline nature of the HT phase(s).

Alkali metal radical anion salts in which the cations are coordinated directly by the radical anions have been studied extensively in solution, but relatively little in the solid state. We have prepared and characterized two such salts from 2,3-bis(2-pyridyl)quinoxaline (dpq) and potassium metal at −60 °C and 10-5 Torr. Crystals from THF show a zig-zag contact ion pair chain structure whereas a dimeric structure is obtained from methylamine. In both systems, the potassium ions occupy sites consisting of four quinoxaline nitrogens and solvent molecules. These salts have been further characterized by thin-film and solution optical spectroscopy, solution EPR and ENDOR spectroscopies, magnetic susceptibility, and cyclic voltammetry measurements.

Hereditary multiple exostoses (EXT) is an autosomal dominant disorder characterized by growth of benign bone tumors. Three chromosomal loci have been implicated in this genetically heterogeneous disease: EXT1 at 8q24, EXT2 at 11p13, and EXT3 on 19p. EXT1 and EXT2 were recently cloned. We evaluated 34 families with EXT to estimate the proportion of disease attributable to EXT1, EXT2, and EXT3 and to investigate the spectrum of EXT1 mutations. Linkage analyses combined with heterogeneity testing provides strong evidence in favor of linkage of disease to both chromosomes 8 and 11, but does not support evidence of linkage to chromosome 19 in this data set. The 11 EXT1 exons were PCR-amplified and sequenced in all 11 isolated cases and in 20 of the 23 familial cases. Twelve different novel EXT1 mutations were detected, including 5 frame-shift deletions or insertions, 1 codon deletion, and 6 single base-pair substitutions distributed across 8 of the exons. Only 2 of the mutations were detected in more than one family. Three mutations affect sites in which alterations were previously reported. Nonchain-terminating missense mutations were identified in codons 280 and 340, both coding for conserved arginine residues. These residues may be crucial to the function of this protein. Although the prevalence of EXT has been estimated to be approximately 1/50,000 individuals, the disease has been reported to occur much more frequently in the Chamorro natives on Guam. Our detection of an EXT1 mutation in one Chamorro subject will allow investigation of a possible founder effect in this population. Combined mutational and heterogeneity analyses in this set of families with multiple exostoses suggest that 66% of our total sample, including 45% of isolated and 77% of familial cases, are attributable to abnormalities in EXT1. Hum Mutat 11:231–239, 1998. © 1998 Wiley-Liss, Inc.

The title electride crystallizes in the orthorhombic space group Pbcn with a = 10.060(4) A, b = 23.134(8) A, c = 8.380(4) A, and z = 4. A second powdered phase of unknown structure, but with rather different properties, forms when rapidly precipitated “seed” powder is used. The crystalline phase contains electron-trapping cavities, each of approximate diameter 4.3 A, connected in zigzag fashion along the c axis by rather open channels of minimum diameter 2.4 A (center-to-center distance 7.9 A). Each cavity is also connected to next-neighbor cavities, 8.2 A away along c, by channels of diameter 1.5 A. Inter-chain channels are

Ultrasound-guided long-axis in-plane sciatic perineural catheter insertion has been described but not validated. For the popliteal-sciatic nerve, we hypothesized that a long-axis in-plane technique, placing the catheter parallel and posterior to the nerve, results in faster onset of sensory anesthesia compared to a short-axis in-plane technique.Preoperatively, patients receiving a popliteal-sciatic perineural catheter were randomly assigned to either the long-axis or short-axis technique. Mepivacaine 2% was administered via the catheter following insertion. The primary outcome was time to achieve complete sensory anesthesia. Secondary outcomes included procedural time, onset time of motor block, and pain on postoperative day 1.Fifty patients were enrolled. In the long-axis group (n = 25), all patients except 1 (4%) had successful catheter placement per protocol. Two patients (8%) in the long-axis group and 1 patient (4%) in the short-axis group (n = 25) did not achieve sensory anesthesia by 30 min and were withdrawn. Seventeen of 24 (71%) and 17 of 22 (77%) patients in the short-axis and long-axis groups, respectively, achieved the primary outcome of complete sensory anesthesia (p = 0.589). The short-axis group (n = 17) required a median (10th-90th ‰) of 18.0 (8.4-30.0) min compared to 18.0 (11.4-27.6) min for the long-axis group (n = 17, p = 0.208) to achieve complete sensory anesthesia. Procedural time was 6.5 (4.0-12.0) min for the short-axis and 9.5 (7.0-12.7) min for the long-axis (p0.001) group. There were no statistically significant differences in other secondary outcomes.Long-axis in-plane popliteal-sciatic perineural catheter insertion requires more time to perform compared to a short-axis in-plane technique without demonstrating any advantages.

As one of the viable concentrating solar power (CSP) technologies, linear Fresnel collectors differ from parabolic troughs by virtue of their low-profile mirror arrays and fixed receiver assemblies. This technology is capable of achieving high concentration ratios and so is applicable to high-temperature solar power plant designs. In addition, its low wind profile and linear nature lead to low system and operation and maintenance (O&M) costs. In this report two linear Fresnel solar plant configurations, namely a direct steam generation (DSG) system and a direct high-temperature molten-salt plant, are examined via a levelized cost of electricity (LCOE) analysis. By treating LCOE as a function of the annual investment energy return (IER, or the ratio of annual net electricity to the total direct system cost) under various assumptions of O&M cost, a few plant scenarios employing high-temperature linear Fresnel technology are carefully configured to meet the aggressive LCOE goals of 8 cents/kWh and 6 cents/kWh. The latter is the Department of Energy (DOE) SunShot Initiative goal aimed at making CSP cost competitive in the current energy market. In particular, a linear Fresnel scenario with the potential to meet the SunShot goal is featured with a collector cost of $100/m2, an annual system energy efficiency of 18%, a storage system cost of $15/kWh-th, and an O&M cost of $7.5/MWh. One of the most aggressive assumptions is an advanced power block with about 52% cycle efficiency and a turbine inlet temperature of 700°C. This work addresses unanswered questions regarding linear Fresnel cost and performance and identifies future research and development directions for linear Fresnel technology, including economic optimization of collectors and receivers, development of physical plant performance models, development of automated O&M mechanisms and sophisticated plant control software.

Supercritical CO2 (s-CO2) operated in a closed-loop Brayton cycle offers the potential of higher cycle efficiency versus superheated or supercritical steam cycles at temperatures relevant for concentrating solar power (CSP) applications. Brayton-cycle systems using s-CO2 have a smaller weight and volume, lower thermal mass, and less complex power blocks versus Rankine cycles due to the higher density of the fluid and simpler cycle design. The simpler machinery and compact size of the s-CO2 process may also reduce the installation, maintenance, and operation cost of the system. In this work we explore s-CO2 Brayton cycle configurations that have attributes that are desirable from the perspective of a CSP application, such as the ability to accommodate dry cooling and achieve greater than 50% efficiency, as specified for the U.S. Department of Energy SunShot goal. Recompression cycles combined with intercooling and/or turbine reheat appear able to hit this efficiency target, even when combined with dry cooling. In addition, the intercooled cycles expand the temperature differential across the primary heat exchanger, which is favorable for CSP systems featuring sensible-heat thermal energy storage.

Summary BackgroundVKORC1 and CYP2C9 are important contributors to warfarin dose variability, but explain less variability for individuals of African descent than for those of European or Asian descent. We aimed to identify additional variants contributing to warfarin dose requirements in African Americans. MethodsWe did a genome-wide association study of discovery and replication cohorts. Samples from African-American adults (aged ≥18 years) who were taking a stable maintenance dose of warfarin were obtained at International Warfarin Pharmacogenetics Consortium (IWPC) sites and the University of Alabama at Birmingham (Birmingham, AL, USA). Patients enrolled at IWPC sites but who were not used for discovery made up the independent replication cohort. All participants were genotyped. We did a stepwise conditional analysis, conditioning first for VKORC1 −1639G→A, followed by the composite genotype of CYP2C9*2 and CYP2C9*3. We prespecified a genome-wide significance threshold of p

Gold-coated gadolinium nanocrystals, with an average diameter of 3.20 ± 0.35 nm, have been synthesized at ambient temperature by alkalide reduction. Whereas uncoated gadolinium nanoparticles react violently with air and water, the gold-coated gadolinium nanocrystals reported here show no reaction even upon long-term exposure. This is the first example of air- and water-stable lanthanide metal nanocrystals, which may allow for the development of magnetic and biomedical applications of gadolinium and other lanthanide metal and alloy nanocrystals.

Genome-wide association studies have, in the last few years, identified thousands of common genetic variants associated with common complex traits and diseases, implicating many genes not previously known to be involved in the biology of those traits. However, these variants have so far explained little of the population variance in trait values or disease susceptibility. As large-scale genome sequencing efforts have revealed the extent of genetic variation at the low end of the frequency range in human populations, the effects of rare variants have been proposed as an explanation of the ‘missing genetic variance.’ Improved technologies for genotyping rare variants, including inexpensive whole-genome and whole-exome sequencing and rare-variant genotyping chips, coupled with novel analytical methods, are making genome-wide scans for the effects of rare variants possible, and seem likely to usher in a new era in the genetic analysis of complex traits.

Data from over 20 years ago demonstrated potential use for insulin-like growth factor (IGF) signaling modulators, specifically with IGF-1R antagonists, in a variety of pediatric and adolescent cancers, particularly in sarcomas. However, in spite of promising preclinical data, IGF-1R inhibitors have not had the success as single agents that was originally hoped for in clinical trials. Several potential mechanisms exist by which tumors are resistant to IGF-1R inhibitors. Notably, these resistance mechanisms are currently best understood in Ewing sarcoma and alveolar rhabdomyosarcoma. Various treatment schema have been proposed as a potential way to overcome this resistance. The use of IGF-1R inhibitors, mechanisms of resistance, and current ongoing clinical studies using IGF-1R inhibitors in pediatric cancers are reviewed here.

Data from over 20 years ago demonstrated potential use for IGF signaling modulators, specifically with IGF-1R antagonists, in a variety of pediatric and adolescent cancers, particularly in sarcomas. However, in spite of promising preclinical data, IGF-1R inhibitors have not had the success as single agents that was originally hoped for in clinical trials. Several potential mechanisms exist by which tumors are resistant to IGF-1R inhibitors. Notably, these resistance mechanisms are currently best understood in Ewing sarcoma and alveolar rhabdomyosarcoma. Various treatment schema have been proposed as a potential way to overcome this resistance. The use of IGF-1R inhibitors, mechanisms of resistance, and current ongoing clinical studies using IGF-1R inhibitors in pediatric cancers are reviewed here.

Hereditary multiple exostoses (EXT) is an autosomal dominant disorder characterized by the formation of cartilage capped prominences that develop from the epiphyses of the long bones. EXT is heterogeneous with three different locations currently identified on chromosomes 8, 11, and 19. Recently, we identified and studied 12 large multigenerational EXT families. Linkage analyses demonstrates that 6 of these families map to 8q24 and 6 to 11p. None of the families map to the chromosome 19 locus. The results suggest that there are two major loci, on chromosomes 8 and 11, involved in the cause of EXT. The locus on chromosome 19 remains to be confirmed.

The properties of the simplest sodide, LiNa(CH3NH2)n, are reported as a function of n. The phase diagram, established by using differential thermal analysis, shows the presence of a compound with n ≈ 6, which melts congruently at 168.5 ± 0.5 K. Two eutectics are present with n = 7.3 ± 0.3, T1 = 166 ± 1 K and n = 3.0 ± 0.2, T2 = 151 ± 1 K. The phase diagram was extended to metal concentrations that correspond to n = 1.45 and indicated the presence of a second compound with 2 ≤ n ≤ 3. The properties of these systems were investigated by EPR and alkali metal NMR spectroscopies and static magnetic susceptibilities. The 23Na NMR results clearly show that sodium is present as Na- for n ≥ 8. At higher metal concentrations the resonance line shifts smoothly toward more paramagnetic values (positive), with larger shifts at higher temperatures. EPR spectroscopy shows a transition from a single nearly symmetric line at large values of n to a strongly asymmetric signal characteristic of conduction electron spin reson...