tbuckley/cabot-search huggingface dataset:
Common Genetic Variant Risk Score Is Associated With Drug-Induced QT Prolongation and Torsade de Pointes Risk
Authors: David G. Strauss, Jose Vicente, Lars Johannesen, Ksenia Blinova, Jay W. Mason, Peter Weeke, Elijah R. Behr, Dan M. Roden, Ray Woosley, Gulum Kosova, Michael A. Rosenberg, Christopher Newton-Cheh
Journal: Circulation (2017)

Background: Drug-induced QT interval prolongation, a risk factor for life-threatening ventricular arrhythmias, is a potential side effect of many marketed and withdrawn medications. The contribution of common genetic variants previously associated with baseline QT interval to drug-induced QT prolongation and arrhythmias is not known. Methods: We tested the hypothesis that a weighted combination of common genetic variants contributing to QT interval at baseline, identified through genome-wide association studies, can predict individual response to multiple QT-prolonging drugs. Genetic analysis of 22 subjects was performed in a secondary analysis of a randomized, double-blind, placebo-controlled, crossover trial of 3 QT-prolonging drugs with 15 time-matched QT and plasma drug concentration measurements. Subjects received single doses of dofetilide, quinidine, ranolazine, and placebo. The outcome was the correlation between a genetic QT score comprising 61 common genetic variants and the slope of an individual subject’s drug-induced increase in heart rate–corrected QT (QTc) versus drug concentration. Results: The genetic QT score was correlated with drug-induced QTc prolongation. Among white subjects, genetic QT score explained 30% of the variability in response to dofetilide ( r =0.55; 95% confidence interval, 0.09–0.81; P =0.02), 23% in response to quinidine ( r =0.48; 95% confidence interval, −0.03 to 0.79; P =0.06), and 27% in response to ranolazine ( r =0.52; 95% confidence interval, 0.05–0.80; P =0.03). Furthermore, the genetic QT score was a significant predictor of drug-induced torsade de pointes in an independent sample of 216 cases compared with 771 controls ( r 2 =12%, P =1×10 −7 ). Conclusions: We demonstrate that a genetic QT score comprising 61 common genetic variants explains a significant proportion of the variability in drug-induced QT prolongation and is a significant predictor of drug-induced torsade de pointes. These findings highlight an opportunity for recent genetic discoveries to improve individualized risk-benefit assessment for pharmacological therapies. Replication of these findings in larger samples is needed to more precisely estimate variance explained and to establish the individual variants that drive these effects. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01873950.
Why space is not one-dimensional: Location may be categorical <i>and</i> imagistic
Authors: Marcel R. Giezen, Brendan Costello, Manuel Carreiras
Journal: Behavioral and Brain Sciences (2017)

Abstract In our commentary, we raise concerns with the idea that location should be considered a gestural component of sign languages. We argue that psycholinguistic studies provide evidence for location as a “categorical” element of signs. More generally, we propose that the use of space in sign languages comes in many flavours and may be both categorical and imagistic. In their target article, Goldin-Meadow &amp; Brentari (G-M&amp;B) discuss several observations suggesting that the use of space is imagistic and may not form part of the categorical properties of sign languages. Specifically, they point out that (1) the number of locations toward which agreeing verbs can be directed is not part of a discrete set, (2) event descriptions by users of different sign languages and hearing nonsigners exhibit marked similarities in the use of space, and (3) location as a phonological parameter is not categorically perceived by native signers. It should be noted that G-M&amp;B acknowledge that categorical properties of location and movement may simply not have been captured yet because the proper investigative tools are not yet readily available.
GENE-08. COMMON GENETIC VARIATIONS IN CELL CYCLE AND DNA REPAIR PATHWAYS ASSOCIATED WITH PEDIATRIC BRAIN TUMOR SUSCEPTIBILITY
Authors: Maral Adel Fahmideh, Catharina Lavebratt, Joachim Schüz, Martin Röösli, Tore Tynes, Michael A. Grotzer, Christoffer Johansen, Claudia E Kuehni, Birgitta Lannering, Michaela Prochazka, Lisbeth S Schmidt, Maria Feychting
Journal: Neuro-Oncology (2017)

BACKGROUND: Knowledge on the role of genetic polymorphisms in the etiology of pediatric brain tumors (PBTs) is limited. Therefore, we investigated the association between single nucleotide polymorphisms (SNPs), identified by candidate gene-association studies on adult brain tumors, and PBT risk. METHODS: The study is based on the largest series of PBT cases to date. Saliva DNA from 245 cases and 489 controls, aged 7–19 years at diagnosis/reference date, was genotyped for 68 SNPs. Data were analyzed using unconditional logistic regression. Stratified analyses were conducted for two histological subtypes: astrocytoma alone and other tumor types combined. RESULTS:EGFR rs730437 (p=0.002) and EGFR rs11506105 (p=0.036) may decrease susceptibility to PBTs, whereas ERCC1 rs3212986 (p=0.009) may increase risk of these tumors. Moreover, stratified analyses indicated that CHAF1A rs243341, CHAF1A rs2992, and XRCC1 rs25487 were associated with a decreased risk of astrocytoma subtype (pDOM=0.040, pDOM=0.049, and pDOM=0.033, respectively). In addition, an increased risk of non-astrocytoma tumor subtype associated with EGFR rs9642393, EME1 rs12450550, ATM rs170548, and GLTSCR1 rs1035938 (pREC=0.021, pREC=0.001, pDOM=0.041, and pREC=0.027, respectively) as well as a decreased risk of this subtype associated with XRCC4 rs7721416 (pREC=0.032) and XRCC4 rs2662242 (pREC=0.024) were detected. CONCLUSIONS: This study indicates that SNPs in EGFR, ERCC1, CHAF1A, XRCC1, EME1, ATM, GLTSCR1, and XRCC4 may be associated with the risk of PBTs. Therefore, genetic polymorphisms in cell cycle and DNA repair pathways associated with susceptibility to adult brain tumors also seem to be associated with PBT risk, suggesting that pediatric and adult brain tumors might share similar etiological pathways.
DIPG-39. LIQUID BIOPSY FOR MONITORING OF TUMOR RESPONSE IN CHILDREN WITH MIDLINE GLIOMAS
Authors: Eshini Panditharatna, Jordana Sandy, Madhuri Kambhampati, Sridevi Yadavilli, Lindsay Kilburn, John Crawford, Suresh Magge, Roger J Packer, Michael Prados, Sabine Mueller, Javad Nazarian
Journal: Neuro-Oncology (2017)

OBJECTIVE: We evaluate the utility of biofluids (CSF, plasma, and urine) from patients and their xenograft models, for detection and quantification of circulating tumor DNA (ctDNA). The goal has been to develop a comprehensive panel for ctDNA detection capable of assessing response to treatment. METHODS: Biofluids (plasma, CSF, and urine) from patients diagnosed with low and high grade midline gliomas were collected for this study. Fifty seven specimens were collected. These include fifty plasma samples collected at diagnosis with each MRI, from 15 patients diagnosed with DIPG, five CSF samples from patients with high grade midline glioma, and two from patients with low grade midline glioma. Major mutations associated with DIPG were selected for monitoring ctDNA. These include H3F3A K27M, HIST1H3B K27M, ACVR1 G328V/R206H, and PPM1D E525X. Plasma and CSF samples collected at diagnosis from low grade glioma patients were analyzed for IDH1 R132H and BRAF V600E mutations. ctDNA was further assessed in preclinical models of DIPG. RESULTS: For monitoring ctDNA, we have developed a liquid biopsy technique using plasma and CSF. Using our sensitive and robust digital droplet PCR (ddPCR) system, we identified the presence of major histone 3 K27M partner mutations associated with DIPG in plasma and CSF ctDNA. We have also successfully conducted multiplexed detection of H3K27M and its partner mutations in CSF samples obtained from DIPG patients. In a high grade thalamic astrocytoma, where biopsy specimen was not available, we tested CSF and determined H3K27M mutation status of the tumor. Furthermore, we have detected H3K27M mutation in ctDNA of plasma samples in xenograft models of DIPG. CONCLUSIONS: Biofluid is a suitable medium for detection and quantification of circulating tumor DNA (ctDNA). Liquid biopsy has the potential to complement, or in some cases eliminate the need for biopsies, and may inform recurrence and tumor response to treatment.
Optimal Conditioning Regimen for Haplo-Identical Stem Cell Transplantation in Adult Patients with Acquired Severe Aplastic Anemia: Prospective De-Escalation Study of TBI and ATG Dose
Authors: Sung-Eun Lee, Sung Soo Park, Young-Woo Jeon, Jae-Ho Yoon, Byung-Sik Cho, Ki-Sung Eom, Yoo-Jin Kim, Seok Lee, Chang-Ki Min, Hee-Je Kim, Seok-Goo Cho, Dong-Wook Kim, Woo-Sung Min, Jong Wook Lee
Journal: Blood (2016)
Imatinib-Related Neutropenia in Chronic-Phase Chronic Myelogenous Leukaemia: Safety and Efficacy of Granulocyte-Colony-Stimulating Factor (Filgrastim) Use.
Authors: Antonio Lazzaro, Patrizia Bernuzzi, Elena Trabacchi, Daniele Vallisa, Annalisa Arcari, Raffaella Bertè, Carlo F. Moroni, Elisa Anselmi, Luigi Cavanna
Journal: Blood (2005)
Multifunctional gold composite nanodevices for αv β3 angiogenic microvascular targeting
Authors: Mohamed Khan, Muhammed Kariapper, Bindu Nair, Wojciech Lesniak, Lajos Balogh
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

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Background: Composite Nanodevices hold great promise for improvement in cancer imaging and therapy (Khan MK, Tech. in Cancer Res. 4: 603; Balogh L, PharmaChem 2: 94). These nanodevices have a PAMAM dendrimer component and an inorganic component which can be separately optimized. The αvβ3 integrins are highly overexpressed in the angiogenic microvasculature present in tumors, and not in normal endothelial cells. We targeted 5 nm gold carrying composite nanodevices (Au-CNDs) to the αvβ3 receptor present on stimulated endothelial cells. The Au-CNDs carry multiple copies of a form of cyclic RGD peptide (cRGD, Arg-Gly-Asp) that strongly binds to αvβ3 and is already in anti-angiogenic cancer clinical trials (Ragusea J, Oral Oncology 40: 228) making the cRGD-Au-CNDs more clinically relevant than other permutations of RGD in the literature (Shukla R, Chem. Commun. 5739 (2005)). Composite nanodevices have more imaging and therapeutic roles than are feasible with dendrimer only devices.

Purpose: To synthesize and characterize an angiogenic microvascular targeted 5 nm Au-CND and demonstrate, specific binding of a targeted Au-CND in vitro to the αvβ3 receptor and to stimulated human dermal microvascular endothelial cells (HDMECs).

Experimental Procedures: cRGD containing biotinylated gold composite nanodevices (cRGD-BT-Au-CND) were fabricated using amine and partially substituted acetamide terminated PAMAM dendrimers, followed by substitution with succinamic acid groups and final conjugation with four cRGD peptides followed by reactive encapsulation of gold. The nanodevices tested include: 5 nm cRGD-BT-Au-CND (targeted) and 5 nm BT-Au-CND (non-targeted). The targeted cRGD-BT-Au-CND binding to αvβ3 integrin coated plates was assessed in vitro , and the specificity of binding examined by competition with free cRGD. Finally the specific binding of the targeted composite nanodevice to stimulated HDMECs was assessed using a fluorescent antibody against the biotin present on the composite nanodevices.

Results: The Au-CNDs were successfully synthesized and characterized. The targeted cRGD-BT-Au-CNDs were shown to specifically bind to the αvβ3 receptor in vitro , using plates coated by human αvβ3 integrin. The non-targeted BT-Au-CNDs showed no binding and free cRGD competed for binding with the targeted CND. The targeted cRGD-BT-Au-CNDs, visualized by immunoflourescence, specifically bound to stimulated endothelial cells (HDMECs) expressing αvβ3.

Conclusions: The angiogenic microvasculature targeted cRGD-BT-Au-CND shows quantitative specific binding to the biologic target αvβ3 receptor in vitro , and to stimulated angiogenic endothelial cells (HDMECs). These efficiently targeted multifunctional gold CNDs is currently being developed for improved tumor imaging, anti-angiogenic therapy and radiation therapy.
Selinexor Shows Synergy in Combination with Pomalidomide and Low Dose Dexamethasone in Patients with Relapsed / Refractory Multiple Myeloma
Authors: Christine Chen, Rami Kotb, Michael Sebag, Richard LeBlanc, Heather J. Sutherland, Darrell White, Christopher P. Venner, Tom Kouroukis, Debra Bergstrom, Arleigh McCurdy, Marc Lalancette, William Bensinger, Suzanne Lentzsch, Aldo Del Col, Michael Kauffman, Sharon Shacham, Jacqueline Jeha, Carla Picklesimer, Jean-Richard Saint-Martin, Cassandra Choe-Juliak, Nizar J. Bahlis
Journal: Blood (2016)
Response to Comment on Cummings and Cohen. Bariatric/Metabolic Surgery to Treat Type 2 Diabetes in Patients With a BMI &amp;lt;35 kg/m2. Diabetes Care 2016;39:924–933
Authors: David E. Cummings, Ricardo V. Cohen
Journal: Diabetes Care (2017)

Halpern et al. (1) thoughtfully critique our article (2) on bariatric/metabolic surgery for type 2 diabetes (T2D) in lower-BMI patients. The traditional 35 kg/m2 BMI threshold for patients with diabetes to be surgical candidates is arbitrary and particularly unsuitable for Asians. The National Institutes of Health established this threshold 26 years ago based on no randomized controlled trials (RCTs) comparing surgical versus nonsurgical approaches. Nevertheless, a quarter century of worldwide practice governed by those standards has validated that among severely obese patients, bariatric/metabolic surgery is efficacious, safe, and cost-effective (3).

A key question now is whether the well-documented benefits of these operations extend to patients with diabetes whose BMI is <35 kg/m2. Among many reasons justifying this question is abundant evidence demonstrating that preoperative BMI does not predict the benefits of surgery on diabetes prevention, remission, or relapse, nor on cardiovascular events, cancer, or death (3).

Halpern et al. (1) emphasize that long-term surgical outcomes data in lower-BMI populations are limited. The relevant database, however, is far from trivial and …
GENE-14. COMPARATIVE CYTOGENETIC ANALYSIS OF DOG AND HUMAN CHOROID PLEXUS TUMORS DEFINES SYNTENIC REGIONS OF GENOMIC LOSS
Authors: Peter Dickinson, Devin Ancona, Miriam Aguilar, Danika Bannasch
Journal: Neuro-Oncology (2017)

Spontaneously occurring choroid plexus tumors (CPTs) in dogs are indistinguishable from human tumor counterparts based on histology and imaging. Leveraging karyotypic differences between dogs and humans may provide insight into evolutionarily conserved cytogenetic alterations and allow for more focussed analysis of orthologous regions within large human chromosomal losses and gains. We used Illumina 173K HD SNP arrays to determine copy number alterations (CNAs) in 12 histologically confirmed spontaneous canine choroid plexus tumor samples (3 papillomas/CPP, 8 carcinomas/CPC, 1 recurrent CPP) and tumor matched normal tissue. Copy number calls and allelic events were determined by matched paired analysis using BioDiscovery Nexus Copy NumberTM software. Hierarchical clustering by aberration profile did not distinguish between CPPs and CPCs. Choroid plexus tumors were characterized by highly recurrent single copy, whole chromosomal losses. Loss of chromosomes CFA 2, and 20 occurred in 100% tumors and losses of CFA 5 and 8 were seen in >90% of tumors. Genes associated with chromosomal instability in these regions included TP53, VHL, CENPH, AURKB, HAUS8 and KIF2A. Using the TSGene2.0 database we identified loss of 53, 61, 75 and 21 candidate tumor suppressor genes on chromosomes 2, 20, 5 and 8 respectively. The pattern of predominantly whole chromosomal losses was most similar to findings in human CPCs compared to CPPs and aCPPs. Several recurrent whole chromosomal losses in dog tumors contained deletions orthologous to regions of some of the most frequently reported whole chromosomal losses in human CPTs, including regions of HSA 3, 11, 16 and 17. The striking prevalence of specific CNAs in dog CPTs is supportive of their biological relevance in CPT oncogenesis and progression. Further analysis of gene expression and concordance with orthologous CNAs may further focus efforts to define common key genetic alterations in the genesis and progression of these tumors across the two species.
The developmental regulator PKL is required to maintain correct DNA methylation patterns at RNA-directed DNA methylation loci
Authors: Rong Yang, Zhimin Zheng, Qing Chen, Lan Yang, Huan Huang, Daisuke Miki, Wenwu Wu, Liang Zeng, Jun Liu, Jin-Xing Zhou, Joe Ogas, Jian-Kang Zhu, Xin-Jian He, Heng Zhang
Journal: Genome biology (2017)

The chromodomain helicase DNA-binding family of ATP-dependent chromatin remodeling factors play essential roles during eukaryote growth and development. They are recruited by specific transcription factors and regulate the expression of developmentally important genes. Here, we describe an unexpected role in non-coding RNA-directed DNA methylation in Arabidopsis thaliana. Through forward genetic screens we identified PKL, a gene required for developmental regulation in plants, as a factor promoting transcriptional silencing at the transgenic RD29A promoter. Mutation of PKL results in DNA methylation changes at more than half of the loci that are targeted by RNA-directed DNA methylation (RdDM). A small number of transposable elements and genes had reduced DNA methylation correlated with derepression in the pkl mutant, though for the majority, decreases in DNA methylation are not sufficient to cause release of silencing. The changes in DNA methylation in the pkl mutant are positively correlated with changes in 24-nt siRNA levels. In addition, PKL is required for the accumulation of Pol V-dependent transcripts and for the positioning of Pol V-stabilized nucleosomes at several tested loci, indicating that RNA polymerase V-related functions are impaired in the pkl mutant. PKL is required for transcriptional silencing and has significant effects on RdDM in plants. The changes in DNA methylation in the pkl mutant are correlated with changes in the non-coding RNAs produced by Pol IV and Pol V. We propose that at RdDM target regions, PKL may be required to create a chromatin environment that influences non-coding RNA production, DNA methylation, and transcriptional silencing.
Follow manufacturers' instructions
Authors: M. Harmer
Journal: BMJ (1994)

kPa (2 4 atmospheres absolute) 100% oxygen for 90 minutes three times daily for the first day and twice daily thereafter.5In cases of surgical delay for any reason and in cases in which the decision is taken not to operate, hyperbaric oxygen should be used immediately if it is available; this may also assist in distinguishing viable from non- viable tissue at subsequent surgery.The availability of hyperbaric oxygen facilities in Britain can be checked with the hyperbaric unit at
Abstract 19174: Gut Microbial Utilization of Choline Significantly Alters Host Lipid, DNA Methylation, and Hepatic Gene Expression Profiles
Authors: Kymberleigh A Romano, Ana Martinez del Campo, Kimberly A Krautkramer, Kazuyuki Kasahara, Eugenio I Vivas, John M Denu, Daniel Amador-Noguez, Emily P Balskus, Federico E Rey
Journal: Circulation (2016)

Choline is an essential nutrient necessary for several biological functions in the human body; in addition to being the precursor to acetylcholine, choline is required for the formation of phosphatidylcholine and the universal methyl donor SAM ( S-adenosyl methionine ). Gut microbial metabolism of dietary choline results in the production of trimethylamine (TMA), a compound that is absorbed by the host and further converted to trimethylamine N-oxide (TMAO) in the liver. While the role of the gut microbiota as a modulator of choline bioavailability has been poorly explored, it is well established that both choline deficiency and TMAO accumulation are associated with cardiovascular disease. We used germ-free mice colonized with defined synthetic communities of bacteria that differ only in their ability to convert choline to TMA to evaluate the impact of microbial choline utilization on host physiology. We found that bacterial utilization of choline significantly reduces the bioavailability of choline to the host as well as significantly alters (i) host gene expression (in liver and adipose tissue), (ii) lipid profiles, and (iii) serum and hepatic metabolomes. Furthermore, conversion of choline to TMA and TMAO results in changes in gene expression consistent with increased fatty acid oxidation, apoptosis, reactive oxygen species generation, fibrin deposition, vasoconstriction and adipogensis concomitant with a decrease in oxidative stress tolerance and clearance of thrombi from the vasculature. Many of the differentially expressed genes are known targets of the nuclear receptors PPAR and FXR. Lastly, colonization with a choline consuming TMAgenic community resulted in significant alterations in global DNA methylation patterns in multiple tissues in as little as two-weeks post colonization.
Guidelines aim to help identify and treat stroke in children
Authors: Zosia Kmietowicz
Journal: BMJ (2017)

New guidelines on recognising and managing stroke in children have been launched by the Royal College of Paediatrics and Child Health and the Stroke Association to help prevent the potential damage that can occur if symptoms go unrecognised.1

Every year around 400 children in the UK have a stroke, and many are left with severe physical and mental impairments.

The guidelines say that most children experiencing a stroke will have similar symptoms to adults—specifically, weakness of the face and on one side of the body and difficulty with speech. Less commonly, childhood strokes may present with seizures or fits affecting one part of the body or, rarely, a new onset sudden severe headache, the guidelines say, …
Abstract 270: The Eya4/six1 Signalling Cascade is Activated in Acquired Heart Disease
Authors: Tatjana Williams, Daniel Oppelt, Peter Nordbeck, Sabine Voll, Jost Schoenberger, Oliver Ritter
Journal: Circulation Research (2015)

Rationale: We previously identified a mutation in the human transcriptional cofactor Eya4 as cause of familial dilated cardiomyopathy (DCM). We now provide evidence that the Eya4/Six1 signalling cascade also is crucial in acquired heart disease. Hypothesis: We hypothesize that the transcriptional complex Eya4/Six1 regulates targets relevant in normal cardiac function. We speculate it, amongst others, regulates expression of p27kip1, a known inhibitor of hypertrophy in adult cardiomyocytes, upon hypertrophic stimuli. Methods and results: We first examined the correlation of Eya4 and p27 in regards to phosphorylation and cellular distribution in failing and normal human hearts. Immunhistology revealed Eya4 is mainly distributed in the cytoplasm while p27 predominantly resides in the nucleus of healthy myocardial tissue. In sections of failing human hearts, Eya4 accumulated in the perinuclear and nuclear region; nuclear p27 levels were significantly diminished, phosphorylated p27 was evenly distributed in the cytoplasm. In a murine model of MI, IH showed Eya4 translocates in a time-dependent manner. WB analyses for p27 showed an age dependent decrease in p27 protein levels upon MI compared to control littermates. We generated transgenic mice with constitutive myocardial overexpression of Eya4 and E193. As judged by MRI, hemodynamic and morphometric analysis both transgenic mouse models developed cardiac phenotypes compared to age-matched wildtype littermates already under basal conditions in an age dependent manner. p27 expression and downstream factors were also altered in both transgenic lines as a result of Eya4, and accordingly, E193 overexpression. In summary, we provide evidence that the Eya4/Six1 signalling cascade is not only relevant in a rare version of heritable DCM but also in more common forms of acquired heart disease. Eya4/Six1 seems to regulate p27, which was shown to be an important regulator of cardiac physiology in postmitotic cardiomyocytes.