bluuebunny/crossref_metadata_2025_split huggingface dataset:
Xenograft-based, platform-independent gene signatures to predict response to alkylating chemotherapy, radiation, and combination therapy for glioblastoma
Authors: Zhao Shuang G , Yu Menggang , Spratt Daniel E , Chang S Laura , Feng Felix Y , Kim Michelle M , Speers Corey W , Carlson Brett L , Mladek Ann C , Lawrence Theodore S , Sarkaria Jann N , Wahl Daniel R 
Published: May 2019

Abstract

Background
Predictive molecular biomarkers to select optimal treatment for patients with glioblastoma and other cancers are lacking. New strategies are needed when large randomized trials with correlative molecular data are not feasible.

Methods
Gene signatures (GS) were developed from 31 orthotopic glioblastoma patient-derived xenografts (PDXs), treated with standard therapies, to predict benefit from radiotherapy (RT-GS), temozolomide (Chemo-GS), or the combination (ChemoRT-GS). Independent validation was performed in a heterogeneously treated clinical cohort of 502 glioblastoma patients with overall survival as the primary endpoint. Multivariate Cox analysis was used to adjust for confounding variables and evaluate interactions between signatures and treatment.

Results
PDX models recapitulated the clinical heterogeneity of glioblastoma patients. RT-GS, Chemo-GS, and ChemoRT-GS were correlated with benefit from treatment in the PDX models. In independent clinical validation, higher RT-GS scores were associated with increased survival only in patients receiving RT (P = 0.0031, hazard ratio [HR] = 0.78 [0.66–0.92]), higher Chemo-GS scores were associated with increased survival only in patients receiving chemotherapy (P < 0.0001, HR = 0.66 [0.55–0.8]), and higher ChemoRT-GS scores were associated with increased survival only in patients receiving ChemoRT (P = 0.0001, HR = 0.54 [0.4–0.74]). RT-GS and ChemoRT-GS had significant interactions with treatment on multivariate analysis (P = 0.0009 and 0.02, respectively), indicating that they are bona fide predictive biomarkers.

Conclusions
Using a novel PDX-driven methodology, we developed and validated 3 platform-independent molecular signatures that predict benefit from standard of care therapies for glioblastoma. These signatures may be useful to personalize glioblastoma treatment in the clinic and this approach may be a generalizable method to identify predictive biomarkers without resource-intensive randomized trials.
The Relationship of Varenicline Agonism of α4β2 Nicotinic Acetylcholine Receptors and Nicotine-Induced Dopamine Release in Nicotine-Dependent Humans
Authors: McCaul Mary E , Wand Gary S , Kuwabara Hiroto , Dannals Robert F , Wong Dean , Xu Xiaoqiang 
Published: May 2019

Abstract

Introduction
Cigarette smoking continues to be one of the most important behavioral causes of morbidity and mortality in the world. Varenicline, an α4β2 nicotinic acetylcholine receptor (nAChR) partial agonist, has been shown to increase smoking quit rates compared with nicotine-based products. This human laboratory, double-blind, placebo-controlled study examined varenicline and placebo effects on α4β2-nAChRs occupancy, nicotine-induced change in [11C]raclopride non-displaceable binding potential (BPND), and behavioral measures of cigarette smoking, nicotine craving, and withdrawal.

Methods
Current nicotine dependent daily smokers (N = 17) were randomized to varenicline 1 mg twice daily or placebo for 13 days. Using positron emission tomography), we characterized α4β2-nAChRs occupancy using [18F]AZAN and dopamine receptor binding using [11C]raclopride as well as behavioral measures of cigarettes smoked, craving, and nicotine withdrawal.

Results
Varenicline compared with placebo resulted in significant reductions in [18F]AZAN BPND in multiple brain regions including thalamus, midbrain, putamen, and ventral striatum. Following administration of a controlled-dose nicotine cigarette, dopamine release was significantly suppressed in the ventral striatum in the varenicline-treated compared with the placebo group. There was a significant relationship between α4β2-nAChRs BPND measured in thalamus during the [18F]AZAN scan and nicotine-induced change in raclopride BPND in the ventral striatum.

Conclusion
This is the first human study to demonstrate a direct relationship between the extent of varenicline occupancy of α4β2-nAChRs and the magnitude of dopamine release following nicotine use.

Implications
It has remained unclear how nicotinic receptor blockade through partial agonist medications such as varenicline promotes smoking cessation. One hypothesized mechanism is downstream dampening of the mesolimbic reward dopamine system. For the first time in human smokers, we observed a direct relationship between the extent of varenicline blockade of α4β2-nACh nicotinic receptors and the magnitude of dopamine release following smoking. This has mechanistic and therapeutic implications for improving smoking cessation interventions.
Anatomic Considerations for Injection of the Lateral Atlanto-Axial Joint
Authors: McNabney Charis , Chavda Anesh , Alabsi Hatim , Sellers Stephanie L , Murphy Darra T , Fenton David 
Published: May 2019

Abstract

Objective
We aimed to define the potential complications of intra-articular steroid injections into the lateral C1-2 articulations and safety margins to the relevant structures.

Methods
A total of 488 contrast-enhanced computed tomography angiogram (CTA) “arch to vertex” studies were retrospectively reviewed for theoretical intersection of the vertebral artery or thecal sac and distance of the named structures from the anticipated/theoretical trajectory of injection into the lateral C1-C2 joint.

Results
Patients were 60.4±15.8 years old and 55.5% male. In total, seven vertebral arteries and 11 thecal sac theoretical intersections were found. In cases without a direct intersection, the distance from the trajectory (range) was 0.71±0.18 (0.22–1.44) cm to the vertebral artery and 0.6±0.22 (0.14–1.8) cm to the thecal sac.

Conclusions
Although injection of steroid into the lateral C1-C2 articulation for pain management has historically been reported to carry risk of severe complications due to close proximity and location variability of surrounding structures, our study quantifies the potential risk of such injections. Further, our analysis suggests that preprocedural imaging should be considered.
Applying Prospect Theory to Participation in a CAPI/Web Panel Survey
Authors: Lynn Peter 
Published: May 2019

Abstract
Prospect theory states that the influential power of avoiding negative outcomes is stronger than that of achieving positive outcomes. In a survey context, this theory has been tested with respect to not only participation in a CATI survey, but also giving consent to data linkage in CATI surveys. No study, however, has tested the theory with respect to participation in a CAPI or web survey. This study does so in a mixed-mode panel context; it also tests the moderating effects of time-in-panel, response history, and mode protocol. Results show that the framing of the survey participation request influences participation propensity in a way consistent with prospect theory, but only for relatively recent panel entrants. The opposite effect is found for long-term panel participants. No difference is found between mode protocols.
1Book / Media Theory
Authors: Hyun Trina 
Published: May 2019

AbstractIn 2018, scholarship in book/media theory sketched the ways in which books embody time, shape our experience of time, and live in time. In particular, authors examine the book as a material object that resists being placed in a cohesive, progressive history (Whitney Trettien, Deidre Lynch, Michelle Sizemore, John Plotz), and that bends and textures linear temporality through the experience of reading (Christina Lupton). This review also discusses new theoretical discourses surrounding the material book, including new materialism (Jonathan Senchyne), the digital notion of ‘interactivity’ (The Multigraph Collective), and the concept of rarity (David McKitterick). Recurring through many of the works this year is a call to reconsider our definitions of the book and the archive, as scholars peer into the less well-known, cut-and-paste world of scrapbooks. This chapter is structured under the following headings: 1. The Time of Reading; 2. Books in Time; 3. Books in History; 4. Bookish Agencies.
Serum IgE and IgG reactivity to Aspergillus recombinant antigens in patients with cystic fibrosis
Authors: Alghamdi Nada S. , Barton Richard , Wilcox Mark , Peckham Daniel 
Published: May 2019

Purpose.The diagnosis of aspergillosis in cystic fibrosis (CF) patients remains a challenge due to overlapping features of both diseases. This is further complicated by inconsistent antibody reactivity to the currently used crude antigen, which has led a more focused evaluation of the efficacy of IgE response to a number of pureAspergillus fumigatusrecombinant proteins in patients with CF and asthma. In this study, we dissected the IgE and IgG responses to multipleA. fumigatusrecombinant antigens in CF patients with differentAspergillusdiseases.Methodology.Serum IgE and IgG antibodies were measured in 12 CF patients with allergic bronchopulmonary aspergillosis (ABPA), 12 withAspergillussensitization (AS) and 12 withAspergillusbronchitis (AB) against recombinant antigens Asp f1, f2, f3, f4 and f6.Results.The ABPA group showed significantly greater IgE reactivity to Asp f1, f2, f3 and f4 compared to patients with AS. Patients with AB expressed higher IgG positivity to Asp f1 and Asp f2 compared with those with ABPA. There were very low IgE antibody levels against all recombinant antigens in patients with AS. Aspf1 IgG reactivity in ABPA patients correlated with positive culture.Conclusion.The use of multiple recombinant antigens may improve the diagnostic accuracy in CF complicated with ABPA or AB. Asp f1 reactivity may relate to the presence of actively growingAspergillusspp., which might be a useful marker for guiding antifungal therapy in ABPA.
Missense mutations in the MLKL ‘brace’ region lead to lethal neonatal inflammation in mice and are present in high frequency in humans
Authors: Hildebrand Joanne M. , Kauppi Maria , Majewski Ian J. , Liu Zikou , Cox Allison , Miyake Sanae , Petrie Emma J. , Silk Michael A. , Li Zhixiu , Tanzer Maria C. , Young Samuel N. , Hall Cathrine , Garnish Sarah E. , Corbin Jason , Stutz Michael D. , Gangatirkar Pradnya , Josefsson Emma C. , Rigbye Kristin , Anderton Holly , Rickard James A. , Tripaydonis Anne , Sheridan Julie , Scerri Thomas S. , Czabotar Peter A. , Zhang Jian-Guo , Allison Cody C. , Pellegrini Marc , Tannahill Gillian M. , Hatchell Esme C. , Willson Tracy A. , Stockwell Dina , de Graaf Carolyn A. , Collinge Janelle , Hilton Adrienne , Silke Natasha , Spall Sukhdeep K. , Chau Diep , Athanasopoulos Vicki , Metcalf Donald , Laxer Ronald M. , Bassuk Alexander G. , Darbro Benjamin W. , Fiatarone Singh Maria A. , Vlahovich Nicole , Hughes David , Kozlovskaia Maria , Ascher David B. , Warnatz Klaus , Venhoff Nils , Thiel Jens , Blum Stefan , Reveille John , Hildebrand Michael S. , Vinuesa Carola G. , McCombe Pamela , Brown Matthew A. , Kile Ben T. , McLean Catriona , Bahlo Melanie , Masters Seth L. , Nakano Hiroyasu , Ferguson Polly J. , Murphy James M. , Alexander Warren S. , Silke John 
Published: May 2019

SUMMARYWe have isolated a mouse strain with a single missense mutation in the gene encoding MLKL, the essential effector of necroptotic cell death. The resulting substitution lies within the two-helix ‘brace’ and confers constitutive, RIPK3 independent, killing activity to MLKL. Mice homozygous forMlklD139Vdevelop lethal inflammation within days of birth, implicating the salivary glands and pericardium as hotspots for necroptosis and inflammatory infiltration. The normal development ofMlklD139Vhomozygotes until birth, and the absence of any overt phenotype in heterozygotes provides importantin vivoprecedent for the capacity of cells to clear activated MLKL. These observations offer an important insight into the potential disease-modulating roles of three common humanMLKLpolymorphisms that encode amino acid substitutions within or adjacent to the brace region. Compound heterozygosity of these variants is found at up to 12-fold the expected frequency in patients that suffer from a pediatric autoinflammatory disease, CRMO.
Different components of the RNAi machinery are required for conidiation, ascosporogenesis, virulence, DON production and fungal inhibition by exogenous dsRNA in the Head Blight pathogenFusarium graminearum
Authors: Gaffar Fatima Yousif , Imani Jafargholi , Karlovsky Petr , Koch Aline , Kogel Karl-Heinz 
Published: May 2019

AbstractGene silencing through RNA interference (RNAi) shapes many biological processes in filamentous fungi, including pathogenicity. In this study we explored the requirement of key components of fungal RNAi machinery, including DICER-like 1 and 2 (FgDCL1,FgDCL2), ARGONAUTE 1 and 2 (FgAGO1,FgAGO2), AGO-interacting proteinFgQIP (QDE2-interacting protein), RecQ helicase (FgQDE3), and four RNA-dependent RNA polymerases (FgRdRP1,FgRdRP2,FgRdRP3,FgRdRP4), in the ascomycete mycotoxin-producing fungal pathogenFusarium graminearum(Fg) for sexual and asexual multiplication, pathogenicity, and its sensitivity to double-stranded (ds)RNA. We corroborate and extend earlier findings that conidiation, ascosporogenesis and Fusarium Head Blight (FHB) symptom development require an operable RNAi machinery. The involvement of RNAi in conidiation is dependent on environmental conditions as it is detectable only under low light (< 2 µmol m−2s−1). Although both DCLs and AGOs partially share their functions, the sexual ascosporogenesis is mediated primarily byFgDCL1 andFgAGO2, whileFgDCL2 andFgAGO1 contribute to asexual conidia formation and germination.FgDCL1 andFgAGO2 also account for pathogenesis as their knock-out (KO) results in reduced FHB development. Apart from KO mutantsΔdcl2andΔago1, mutantsΔrdrp2, Δrdrp3, Δrdrp4, Δqde3andΔqipare strongly compromised for conidiation, while KO mutations in allRdPRs, QDE3andQIPstrongly affect ascosporogenesis. Analysis of trichothecenes mycotoxins in wheat kernels showed that the relative amount of deoxynivalenol (DON), calculated as [DON] per amount of fungal genomic DNA, was reduced in all spikes infected with RNAi mutants, suggesting the possibility that the fungal RNAi pathways affectFg’s DON production in wheat spikes. Moreover, gene silencing by exogenous target gene specific dsRNA (spray-induced gene silencing, SIGS) is dependent on fungal DCLs, AGOs, and QIP, but not on QDE3. Together these data show that inF. graminearumdifferent key components of the RNAi machinery are crucial in different steps of fungal development and pathogenicity.
KPHMMER: Hidden Markov Model generator for detecting KEGG PATHWAY-specific genes
Authors: Suetake Hirotaka , Kotera Masaaki 
Published: May 2019

AbstractMotivationReinforcement of HMMER search for secondary metabolism-specific Pfam domains should contribute to discover novel biosynthetic machinery of clinically important natural products.ResultsHere we provide a Python-based command line tool, named as KPHMMER, to extract the Pfam domains that are specific in the user-defined set of pathways in the user-defined set of organisms registered in the KEGG database. KPHMMER outperformed the previous study in detecting secondary metabolism-specific Pfam domain set. Furthermore, it was proven that KPHMMER helps reduce the computational cost compared with the case using the whole Pfam-A HMM file. We believe that KPHMMER is a powerful tool enabling to deal with many other genome-sequenced species for more general purpose.AvailabilityKPHMMER is implemented as a Python package freely available via the package management system “pip” and also at https://github.com/suecharo/KPHMMERContactmaskot@chemsys.t.u-tokyo.ac.jp
A genomic approach to inferring kinship reveals limited intergenerational dispersal in the yellow fever mosquito
Authors: Jasper Moshe , Schmidt Thomas L. , Ahmad Nazni W. , Sinkins Steven P. , Hoffmann Ary A 
Published: May 2019

AbstractUnderstanding past dispersal and breeding events can provide insight into ecology and evolution, and can help inform strategies for conservation and the control of pest species. However, parent-offspring dispersal can be difficult to investigate in rare species and in small pest species such as mosquitoes. Here we develop a methodology for estimating parent-offspring dispersal from the spatial distribution of close kin, using pairwise kinship estimates derived from genome-wide single nucleotide polymorphisms (SNPs). SNPs were scored in 162Aedes aegypti(yellow fever mosquito) collected from eight close-set, high-rise apartment buildings in an area of Malaysia with high dengue incidence. We used the SNPs to reconstruct kinship groups across three orders of kinship. We transformed the geographical distances between all kin pairs within each kinship category into axial standard deviations of these distances, then decomposed these into components representing past dispersal events. From these components, we isolated the axial standard deviation of parent-offspring dispersal, and estimated neighbourhood area (129 m), median parent-offspring dispersal distance (75 m), and oviposition dispersal radius within a gonotrophic cycle (36 m). We also analysed genetic structure using distance-based redundancy analysis and linear regression, finding isolation by distance both within and between buildings and estimating neighbourhood size at 268 individuals. These findings indicate the scale required to suppress local outbreaks of arboviral disease and to target releases of modified mosquitoes for mosquito and disease control. Our methodology is readily implementable for studies of other species, including pests and species of conservation significance.
NGSEA: network-based gene set enrichment analysis for interpreting gene expression phenotypes with functional gene sets
Authors: Han Heonjong , Lee Sangyoung , Lee Insuk 
Published: May 2019

ABSTRACTGene set enrichment analysis (GSEA) is a popular tool to identify underlying biological processes in clinical samples using their gene expression phenotypes. GSEA measures the enrichment of annotated gene sets that represent biological processes for differentially expressed genes (DEGs) in clinical samples. GSEA may be suboptimal for functional gene sets, however, because DEGs from the expression dataset may not be functional genes per se but dysregulated genes perturbed by bona fide functional genes. To overcome this shortcoming, we developed network-based GSEA (NGSEA), which measures the enrichment score of functional gene sets using the expression difference of not only individual genes but also their neighbors in the functional network. We found that NGSEA outperformed GSEA in identifying pathway gene sets for matched gene expression phenotypes. We also observed that NGSEA substantially improved the ability to retrieve known anti-cancer drugs from patient-derived gene expression data using drug-target gene sets compared with another method, Connectivity Map. We also repurposed FDA-approved drugs using NGSEA and experimentally validated budesonide as a chemical with anti-cancer effects for colorectal cancer. We, therefore, expect that NGSEA will facilitate both pathway interpretation of gene expression phenotypes and anti-cancer drug repositioning. NGSEA is freely available at www.inetbio.org/ngsea.
Immune Profiling Panel: a proof of concept study of a new multiplex molecular tool to assess the immune status of critically-ill patients
Authors: Tawfik Dina M. , Vachot Laurence , Bocquet Adeline , Venet Fabienne , Rimmelé Thomas , Monneret Guillaume , Blein Sophie , Montogomery Jesse L. , Hemmert Andrew C. , Pachot Alexandre , Moucadel Virginie , Marcos Javier Yugueros , Brengel-Pesce Karen , Mallet François , Textoris Julien 
Published: May 2019

AbstractBackgroundCritical illness such as sepsis is a life-threatening syndrome defined as a dysregulated host response to infection and is characterized by patients exhibiting various impaired immune profiles. In the field of diagnosis, a gap still remains in identifying the immune profile of critically-ill patients in the ICU. The availability of an immune profiling tool holds a great potential in providing patients at high risk with more accurate and precise management. In this study, a multiplex immune profiling panel prototype was assessed for its ability to semi-quantify immune markers directly from blood, using the FilmArray® System.ResultsThe Immune Profiling Panel (IPP) prototype consists of 16 biomarkers that target both the innate and adaptive immune responses, pro- and anti-inflammatory mediators as well as genes involved in diverse regulatory pathways. The analytical studies carried out on healthy volunteers showed minimal inter- and intra-variability in testing the samples across the tested lots. The majority of the assays were linear with an R2 higher than 0.8. Results from the IPP pouch were comparable to qPCR and were within the limits of agreement. Finally, quantification cycle values of the target genes were normalized against reference genes to account for the different composition of cells among specimens. The use of the selected panel of markers in IPP demonstrated various gene modulations that could distinctly differentiate three profiles: healthy, borderline mHLA-DR septic shock patients and low mHLA-DR septic shock patients.ConclusionThe Immune Profiling Panel allowed host transcriptomic analysis of immune response biomarkers directly from whole blood in less than an hour. The use of IPP showed great potential for the development of a fully automated, rapid and easy-to-use immune profiling tool, enabling the stratification of critically-ill patients at high risk in the ICU.
Manganese/iron-supported sulfate-dependent anaerobic oxidation of methane by archaea in lake sediments
Authors: Su Guangyi , Zopfi Jakob , Yao Haoyi , Steinle Lea , Niemann Helge , Lehmann Moritz F. 
Published: May 2019

AbstractAnaerobic oxidation of methane (AOM) by methanotrophic archaea is an important sink of this greenhouse gas in marine sediments. However, evidence for AOM in freshwater habitats is rare, and little is known about the pathways, electron acceptors and microbes involved. Here, we show that AOM occurs in anoxic sediments of a lake in southern Switzerland (Lake Cadagno). Combined AOM-rate and 16S rRNA gene-sequencing data suggest thatCandidatusMethanoperedens archaea are responsible for the observed methane oxidation. Members of the Methanoperedenaceae family were previously reported to conduct nitrate- or iron/manganese-dependent AOM. However, we demonstrate for the first time that the methanotrophic archaea do not necessarily rely upon these oxidants as terminal electron acceptors directly, but mainly perform canonical sulfate-dependent AOM, which under sulfate-starved conditions can be supported by metal (Mn, Fe) oxides through oxidation of reduced sulfur species to sulfate. The correspondence of high abundances of Desulfobulbaceae andCandidatusMethanoperedens at the same sediment depth confirm the interdependence of anaerobic methane-oxidizing archaea and sulfate-reducing bacteria. The relatively high abundance and widespread distribution ofCandidatusMethanoperedens in lake sediments highlight their potentially important role in mitigating methane emissions from terrestrial freshwater environments to the atmosphere, analogous to ANME-1, -2 and -3 in marine settings.