bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Airway Transcriptome as a Biomarker for Early Lung Cancer Detection
Authors: Billatos Ehab , Vick Jessica L. , Lenburg Marc E. , Spira Avrum E. 
Published: February 2018

Abstract
Lung cancer remains the leading cause of cancer-related death due to its advanced stage at diagnosis. Early detection of lung cancer can be improved by better defining who should be screened radiographically and determining which imaging-detected pulmonary nodules are malignant. Gene expression biomarkers measured in normal-appearing airway epithelium provide an opportunity to use lung cancer–associated molecular changes in this tissue for early detection of lung cancer. Molecular changes in the airway may result from an etiologic field of injury and/or field cancerization. The etiologic field of injury reflects the aberrant physiologic response to carcinogen exposure that creates a susceptible microenvironment for cancer initiation. In contrast, field cancerization reflects effects of “first-hit” mutations in a clone of cells from which the tumor ultimately arises or the effects of the tumor on the surrounding tissue. These fields might have value both for assessing lung cancer risk and diagnosis. Cancer-associated gene expression changes in the bronchial airway have recently been used to develop and validate a 23-gene classifier that improves the diagnostic yield of bronchoscopy for lung cancer among intermediate-risk patients. Recent studies have demonstrated that these lung cancer–related gene expression changes extend to nasal epithelial cells that can be sampled noninvasively. While the bronchial gene expression biomarker is being adopted clinically, further work is necessary to explore the potential clinical utility of gene expression profiling in the nasal epithelium for lung cancer diagnosis, lung cancer risk assessment, and precision medicine for lung cancer treatment and chemoprevention. Clin Cancer Res; 24(13); 2984–92. ©2018 AACR.
Disruption of Wnt/β-Catenin Exerts Antileukemia Activity and Synergizes with FLT3 Inhibition in FLT3-Mutant Acute Myeloid Leukemia
Authors: Jiang Xuejie , Mak Po Yee , Mu Hong , Tao Wenjing , Mak Duncan H. , Kornblau Steven , Zhang Qi , Ruvolo Peter , Burks Jared K. , Zhang Weiguo , McQueen Teresa , Pan Rongqing , Zhou Hongsheng , Konopleva Marina , Cortes Jorge , Liu Qifa , Andreeff Michael , Carter Bing Z. 
Published: February 2018

Abstract
Purpose: Wnt/β-catenin signaling is required for leukemic stem cell function. FLT3 mutations are frequently observed in acute myeloid leukemia (AML). Anomalous FLT3 signaling increases β-catenin nuclear localization and transcriptional activity. FLT3 tyrosine kinase inhibitors (TKI) are used clinically to treat FLT3-mutated AML patients, but with limited efficacy. We investigated the antileukemia activity of combined Wnt/β-catenin and FLT3 inhibition in FLT3-mutant AML.
Experimental Design: Wnt/β-catenin signaling was inhibited by the β-catenin/CBP antagonist C-82/PRI-724 or siRNAs, and FLT3 signaling by sorafenib or quizartinib. Treatments on apoptosis, cell growth, and cell signaling were assessed in cell lines, patient samples, and in vivo in immunodeficient mice by flow cytometry, Western blot, RT-PCR, and CyTOF.
Results: We found significantly higher β-catenin expression in cytogenetically unfavorable and relapsed AML patient samples and in the bone marrow–resident leukemic cells compared with circulating blasts. Disrupting Wnt/β-catenin signaling suppressed AML cell growth, induced apoptosis, abrogated stromal protection, and synergized with TKIs in FLT3-mutated AML cells and stem/progenitor cells in vitro. The aforementioned combinatorial treatment improved survival of AML-xenografted mice in two in vivo models and impaired leukemia cell engraftment. Mechanistically, the combined inhibition of Wnt/β-catenin and FLT3 cooperatively decreased nuclear β-catenin and the levels of c-Myc and other Wnt/β-catenin and FLT3 signaling proteins. Importantly, β-catenin inhibition abrogated the microenvironmental protection afforded the leukemic stem/progenitor cells.
Conclusions: Disrupting Wnt/β-catenin signaling exerts potent activities against AML stem/progenitor cells and synergizes with FLT3 inhibition in FLT3-mutant AML. These findings provide a rationale for clinical development of this strategy for treating FLT3-mutated AML patients. Clin Cancer Res; 24(10); 2417–29. ©2018 AACR.
Integrated Pharmacokinetic/Pharmacodynamic Model of a Bispecific CD3xCD123 DART Molecule in Nonhuman Primates: Evaluation of Activity and Impact of Immunogenicity
Authors: Campagne Olivia , Delmas Audrey , Fouliard Sylvain , Chenel Marylore , Chichili Gurunadh R. , Li Hua , Alderson Ralph , Scherrmann Jean-Michel , Mager Donald E. 
Published: February 2018

AbstractPurpose: Flotetuzumab (MGD006 or S80880) is a bispecific molecule that recognizes CD3 and CD123 membrane proteins, redirecting T cells to kill CD123-expressing cells for the treatment of acute myeloid leukemia. In this study, we developed a mathematical model to characterize MGD006 exposure–response relationships and to assess the impact of its immunogenicity in cynomolgus monkeys.Experimental Design: Thirty-two animals received multiple escalating doses (100-300-600-1,000 ng/kg/day) via intravenous infusion continuously 4 days a week. The model reflects sequential binding of MGD006 to CD3 and CD123 receptors. Formation of the MGD006/CD3 complex was connected to total T cells undergoing trafficking, whereas the formation of the trimolecular complex results in T-cell activation and clonal expansion. Activated T cells were used to drive the peripheral depletion of CD123-positive cells. Anti-drug antibody development was linked to MGD006 disposition as an elimination pathway. Model validation was tested by predicting the activity of MGD006 in eight monkeys receiving continuous 7-day infusions.Results: MGD006 disposition and total T-cell and CD123-positive cell profiles were well characterized. Anti-drug antibody development led to the suppression of T-cell trafficking but did not systematically abolish CD123-positive cell depletion. Target cell depletion could persist after drug elimination owing to the self-proliferation of activated T cells generated during the first cycles. The model was externally validated with the 7-day infusion dosing schedule.Conclusions: A translational model was developed for MGD006 that features T-cell activation and expansion as a key driver of pharmacologic activity and provides a mechanistic quantitative platform to inform dosing strategies in ongoing clinical studies. Clin Cancer Res; 24(11); 2631–41. ©2018 AACR.
Androgen Deprivation Therapy Potentiates the Efficacy of Vascular Targeted Photodynamic Therapy of Prostate Cancer Xenografts
Authors: Kim Kwanghee , Watson Philip A. , Lebdai Souhil , Jebiwott Sylvia , Somma Alexander J. , La Rosa Stephen , Mehta Dipti , Murray Katie S. , Lilja Hans , Ulmert David , Monette Sebastien , Scherz Avigdor , Coleman Jonathan A. 
Published: February 2018

Abstract
Purpose: WST11 vascular targeted photodynamic therapy (VTP) is a local ablation approach relying upon rapid, free radical-mediated destruction of tumor vasculature. A phase III trial showed that VTP significantly reduced disease progression when compared with active surveillance in patients with low-risk prostate cancer. The aim of this study was to identify a druggable pathway that could be combined with VTP to improve its efficacy and applicability to higher risk prostate cancer tumors.
Experimental Design: Transcriptome analysis of VTP-treated tumors (LNCaP-AR xenografts) was used to identify a candidate pathway for combination therapy. The efficacy of the combination therapy was assessed in mice bearing LNCaP-AR or VCaP tumors.
Results: Gene set enrichment analysis identifies the enrichment of androgen-responsive gene sets within hours after VTP treatment, suggesting that the androgen receptor (AR) may be a viable target in combination with VTP. We tested this hypothesis in mice bearing LNCaP-AR xenograft tumors by using androgen deprivation therapy (ADT), degarelix, in combination with VTP. Compared with either ADT or VTP alone, a single dose of degarelix in concert with VTP significantly inhibited tumor growth. A sharp decline in serum prostate-specific antigen (PSA) confirmed AR inhibition in this group. Tumors treated by VTP and degarelix displayed intense terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling staining 7 days after treatment, supporting an increased apoptotic frequency underlying the effect on tumor inhibition.
Conclusions: Improvement of local tumor control following androgen deprivation combined with VTP provides the rationale and preliminary protocol parameters for clinical trials in patients presented with locally advanced prostate cancer. Clin Cancer Res; 24(10); 2408–16. ©2018 AACR.
Intrinsic Functional Potential of NK-Cell Subsets Constrains Retargeting Driven by Chimeric Antigen Receptors
Authors: Oei Vincent Yi Sheng , Siernicka Marta , Graczyk-Jarzynka Agnieszka , Hoel Hanna Julie , Yang Weiwen , Palacios Daniel , Almåsbak Hilde , Bajor Malgorzata , Clement Dennis , Brandt Ludwig , Önfelt Björn , Goodridge Jodie , Winiarska Magdalena , Zagozdzon Radoslaw , Olweus Johanna , Kyte Jon-Amund , Malmberg Karl-Johan 
Published: February 2018

AbstractNatural killer (NK) cells hold potential as a source of allogeneic cytotoxic effector cells for chimeric antigen receptor (CAR)-mediated therapies. Here, we explored the feasibility of transfecting CAR-encoding mRNA into primary NK cells and investigated how the intrinsic potential of discrete NK-cell subsets affects retargeting efficiency. After screening five second- and third-generation anti-CD19 CAR constructs with different signaling domains and spacer regions, a third-generation CAR with the CH2-domain removed was selected based on its expression and functional profiles. Kinetics experiments revealed that CAR expression was optimal after 3 days of IL15 stimulation prior to transfection, consistently achieving over 80% expression. CAR-engineered NK cells acquired increased degranulation toward CD19+ targets, and maintained their intrinsic degranulation response toward CD19− K562 cells. The response of redirected NK-cell subsets against CD19+ targets was dependent on their intrinsic thresholds for activation determined through both differentiation and education by killer cell immunoglobulin-like receptors (KIR) and/or CD94/NKG2A binding to self HLA class I and HLA-E, respectively. Redirected primary NK cells were insensitive to inhibition through NKG2A/HLA-E interactions but remained sensitive to inhibition through KIR depending on the amount of HLA class I expressed on target cells. Adaptive NK cells, expressing NKG2C, CD57, and self-HLA–specific KIR(s), displayed superior ability to kill CD19+, HLA low, or mismatched tumor cells. These findings support the feasibility of primary allogeneic NK cells for CAR engineering and highlight a need to consider NK-cell diversity when optimizing efficacy of cancer immunotherapies based on CAR-expressing NK cells. Cancer Immunol Res; 6(4); 467–80. ©2018 AACR.
Ventricular Fibrillation Conversion Testing After Implantation of a Subcutaneous Implantable Cardioverter Defibrillator
Authors: Friedman Daniel J. , Parzynski Craig S. , Heist E. Kevin , Russo Andrea M. , Akar Joseph G. , Freeman James V. , Curtis Jeptha P. , Al-Khatib Sana M. 
Published: February 2018

Background:
Compared with transvenous implantable cardioverter defibrillators (ICDs), subcutaneous (S)-ICDs require a higher energy for effective defibrillation. Although ventricular fibrillation conversion testing (CT) is recommended after S-ICD implantation to ensure an adequate margin between the defibrillation threshold and maximum device output (80J), prior work found that adherence to this recommendation is declining.

Methods:
We studied first-time recipients of S-ICDs (between September 28, 2012, and April 1, 2016) in the National Cardiovascular Database Registry ICD Registry to determine predictors of use of CT, predictors of an insufficient safety margin (ISM, defined as ventricular fibrillation conversion energy >65J) during testing, and inhospital outcomes associated with use of CT. Multivariable logistic regression analysis was used to predict use of CT and ISM. Inverse probability weighted logistic regression analysis was used to examine the association between use of CT and inhospital adverse events including death.

Results:
CT testing was performed in 70.7% (n=5624) of 7960 patients with S-ICDs. Although deferral of CT was associated with several patient characteristics (including increased body mass index, increased body surface area, severely reduced ejection fraction, dialysis dependence, warfarin use, anemia, and hypertrophic cardiomyopathy), the facility effect was comparatively more important (area under the curve for patient level versus generalized linear mixed model: 0.619 versus 0.877). An ISM occurred in 6.9% (n=336) of 4864 patients without a prior ICD and was more common among white patients and those with ventricular pacing on the preimplant ECG, higher preimplant blood pressure, larger body surface area, higher body mass index, and lower ejection fraction. A risk score was able to identify patients at low (<5%), medium (5% to 10%), and high risk (>10%) for ISM. CT testing was not associated with a composite of inhospital complications including death.

Conclusions:
Use of CT testing after S-ICD implantation was driven by facility preference to a greater extent than patient factors and was not associated with a composite of inhospital complications or death. ISM was relatively uncommon and is associated with several widely available patient characteristics. These data may inform ICD system selection and a targeted approach to CT.
Divine Provision and the “Preternatural Imagination” of Edward Burne-Jones in the Mosaics of “The American Church” in Rome
Authors: Hostetter Smith Rachel 
Published: February 2018

Abstract
This essay examines the multiplicity of ways the building and decoration of the American church of St. Paul’s Within-the-Walls in Rome signaled the dawning of a “new age,” politically and spiritually, as the first Protestant church constructed within the city of Rome, initiated immediately after the city was freed from papal rule in 1870. The mosaics, designed by Pre-Raphaelite artist Edward Burne-Jones and completed with the help of his assistant Thomas Rooke in the decades that follow, present Christ, and the Church in particular, as sources of divine sustenance and verdant life in the barren wilderness of this world. But it is the splendor of their design and the material magnificence of the mosaics themselves that create the first powerful and most lasting impact. Viewed through the lens of what P. T. Forsyth described as the “preternatural imagination” of Burne-Jones, these mosaics are distinctly contemporary works deeply rooted in religious and artistic tradition that address the transitional times for which they were made.
Associating sex-biased and seasonal behaviour with contact patterns and transmission risk in Gopherus agassizii
Authors: Aiello C.M. , Esque T.C. , Nussear K.E. , Emblidge P.G. , Hudson P.J. 
Published: February 2018

AbstractInteractions between wildlife hosts act as transmission routes for directly transmitted pathogens and vary in ways that affect transmission efficiency. Identifying drivers of contact variation can allow both contact inference and estimation of transmission dynamics despite limited data. In desert tortoises, mating strategy, burrow use and seasonal change influence numerous behaviours and likely shape contact patterns. In this study, we ask to what extent tortoise contact behaviour varies between sexes and seasons, and whether space or burrow-use data can be used to infer contact characteristics consistent with those recorded by proximity loggers. We identified sex and season-biased contact behaviour in both wild and captive populations indicative of female-female avoidance and seasonal male mate-seeking behaviour. Space and burrow-use patterns were informative, but did not always predict the extent of sex or seasonal biases on contact. We discuss the implications these findings have for transmission patterns and disease mitigation in tortoise populations.
Behavioural dominance of the invasive red-billed leiothrix (Leiothrix lutea) over European native passerine-birds in a feeding context
Authors: Pereira Pedro Filipe , Lourenço Rui , Mota Paulo Gama 
Published: February 2018

AbstractBehavioural dominance and aggressiveness may be crucial traits facilitating the establishment of invasive species. Few studies considered agonistic interactions between exotic and native bird species in feeding contexts, particularly when the exotic has social habits. We aimed to know if individuals of a social invasive species, the red-billed leiothrixLeiothrix lutea, are: more aggressive; the initiators of the first interaction; and dominant (i.e., won most interactions) over native opponents in a feeding context. We performed an experiment in a closed environment forcing dyadic interactions between an individual of a native species facing a leiothrix individual. We found that the leiothrix was the initiator in most experiments, being apparently dominant over natives. However, the invader was not more aggressive than natives. This can increase the risk of injury for natives because the leiothrix has a relatively larger body size. We discuss possible negative impacts of the leiothrix on native species.
Comments on taxonomic status and host association of some Laimaphelenchus spp. (Rhabditida: Aphelenchoidea)
Authors: Pedram Majid , Pourhashemi Mehdi , Hosseinzadeh Jaafar , Koolivand Davoud 
Published: February 2018

SummaryA reverse taxonomic approach for characterisation of several populations of an aphelenchid nematode recovered from declined oak trees in the Zagros forests, Ilam, western Iran, revealed that their 28S rDNA D2-D3 sequences matched two available sequences of the same genomic fragment belonging to two species,Laimaphelenchus belgradiensisandL. hyrcanus. Further morphological studies yielded new morphological traits that had been overlooked in their original descriptions, and a new hypothesis helping to disentangle these taxa, which have the same 28S sequences and the same phylogenetic placement, is proposed. In a similar fashion, the taxonomic status of some other species of the genus having a similar morphology or similar genomic sequences are reviewed. The possibility of proposing new synonyms was evaluated and tentative reasons for the new habitat of the recovered populations ofLaimaphelenchusfrom the Zagros forests discussed.
Cardiac surgery patients’ e-health literacy and their use of a digital portal
Authors: Khan Delvin , Fjerbæk Annette , Andreasen Jan J , Thorup Charlotte B , Dinesen Birthe 
Published: February 2018

Objective: To determine how cardiac patients use the Activeheart.dk digital toolbox Methods: Mixed-methods study. A total of n = 33 cardiac surgical patients were enrolled in a study, which encouraged use of the Activeheart portal for 4 weeks after discharge. Patients were surveyed with respect to their demographic characteristics, e-health literacy skills, use of the Internet and use of the portal. In addition to the questionnaire survey, qualitative interviews were conducted with six randomly selected patients in order to study users’ experiences with and use of the portal. Results: Quantitative results showed no relation between cardiac patients’ prior e-health literacy skills and their use of the portal. Approximately 25 out of 31 patients stated that they had the skills to seek, locate and use health information on the Internet. Among the 17 patients who completed the first and second questionnaires, nine rarely used Activeheart.dk, four used it several times per month, and four several times per week. In 10 out of 16 replies, Activeheart.dk was rated as relevant or very relevant. Themes from the qualitative interviews revealed that the effects of medication and emotional, physical and cognitive changes had a higher impact on the use of the portal than prior e-health literacy skills. Conclusion: While participants’ e-health literacy skills ratings were high, and while participants stated that the content of the portal was relevant, their actual use of the portal remained limited. No relationship was found between participants’ e-health literacy skills and their use of the portal. Factors such as patient motivation, resources and timing of the intervention’s introduction seemed to be of greater importance.
Improving mental health knowledge of the Charedi Orthodox Jewish Community in North London: A partnership project
Authors: Perry Aradhana , Gardener Chelsea , Dove Jonathan , Eiger Yocheved , Loewenthal Kate 
Published: February 2018

Introduction: This article describes a successful community-based partnership project between statutory and third-sector services targeting the strictly Orthodox Jewish community (OJC). Methods: The City and Hackney Black and Minority Ethnic (BME) Access Service (East London NHS Foundation Trust (ELFT)) collaborated with Bikur Cholim, a local third-sector organisation based in the heart of a north London Charedi OJC, to develop a brief culturally tailored psychoeducational group intervention focusing on mental health promotion and prevention. In total, 34 carers in the Charedi OJC were provided with general information on mental health, the availability of support services and self-care. Results: Overall improvements in well-being, increased intentions to access services, particularly talking therapies, and qualitative feedback indicated that the group was very well received. Conclusion: The project endorses the value of culturally relevant psychoeducation, enabling suggestions for culturally appropriate service development.
Is Graphology Useful in Assessing Major Depression?
Authors: Giannini Marco , Pellegrini Pietro , Gori Alessio , Loscalzo Yura 
Published: February 2018

This study aimed to develop a handwriting analysis protocol for assessing severe major depressive disorder, in order to evaluate whether graphological analysis could be considered an objective tool and hence if it could be useful for clinicians in their early diagnosis. We modified and improved the methodology described by Lorusso et al. by proposing different graphic indexes based both on the literature and on the observation of a preliminary sample of 13 handwritings of patients affected by major depressive disorder. Then, we recruited 80 participants, divided into two groups: clinical sample ( n = 44) and control group ( n = 36). We used Cohen's Kappa to evaluate the reliability of agreement among four professional graphologists and the consensus between the psychiatric assessment and the ratings given by the judges. We found satisfactory results. Using our protocol, we obtained higher values for Cohen’s Kappa as compared with Lorusso et al. The agreement among graphologists is K = .62, while the K values for the agreement between psychiatric assessment and graphologists range between .47 and .60. The substantial improvements obtained in comparison with Lorusso et al. are encouraging and support further attempts.