bluuebunny/crossref_metadata_2025 huggingface dataset:
Australian landscape memoir as conservationist vehicle: Winton, Tredinnick, Greer
Authors: Huddart David , Huggan Graham
Published: December 2020

In this essay, we propose to study three recent Australian landscape memoirs – Tim Winton’s Island Home (2015), Mark Tredinnick’s The Blue Plateau (2009) and Germaine Greer’s White Beech (2013) – all of which demonstrate the capacity of landscapes to act as perceptual conduits for the fundamental tension between world and self. Our main contention is that landscape memoir acts as a pre-eminent vehicle for this tension, which is captured across different times and spaces and among multiple, intricately co-constituted life-worlds. Landscape memoir, in this and other ways, functions as both a multi-sensory phenomenological instrument for the recording of physical and emotional engagement with landscape and a distinct, episodically organised mode of life writing that seeks to understand the fractured nature of individual selfhood in the context of a more-than-human world. The essay also looks at the capacity of memoirs of this kind to operate as vehicles for conservationist thinking and action. In each of our three main cases, landscape mediates between an insecure self and a world or worlds that are portrayed as being threatened, although this is not enough in itself to establish a basis for the three works as ‘conservationist’ texts. However, all three can be seen as individual enquiries into different kinds of conservation that use the techniques and characteristics of landscape memoir to reflect on the material possibilities of personal and collective recovery (Winton) and ecological restoration (Greer); or, over and against these, to mark the elegiac registration of irretrievable loss (Tredinnick).
The politics of educational transitions: Evidence from Catalonia
Authors: Tarabini Aina , Jacovkis Judith
Published: December 2020

Transitions to upper secondary education are of crucial importance to understanding educational inequalities. They are also vital in explaining the contemporary dynamics of Early School Leaving. Global hegemonic discourses around educational transitions and Early School Leaving shape student pathways in terms of rational and linear choices, assuming equal opportunities for lifelong learning. Simultaneously, the European Strategy attributes key roles to Vocational Education and Training and to guidance in order to smooth educational transitions, reduce Early School Leaving and meet the needs of the knowledge-based economy. The aim of the article is to problematise the linear relationship between Early School Leaving, Vocational Education and Training, and guidance policies representing the dominant contemporary rhetoric concerned with ensuring smooth transitions and opening up long-term educational pathways for young people. The article provides an in-depth analysis of the political construction of the transition from lower to upper secondary education in Catalonia, identifying how it is conceptualised at a discursive level by policy actors and also how it is implemented at the institutional level. The results aim to be regarded as a useful analytical resource to inform critical policy analyses of educational transitions and their implications in terms of social inequalities.
Lying to patients: Ethics of deception in nursing
Authors: Curtis Drew A , Braziel Jennifer M , Redfearn Robert A , Hall Jaimee
Published: December 2020

While the ethical use of deception has been discussed in literature, the ethics and acceptability of nursing deception has yet to be studied. The current study examined nurses’ and nursing students’ ratings of the ethics and acceptability of nursing deception. We predicted that nurses and nursing students would rate a truthful vignette as more ethical than a deceptive vignette. We also predicted that participants would rate nursing deception as unethical and unacceptable. A mixed design was used to examine ethics scores as a within-subjects factor and order as a between-groups design factor. A total of 131 nurses and nursing students were recruited from university nursing programs and hospitals in Texas. Participants were provided with a truthful vignette and deceptive vignette and used the Multidimensional Ethics Scale-Revised 1 to rate each vignette. Participants also completed the Lies in Nursing Ethics Questionnaire. The truthful nursing vignette was rated as more ethical than the deceptive vignette. Results indicated that most participants rated nursing deception as unethical, unacceptable, and a violation of the ANA ethical code. Some participants deemed that nursing deception may be acceptable within some cases. Age and years of experience were not related to the perceived ethics and acceptability of nursing deception.

Nurses and nursing students believe that using deception with patients is unethical and unacceptable. However, some participants believed that deception may be warranted within some cases. These findings may reflect nurses’ placing the patient at the core of their values and viewing honesty as important for the nurse-patient relationship. Further implications and directions are discussed.
The Angelus: Devotional Television, Changing Times
Authors: McCarthy Anna
Published: December 2020

The ringing of the Angelus, a Catholic call to prayer, is a staple of Irish state television broadcasting, occurring at 6 o’clock every evening. Over the years, the image track accompanying the bell has changed, transitioning from still to moving images and incorporating an increasingly secular pictorial repertoire. Although the Angelus is TV you are not supposed to watch, the document archives at Radió Teleifís Éireann offer plenty of rich evidence that people have always watched the Angelus closely, that they feel a personal stake in its modes of representation, and that they approach religious images as statements about religion and the Church.
The Combined Detection of Immune Genes for Predicting the Prognosis of Patients With Non-Small Cell Lung Cancer
Authors: Tian Wen-Juan , Liu Shan-Shan , Li Bu-Rong
Published: December 2020

Lung cancer is one of the leading causes of cancer-related death. In recent years, there has been an increasing interest in the fields of tumor and immunity. This study focused on the possible prognostic value of immune genes in non-small cell lung cancer patients. We used The Cancer Genome Atlas (TCGA) to download gene expression data and clinical information of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). The immune gene list was downloaded from the Immport database. We then constructed immune gene prognostic models on the basis of Cox regression analysis. We further evaluated the clinical significance of the models via survival analysis, receiver operating characteristic (ROC) curves, and independent prognostic factor analysis. Moreover, we analyzed the associations of prognostic models with both mutation burdens and neoantigens. Using the Gene Expression Omnibus (GEO) and Kaplan–Meier plotter databases, we evaluated the validity of the prognostic models. The prognostic model of LUAD included 13 immune genes, and the prognostic model of LUSC contained 10 immune genes. High-risk patients based on prognostic models had a lower 5-year survival rate than did low-risk patients. The ROC curve analysis demonstrated the prediction accuracy of the prognostic models, as the area under the curve (AUC) was 0.742, 0.707, and 0.711 for LUAD, and 0.668, 0.703, and 0.668 for LUSC, when the predicted survival times were 1, 3, and 5 years, respectively. The mutation burden analysis showed that mutation level was associated with the risk score in patients with LUAD. The analysis based on GEO and Kaplan–Meier plotter demonstrated the prognostic validity of the models. Therefore, immune gene-related models of LUAD and LUSC can predict prognosis. Further study of these genes may enable us to better distinguish between LUAD and LUSC and lead to improvement in immunotherapy for lung cancer.
Diabetic Foot Infections: Bacterial Isolates From the Centers and Hospitals of Latin American Countries
Authors: Carro Gabriela Verónica , Saurral Ruben , Salvador Sagüez Francisco , Witman Erica Lorena
Published: December 2020

Diabetic foot infections (DFIs) are one of the most important reasons for lower limb amputations. An adequate approach to the management of DFI implies control of infection using strategies of tissue debridement and empirical antibiotic treatment based on local microbiology. The aim of this study was to determine the bacterial isolates profile and antibiotic susceptibility patterns in samples from DFI from Latin American centers, on the premise that microbiology of this region differs from that of other continents and influences antimicrobial election. Three hundred and eighty-two samples from soft tissue and bone were studied from 17 centers of 4 countries. Three hundred and seven (80.4%; 95% confidence interval = 75.9-84.2) were positive. Gram negatives (GN) were isolated in 43.8% of all samples, not only in severe but also in mild infections, 51% in bone samples, more frequently in presence of ischemia (47% vs 38%; P = .07) and in wounds with longer duration of the lesion (30-20 days; P < .01). Staphylococcus aureus was the most frequent single germ (19.9%). Gram positives were isolated more frequently in patients without ischemia (53% vs 40%; P = .01). Enterococcus faecalis was the most frequent germ in bone samples (16.8%). Ciprofloxacin and trimethoprim-sulfamethoxazole were the oral antimicrobials most effective against GN. Trimethoprim-sulfamethoxazole and rifampicin were the oral antimicrobials most effective against Staphylococcus. Because of GN high antibiotic resistance patterns, patients treated in an ambulatory setting have to be controlled early after starting empiric treatment to assess response to therapy and hospitalize for parenteral antibiotics if oral treatment fails.
Calming the Storm: Natural Disasters, Crisis Management, and School Leadership
Authors: Potter Phillip D. , Pavlakis Alexandra E. , Roberts J. Kessa
Published: December 2020

Natural disasters can negatively impact students’ educational outcomes and well-being. After a natural disaster, families and communities often rely on schools to foster stability and serve as a conduit to resources. Yet, school principals face many challenges, often with little guidance, in how to best respond to natural disasters. This case demonstrates that, in the aftermath of a natural disaster, educational leaders may be required to communicate effectively with staff and media; make operational, managerial, and logistical decisions quickly and under immense pressure; efficiently assess families’ needs; manage the outpouring of philanthropy; and integrate parent and community voice in governance.
Data management in substance use disorder treatment research: Implications from data harmonization of National Institute on Drug Abuse-funded randomized controlled trials
Authors: Susukida Ryoko , Amin-Esmaeili Masoumeh , Mayo-Wilson Evan , Mojtabai Ramin
Published: December 2020

Background:

Secondary analysis of data from completed randomized controlled trials is a critical and efficient way to maximize the potential benefits from past research. De-identified primary data from completed randomized controlled trials have been increasingly available in recent years; however, the lack of standardized data products is a major barrier to further use of these valuable data. Pre-statistical harmonization of data structure, variables, and codebooks across randomized controlled trials would facilitate secondary data analysis, including meta-analyses and comparative effectiveness studies. We describe a pre-statistical data harmonization initiative to standardize de-identified primary data from substance use disorder treatment randomized controlled trials funded by the National Institute on Drug Abuse available on the National Institute on Drug Abuse Data Share website.

Methods:

Standardized datasets and codebooks with consistent data structures, variable names, labels, and definitions were developed for 36 completed randomized controlled trials. Common data domains were identified to bundle data files from individual randomized controlled trials according to relevant concepts. Variables were harmonized if at least two randomized controlled trials used the same instruments. The structures of the harmonized data were determined based on the feedback from clinical trialists and substance use disorder research experts.

Results:

We have created a harmonized database of variables across 36 randomized controlled trials with a build-in label and a brief definition for each variable. Data files from the randomized controlled trials have been consistently categorized into eight domains (enrollment, demographics, adherence, adverse events, physical health measures, mental-behavioral-cognitive health measures, self-reported substance use measures, and biologic substance use measures). Standardized codebooks and concordance tables have also been developed to help identify instruments and variables of interest more easily.

Conclusion:

The harmonized data of randomized controlled trials of substance use disorder treatments can potentially promote future secondary data analysis of completed randomized controlled trials, allowing combining data from multiple randomized controlled trials and provide guidance for future randomized controlled trials in substance use disorder treatment research.
Composite grading algorithm for the National Cancer Institute’s Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE)
Authors: Basch Ethan , Becker Claus , Rogak Lauren J , Schrag Deborah , Reeve Bryce B , Spears Patricia , Smith Mary Lou , Gounder Mrinal M , Mahoney Michelle R , Schwartz Gary K , Bennett Antonia V , Mendoza Tito R , Cleeland Charles S , Sloan Jeff A , Bruner Deborah Watkins , Schwab Gisela , Atkinson Thomas M , Thanarajasingam Gita , Bertagnolli Monica M , Dueck Amylou C
Published: December 2020

Background:

The Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events is an item library designed for eliciting patient-reported adverse events in oncology. For each adverse event, up to three individual items are scored for frequency, severity, and interference with daily activities. To align the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events with other standardized tools for adverse event assessment including the Common Terminology Criteria for Adverse Events, an algorithm for mapping individual items for any given adverse event to a single composite numerical grade was developed and tested.

Methods:

A five-step process was used: (1) All 179 possible Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events score combinations were presented to 20 clinical investigators to subjectively map combinations to single numerical grades ranging from 0 to 3. (2) Combinations with <75% agreement were presented to investigator committees at a National Clinical Trials Network cooperative group meeting to gain majority consensus via anonymous voting. (3) The resulting algorithm was refined via graphical and tabular approaches to assure directional consistency. (4) Validity, reliability, and sensitivity were assessed in a national study dataset. (5) Accuracy for delineating adverse events between study arms was measured in two Phase III clinical trials (NCT02066181 and NCT01522443).

Results:

In Step 1, 12/179 score combinations had <75% initial agreement. In Step 2, majority consensus was reached for all combinations. In Step 3, five grades were adjusted to assure directional consistency. In Steps 4 and 5, composite grades performed well and comparably to individual item scores on validity, reliability, sensitivity, and between-arm delineation.

Conclusion:

A composite grading algorithm has been developed and yields single numerical grades for adverse events assessed via the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events, and can be useful in analyses and reporting.
A highly selective fluorescent probe for the sensing of Cu2+ based on the hydrolysis of a quinoline-2-carboxylate and its application in cell imaging
Authors: You Qihua , Zhuo Yihua , Feng Yadong , Xiao Yujuan , Zhang Yanyu , Zhang Lei
Published: December 2020

A highly selective OFF–ON fluorescent probe is developed for the sensing of Cu2+ based on the hydrolysis of a quinoline-2-carboxylate moiety. The probe is weakly fluorescent due to esterification of the phenolic group. Upon treatment with 1 equiv. of Cu2+, the probe exhibits strong fluorescence at 570 nm. The probe also exhibits high selectivity for Cu2+ over other cations with a low detection limit of 0.2 μM, which is sensitive enough to meet the standard of the World Health Organization for Cu2+ in drinking water (30 μM). Moreover, the probe shows a very low cell cytotoxicity, and imaging experiments demonstrate that the probe can be used for the sensing of Cu2+ in living cells.
Cancer, familial cancer and genomics: A primary care perspective
Authors: Hayward Judith , Kulkarni Anju , Rafi Imran
Published: December 2020

Advances in genomics have vastly increased our understanding of inherited cancer risk and underlying cancer predisposition syndromes, thereby underpinning a revolution in the diagnosis and treatment of cancer itself. Concern regarding family history of cancer is a common presentation within primary care. This article provides an overview of the role of primary care practitioners in the clinical identification and management of inherited cancer risk within primary care including risk assessment, screening and surveillance. The article will consider management issues, including access to genomic testing and advice on risk-reduction measures. The role of genomics in cancer diagnosis and treatment and future applications will be outlined.
The BRI and China’s Soft Power in Europe: Why Chinese Narratives (Initially) Won
Authors: Turcsanyi Richard , Kachlikova Eva
Published: December 2020

The article aims to contribute to our understanding of China’s soft power in Europe and the impact of the Belt and Road Initiative (BRI) in this regard. We conduct analyses of two leading newspapers in the United Kingdom, in Spain, and in Poland to discover how the BRI was framed there in the period from mid-2013 to mid-2017. The empirical results show that the media reported about the initiative quite positively – especially compared to the general media picture of China in Europe – and to a considerable extent followed Chinese narratives of economic opportunities while overlooking geopolitical and security worries. Theories of “journalistic routines” and linguistic “affective sticking points” will be suggested as possible explanations of these dynamics, highlighting both the fact that Chinese narratives outnumbered European ones in the initial period quantitatively, and were able to offer something that resonated with the audience qualitatively.
Assessment of confinement’s influence on a concrete target’s ability to approximate semi-infinite perforation performance
Authors: Brown Jared L , Howard Isaac L , Frank Andreas O , Roth M. Jason
Published: December 2020

The ability to accurately evaluate impact penetration resistance of a structural element in an experimental setting often requires the experimental impact specimen configuration to be as close as possible to a structural element in a fielded protective design scheme. This includes the target’s capability to estimate the semi-infinite response of a structural element such as a wall where inertial confinement is provided by undamaged material surrounding the area damaged by impact. Artificially simulating this confinement in an experimental target can take several forms, including use of a circumferential steel ring as a confining medium. Experimental data gathered from impact tests were utilized to create a representative numerical simulation of a confined target design. This simulation evaluated artificial and inertial confinement on concrete perforation by varying target to projectile diameters with and without artificial confinement. Perforation performance was found to be unaffected by confinement type when the target diameter to projectile diameter ratio was 16. Semi-infinite surface approximation was found to occur when the target diameter to projectile diameter ratio was 64 despite the confinement type at higher impact velocities; however, this ratio could be reduced while maintaining semi-infinite performance for lower velocity impacts.
A qualitative analysis of sarcasm, irony and related #hashtags on Twitter
Authors: Sykora Martin , Elayan Suzanne , Jackson Thomas W
Published: December 2020

As the use of automated social media analysis tools surges, concerns over accuracy of analytics have increased. Some tentative evidence suggests that sarcasm alone could account for as much as a 50% drop in accuracy when automatically detecting sentiment. This paper assesses and outlines the prevalence of sarcastic and ironic language within social media posts. Several past studies proposed models for automatic sarcasm and irony detection for sentiment analysis; however, these approaches result in models trained on training data of highly questionable quality, with little qualitative appreciation of the underlying data. To understand the issues and scale of the problem, we are the first to conduct and present results of a focused manual semantic annotation analysis of two datasets of Twitter messages (in total 4334 tweets), associated with; (i) hashtags commonly employed in automated sarcasm and irony detection approaches, and (ii) tweets relating to 25 distinct events, including, scandals, product releases, cultural events, accidents, terror incidents, etc. We also highlight the contextualised use of multi-word hashtags in the communication of humour, sarcasm and irony, pointing out that many sentiment analysis tools simply fail to recognise such hashtag-based expressions. Our findings also offer indicative evidence regarding the quality of training data used for automated machine learning models in sarcasm, irony and sentiment detection. Worryingly only 15% of tweets labelled as sarcastic were truly sarcastic. We highlight the need for future research studies to rethink their approach to data preparation and a more careful interpretation of sentiment analysis.
Halofuginone functions as a therapeutic drug for chronic periodontitis in a mouse model
Authors: Wang Jiang , Wang Bo , Lv Xin , Wang Yingjie
Published: December 2020

Periodontitis is an inflammatory disease caused by host immune response, resulting in a loss of periodontium and alveolar bone. Immune cells, such as T cells and macrophages, play a critical role in the periodontitis onset. Halofuginone, a natural quinazolinone alkaloid, has been shown to possess anti-fibrosis, anti-cancer, and immunomodulatory properties. However, the effect of halofuginone on periodontitis has never been reported. In this study, a ligature-induced mice model of periodontitis was applied to investigate the potential beneficial effect of halofuginone on periodontitis. We demonstrated that the administration of halofuginone significantly reduced the expression levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) in vivo, and markedly suppressed immune cell infiltration into the infected sites. Furthermore, we also observed that halofuginone treatment blocked the T-helper 17 (Th17) cell differentiation in vivo and in vitro. We demonstrated for the first time that halofuginone alleviated the onset of periodontitis through reducing immune responses.
Plate fixation versus titanium elastic nailing in midshaft clavicle fractures based on fracture classifications
Authors: Park Jun Sung , Ko Sang Hyun , Hong Taek Ho , Ryu Dong Jin , Kwon Dae Gyu , Kim Myung-Ku , Jeon Yoon Sang
Published: December 2020

Background:

The best strategy for implant selection in midshaft clavicular fractures (MCF) remains controversial. The present study aims to determine the optimal strategy for implant selection by comparing plate and Titanium Elastic Nail (TEN) with respect to outcomes and related complications and analyze the results based on fracture patterns.

Methods:

A total of 97 patients with MCF who underwent plate (48 patients) or TEN (49 patients) fixation were retrospectively reviewed. Both groups were divided into three subgroups by fracture type using the AO Foundation/Orthopaedic Trauma Association classification: simple fracture (type A), wedge fracture (type B), and multi-fragmentary fracture (type C). The observed outcome measures were bone union rate, related complications, functional scores, and patient satisfaction score. These outcomes were analyzed based on the fracture classification.

Results:

Both groups demonstrated excellent union rates (p = 0.495) and similar functional scores (p > 0.05). Visual analog scale (VAS) for satisfaction was better in TEN than plate fixation (p < 0.001). In type A and B subgroups, there were no significant difference in functional scores between plate and TEN fixation (p > 0.05). In type C subgroup, however, both VAS for pain and DASH score in TEN fixation were significantly worse than in plate fixation at 2 and 6 weeks postoperatively (p < 0.05). The incidences of clavicle shortening and skin irritation are higher especially in type C subgroup of TEN fixation (p < 0.05).

Conclusion:

Patient satisfaction of TEN fixation was higher than that of plate fixation, but TEN fixation had a higher incidence of early postoperative pain and migration in type C fractures. Therefore, type A and B fractures can successfully be treated with plate or TEN fixation, but type C fractures should be treated with plate fixation.
Employee selection, education, and firm-provided training
Authors: Barrenechea-Méndez Marco , Ortín-Ángel Pedro , Rodes Eduardo C.
Published: December 2020

Theoretical debate suggests at least three strategies for firms to provide training to employees in the same job position: individualized and egalitarian with or without adaptation to the abilities of the recruited employees. The article provides a formal framework for deriving distinctive empirical implications regarding the relationship of these strategies with the firms’ selection policies, which are tested using a dataset of blue-collar workers in Spanish industrial plants. The evidence is consistent with the empirical implications of the egalitarian strategy with adaptation. This strategy entails providing the same level of training to all workers in the same job position and setting this level according to the average ability of recruited workers. Paradoxically, this strategy has not been used to interpret the results of the existing empirical literature.

JEL CLASSIFICATION

M53; M54; M21; J24
Memsahibs and ayahs during the Mutiny: In English memoirs and fiction
Authors: Sen Sucharita
Published: December 2020

Drawing upon the personal accounts of British women who lived through the Mutiny (1857–58), this article argues that these accounts, being characterised by diversity, both supported and contradicted the official discourse of the British Raj. While the domestic spaces in the household were shaken by the storm of the Mutiny, interpersonal relations sometimes transcended the animosity which the Mutiny had garnered. By bringing the contemporary British fiction into the spectrum of analysis, this article argues that the Mutiny fiction and personal accounts have a common chord in their portrayal of the loyalty of the native servants in the hour of crises for their employers. These relationships, however, also implied the status of white superiority over coloured subordination as also the memsahib’s special preserve of idleness.
Kunti’s cry: Responses in India to the cause of emigrant women, Fiji 1913–16
Authors: Basu Rajsekhar
Published: December 2020

The publication in August 1913 of a letter attributed to Kunti, an Indian woman in Fiji, raised an outcry in India. First, the Hindi press took it up; then the Marwaris of Calcutta organised a campaign for the relief of emigrant labourers; and finally, the protection of Indian women in Fiji became a part of the nationalist campaign against indentured labour. This article examines the ideological basis of the agitation, arising from traditional male chauvinism merging with the anti-colonial upsurge, treating especially the reaction in the Hindi press, the Marwari intervention and the nationalist campaign.
Elagolix in the treatment of endometriosis: impact beyond pain symptoms
Authors: Archer David F. , Soliman Ahmed M. , Agarwal Sanjay K. , Taylor Hugh S.
Published: December 2020

While the most common symptom associated with endometriosis is pelvic pain, the systemic manifestations of the disease and the accompanying adverse psychological, emotional, social, familial, sexual, educational and workplace effects are increasingly recognized. Elagolix is an oral gonadotropin-releasing hormone receptor antagonist that is approved for the management of moderate to severe pain associated with endometriosis. However, the benefits of elagolix extend beyond reducing pain symptoms. This article reviews the non-pain systemic manifestations associated with endometriosis and summarizes the beneficial effects of elagolix on non-pain outcomes. This includes improvements in quality of life, reductions in fatigue and improvements in workplace and household productivity. These results indicate that elagolix provides non-pain benefits in women with endometriosis and improves outcomes that are clinically meaningful to patients.
Phase 2 study of the safety and efficacy of umbralisib in patients with CLL who are intolerant to BTK or PI3Kδ inhibitor therapy
Authors: Mato Anthony R. , Ghosh Nilanjan , Schuster Stephen J. , Lamanna Nicole , Pagel John M. , Flinn Ian W. , Barrientos Jacqueline C. , Rai Kanti R. , Reeves James A. , Cheson Bruce D. , Barr Paul M. , Kambhampati Suman , Lansigan Frederick , Pu Jeffrey J. , Skarbnik Alan P. , Roeker Lindsey , Fonseca Gustavo A. , Sitlinger Andrea , Hamadeh Issam S. , Dorsey Colleen , LaRatta Nicole , Weissbrot Hanna , Luning Prak Eline T. , Tsao Patricia , Paskalis Dana , Sportelli Peter , Miskin Hari P. , Weiss Michael S. , Svoboda Jakub , Brander Danielle M.
Published: December 2020

Intolerance is the most common reason for kinase inhibitor (KI) discontinuation in chronic lymphocytic leukemia (CLL). Umbralisib, a novel highly selective phosphatidylinositol 3-kinase δ (PI3Kδ)/CK1ε inhibitor, is active and well tolerated in CLL patients. In this phase 2 trial (NCT02742090), umbralisib was initiated at 800 mg/d in CLL patients requiring therapy, who were intolerant to prior BTK inhibitor (BTKi) or PI3K inhibitor (PI3Ki) therapy, until progression or toxicity. Primary end point was progression-free survival (PFS). Secondary end points included time to treatment failure and safety. DNA was genotyped for CYP3A4, CYP3A5, and CYP2D6 polymorphisms. Fifty-one patients were enrolled (44 BTKi intolerant and 7 PI3Kδi intolerant); median age was 70 years (range, 48-96), with a median of 2 prior lines of therapy (range, 1-7), 24% had del17p and/or TP53 mutation, and 65% had unmutated IGHV. Most common adverse events (AEs) leading to prior KI discontinuation were rash (27%), arthralgia (18%), and atrial fibrillation (16%). Median PFS was 23.5 months (95% CI, 13.1–not estimable), with 58% of patients on umbralisib for a longer duration than prior KI. Most common (≥5%) grade ≥3 AEs on umbralisib (all causality) were neutropenia (18%), leukocytosis (14%), thrombocytopenia (12%), pneumonia (12%), and diarrhea (8%). Six patients (12%) discontinued umbralisib because of an AE. Eight patients (16%) had dose reductions and were successfully rechallenged. These are the first prospective data to confirm that switching from a BTKi or alternate PI3Ki to umbralisib in this BTKi- and PI3Ki–intolerant CLL population can result in durable well-tolerated responses.
Large-scale circular RNA deregulation in T-ALL: unlocking unique ectopic expression of molecular subtypes
Authors: Buratin Alessia , Paganin Maddalena , Gaffo Enrico , Dal Molin Anna , Roels Juliette , Germano Giuseppe , Siddi Maria Teresa , Serafin Valentina , De Decker Matthias , Gachet Stéphanie , Durinck Kaat , Speleman Frank , Taghon Tom , te Kronnie Geertruij , Van Vlierberghe Pieter , Bortoluzzi Stefania
Published: December 2020

Circular RNAs (circRNAs) are stable RNA molecules that can drive cancer through interactions with microRNAs and proteins and by the expression of circRNA encoded peptides. The aim of the study was to define the circRNA landscape and potential impact in T-cell acute lymphoblastic leukemia (T-ALL). Analysis by CirComPara of RNA-sequencing data from 25 T-ALL patients, immature, HOXA overexpressing, TLX1, TLX3, TAL1, or LMO2 rearranged, and from thymocyte populations of human healthy donors disclosed 68 554 circRNAs. Study of the top 3447 highly expressed circRNAs identified 944 circRNAs with significant differential expression between malignant T cells and normal counterparts, with most circRNAs displaying increased expression in T-ALL. Next, we defined subtype-specific circRNA signatures in molecular genetic subgroups of human T-ALL. In particular, circZNF609, circPSEN1, circKPNA5, and circCEP70 were upregulated in immature, circTASP1, circZBTB44, and circBACH1 in TLX3, circHACD1, and circSTAM in HOXA, circCAMSAP1 in TLX1, and circCASC15 in TAL-LMO. Backsplice sequences of 14 circRNAs ectopically expressed in T-ALL were confirmed, and overexpression of circRNAs in T-ALL with specific oncogenic lesions was substantiated by quantification in a panel of 13 human cell lines. An oncogenic role of circZNF609 in T-ALL was indicated by decreased cell viability upon silencing in vitro. Furthermore, functional predictions identified circRNA-microRNA gene axes informing modes of circRNA impact in molecular subtypes of human T-ALL.
Finding a suitable library size to call variants in RNA-Seq
Authors: Quaglieri Anna , Flensburg Christoffer , Speed Terence P. , Majewski Ian J.
Published: December 2020

Background

RNA sequencing allows the study of both gene expression changes and transcribed mutations, providing a highly effective way to gain insight into cancer biology. When planning the sequencing of a large cohort of samples, library size is a fundamental factor affecting both the overall cost and the quality of the results. Here we specifically address how overall library size influences the detection of somatic mutations in RNA-seq data in two acute myeloid leukaemia datasets.

Results 

We simulated shallower sequencing depths by downsampling 45 acute myeloid leukaemia samples (100 bp PE) that are part of the Leucegene project, which were originally sequenced at high depth. We compared the sensitivity of six methods of recovering validated mutations on the same samples. The methods compared are a combination of three popular callers (MuTect, VarScan, and VarDict) and two filtering strategies. We observed an incremental loss in sensitivity when simulating libraries of 80M, 50M, 40M, 30M and 20M fragments, with the largest loss detected with less than 30M fragments (below 90%, average loss of 7%). The sensitivity in recovering insertions and deletions varied markedly between callers, with VarDict showing the highest sensitivity (60%). Single nucleotide variant sensitivity is relatively consistent across methods, apart from MuTect, whose default filters need adjustment when using RNA-Seq. We also analysed 136 RNA-Seq samples from the TCGA-LAML cohort (50 bp PE) and assessed the change in sensitivity between the initial libraries (average 59M fragments) and after downsampling to 40M fragments. When considering single nucleotide variants in recurrently mutated myeloid genes we found a comparable performance, with a 6% average loss in sensitivity using 40M fragments.

Conclusions

Between 30M and 40M 100 bp PE reads are needed to recover 90–95% of the initial variants on recurrently mutated myeloid genes. To extend this result to another cancer type, an exploration of the characteristics of its mutations and gene expression patterns is suggested.
A novel computational strategy for DNA methylation imputation using mixture regression model (MRM)
Authors: Yu Fangtang , Xu Chao , Deng Hong-Wen , Shen Hui
Published: December 2020

Background

DNA methylation is an important heritable epigenetic mark that plays a crucial role in transcriptional regulation and the pathogenesis of various human disorders. The commonly used DNA methylation measurement approaches, e.g., Illumina Infinium HumanMethylation-27 and -450 BeadChip arrays (27 K and 450 K arrays) and reduced representation bisulfite sequencing (RRBS), only cover a small proportion of the total CpG sites in the human genome, which considerably limited the scope of the DNA methylation analysis in those studies.

Results

We proposed a new computational strategy to impute the methylation value at the unmeasured CpG sites using the mixture of regression model (MRM) of radial basis functions, integrating information of neighboring CpGs and the similarities in local methylation patterns across subjects and across multiple genomic regions. Our method achieved a better imputation accuracy over a set of competing methods on both simulated and empirical data, particularly when the missing rate is high. By applying MRM to an RRBS dataset from subjects with low versus high bone mineral density (BMD), we recovered methylation values of ~ 300 K CpGs in the promoter regions of chromosome 17 and identified some novel differentially methylated CpGs that are significantly associated with BMD.

Conclusions

Our method is well applicable to the numerous methylation studies. By expanding the coverage of the methylation dataset to unmeasured sites, it can significantly enhance the discovery of novel differential methylation signals and thus reveal the mechanisms underlying various human disorders/traits.
Stress-related changes in leukocyte profiles and telomere shortening in the shortest-lived tetrapod, Furcifer labordi
Authors: Eckhardt Falk , Pauliny Angela , Rollings Nicky , Mutschmann Frank , Olsson Mats , Kraus Cornelia , Kappeler Peter M.
Published: December 2020

Background

Life history theory predicts that during the lifespan of an organism, resources are allocated to either growth, somatic maintenance or reproduction. Resource allocation trade-offs determine the evolution and ecology of different life history strategies and define an organisms’ position along a fast–slow continuum in interspecific comparisons. Labord’s chameleon (Furcifer labordi) from the seasonal dry forests of Madagascar is the tetrapod species with the shortest reported lifespan (4–9 months). Previous investigations revealed that their lifespan is to some degree dependent on environmental factors, such as the amount of rainfall and the length of the vegetation period. However, the intrinsic mechanisms shaping such a fast life history remain unknown. Environmental stressors are known to increase the secretion of glucocorticoids in other vertebrates, which, in turn, can shorten telomeres via oxidative stress. To investigate to what extent age-related changes in these molecular and cellular mechanisms contribute to the relatively short lifetime ofF. labordi, we assessed the effects of stressors indirectly via leukocyte profiles (H/L ratio) and quantified relative telomere length from blood samples in a wild population in Kirindy Forest. We compared our findings with the sympatric, but longer-lived sister speciesF.cf.nicosiai,which exhibit the same annual timing of reproductive events, and with wild-caughtF. labordithat were singly housed under ambient conditions.

Results

We found that H/L ratios were consistently higher in wildF. labordicompared toF.cf.nicosiai. Moreover,F. labordialready exhibited relatively short telomeres during the mating season when they were 3–4 months old, and telomeres further shortened during their post-reproductive lives. At the beginning of their active season, telomere length was relatively longer inF.cf.nicosiai, but undergoing rapid shortening towards the southern winter, when both species gradually die off. CaptiveF. labordishowed comparatively longer lifespans and lower H/L ratios than their wild counterparts.

Conclusion

We suggest that environmental stress and the corresponding accelerated telomere attrition have profound effects on the lifespan ofF. labordiin the wild, and identify physiological mechanisms potentially driving their relatively early senescence and mortality.
Intricate genetic variation networks control the adventitious root growth angle in apple
Authors: Zheng Caixia , Shen Fei , Wang Yi , Wu Ting , Xu Xuefeng , Zhang Xinzhong , Han Zhenhai
Published: December 2020

Background

The root growth angle (RGA) typically determines plant rooting depth, which is significant for plant anchorage and abiotic stress tolerance. Several quantitative trait loci (QTLs) for RGA have been identified in crops. However, the underlying mechanisms of the RGA remain poorly understood, especially in apple rootstocks. The objective of this study was to identify QTLs, validate genetic variation networks, and develop molecular markers for the RGA in apple rootstock.

Results

Bulked segregant analysis by sequencing (BSA-seq) identified 25 QTLs for RGA using 1955 hybrids of the apple rootstock cultivars ‘Baleng Crab’ (Malus robustaRehd., large RGA) and ‘M9’ (M. pumilaMill., small RGA). With RNA sequencing (RNA-seq) and parental resequencing, six major functional genes were identified and constituted two genetic variation networks for the RGA. Two single nucleotide polymorphisms (SNPs) of theMdLAZY1promoter damaged the binding sites of MdDREB2A and MdHSFB3, while one SNP ofMdDREB2AandMdIAA1affected the interactions of MdDREB2A/MdHSFB3 and MdIAA1/MdLAZY1, respectively. A SNP within theMdNPR5promoter damaged the interaction betweenMdNPR5and MdLBD41, while one SNP ofMdLBD41interrupted the MdLBD41/MdbHLH48 interaction that affected the binding ability of MdLBD41 on theMdNPR5promoter. Twenty six SNP markers were designed on candidate genes in each QTL interval, and the marker effects varied from 0.22°-26.11°.

Conclusions

Six diagnostic markers, SNP592, G122, b13, Z312, S1272, and S1288, were used to identify two intricate genetic variation networks that control the RGA and may provide new insights into the accuracy of the molecular markers. The QTLs and SNP markers can potentially be used to select deep-rooted apple rootstocks.
MALDI-TOF mass spectrometry for sub-typing of Streptococcus pneumoniae
Authors: Kann Sivkheng , Sao Sena , Phoeung Chanleakhena , By Youlet , Bryant Juliet , Komurian-Pradel Florence , Saphonn Vonthanak , Chou Monidarin , Turner Paul
Published: December 2020

Background

Serotyping of Streptococcus pneumoniae is important for monitoring of vaccine impact. Unfortunately, conventional and molecular serotyping is expensive and technically demanding. This study aimed to determine the ability of matrix-assisted laser desorption-ionisation time-of-flight (MALDI-TOF) mass spectrometry to discriminate between pneumococcal serotypes and genotypes (defined by global pneumococcal sequence cluster, GPSC). In this study, MALDI-TOF mass spectra were generated for a diverse panel of whole genome sequenced pneumococcal isolates using the bioMerieux VITEK MS in clinical diagnostic (IVD) mode. Discriminatory mass peaks were identified and hierarchical clustering was performed to visually assess discriminatory ability. Random forest and classification and regression tree (CART) algorithms were used to formally determine how well serotypes and genotypes were identified by MALDI-TOF mass spectrum.

Results

One hundred and ninety-nine pneumococci, comprising 16 serotypes and non-typeable isolates from 46 GPSC, were analysed. In the primary experiment, hierarchical clustering revealed poor congruence between MALDI-TOF mass spectrum and serotype. The correct serotype was identified from MALDI-TOF mass spectrum in just 14.6% (random forest) or 35.4% (CART) of 130 isolates. Restricting the dataset to the nine dominant GPSC (61 isolates / 13 serotypes), discriminatory ability improved slightly: the correct serotype was identified in 21.3% (random forest) and 41.0% (CART). Finally, analysis of 69 isolates of three dominant serotype-genotype pairs (6B-GPSC1, 19F-GPSC23, 23F-GPSC624) resulted in the correct serotype identification in 81.1% (random forest) and 94.2% (CART) of isolates.

Conclusions

This work suggests that MALDI-TOF is not a useful technique for determination of pneumococcal serotype. MALDI-TOF mass spectra appear more associated with isolate genotype, which may still have utility for future pneumococcal surveillance activities.
Elderly patients with atrial fibrillation in routine clinical practice—peri-procedural management of edoxaban oral anticoagulation therapy is associated with a low risk of bleeding and thromboembolic complications: a subset analysis of the prospective, observational, multinational EMIT-AF study
Authors: Unverdorben M. , von Heymann C. , Santamaria A. , Saxena M. , Vanassche T. , Jin J. , Laeis P.  , Wilkins R. , Chen C. , Colonna P.
Published: December 2020

Background

Annually > 10% of patients with atrial fibrillation on oral anticoagulation undergo invasive procedures. Optimal peri-procedural management of anticoagulation, as judged by major bleeding and thromboembolic events, especially in the elderly, is still debated.

Methods

Procedures from 1442 patients were evaluated. Peri-procedural edoxaban management was guided only by the experience of the attending physician. The primary safety outcome was the rate of major bleeding. Secondary outcomes included the peri-procedural administration of edoxaban, other bleeding events, and the main efficacy outcome, a composite of acute coronary syndrome, non-hemorrhagic stroke, transient ischemic attack, systemic embolic events, deep vein thrombosis, pulmonary embolism, and mortality.

Results

Of the 1442 patients, 280 (19%) were < 65, 550 (38%) were 65–74, 514 (36%) 75–84, and 98 (7%) were 85 years old or older. With increasing age, comorbidities and risk scores were higher. Any bleeding complications were uncommon across all ages, ranging from 3.9% in patients < 65 to 4.1% in those 85 years or older; major bleeding rates in any age group were ≤ 0.6%. Interruption rates and duration increased with advancing age. Thromboembolic events were more common in the elderly, with all nine events occurring in those > 65, and seven in patients aged > 75 years.

Conclusion

Despite increased bleeding risk factors in the elderly, bleeding rates were small and similar across all age groups. However, there was a trend toward more thromboembolic complications with advancing age. Further efforts to identify the optimal management to reduce ischemic complications are needed.

Trial registration: NCT# 02950168, October 31, 2016