bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endothelial-mesenchymal transition harnesses HSP90α-secreting M2-macrophages to exacerbate pancreatic ductal adenocarcinoma
Authors: Fan Chi-Shuan , Chen Li-Li , Hsu Tsu-An , Chen Chia-Chi , Chua Kee Voon , Li Chung-Pin , Huang Tze-Sing 
Published: December 2019

AbstractBackgroundEndothelial-to-mesenchymal transition (EndoMT) can provide a source of cancer-associated fibroblasts which contribute to desmoplasia of many malignancies including pancreatic ductal adenocarcinoma (PDAC). We investigated the clinical relevance of EndoMT in PDAC, and explored its underlying mechanism and therapeutic implication.MethodsExpression levels of 29 long non-coding RNAs were analyzed from the cells undergoing EndoMT, and an EndoMT index was proposed to survey its clinical associations in the PDAC patients of The Cancer Genome Atlas database. The observed clinical correlation was further confirmed by a mouse model inoculated with EndoMT cells-involved PDAC cell grafts. In vitro co-culture with EndoMT cells or treatment with the conditioned medium were performed to explore the underlying mechanism. Because secreted HSP90α was involved, anti-HSP90α antibody was evaluated for its inhibitory efficacy against the EndoMT-involved PDAC tumor.ResultsA combination of low expressions of LOC340340, LOC101927256, and MNX1-AS1 was used as an EndoMT index. The clinical PDAC tissues with positive EndoMT index were significantly correlated with T4-staging and showed positive for M2-macrophage index. Our mouse model and in vitro cell-culture experiments revealed that HSP90α secreted by EndoMT cells could induce macrophage M2-polarization and more HSP90α secretion to promote PDAC tumor growth. Furthermore, anti-HSP90α antibody showed a potent therapeutic efficacy against the EndoMT and M2-macrophages-involved PDAC tumor growth.ConclusionsEndoMT cells can secrete HSP90α to harness HSP90α-overproducing M2-type macrophages to promote PDAC tumor growth, and such effect can be targeted and abolished by anti-HSP90α antibody.
Benchmarking transposable element annotation methods for creation of a streamlined, comprehensive pipeline
Authors: Ou Shujun , Su Weija , Liao Yi , Chougule Kapeel , Agda Jireh R. A. , Hellinga Adam J. , Lugo Carlos Santiago Blanco , Elliott Tyler A. , Ware Doreen , Peterson Thomas , Jiang Ning , Hirsch Candice N. , Hufford Matthew B. 
Published: December 2019

Abstract
Background
Sequencing technology and assembly algorithms have matured to the point that high-quality de novo assembly is possible for large, repetitive genomes. Current assemblies traverse transposable elements (TEs) and provide an opportunity for comprehensive annotation of TEs. Numerous methods exist for annotation of each class of TEs, but their relative performances have not been systematically compared. Moreover, a comprehensive pipeline is needed to produce a non-redundant library of TEs for species lacking this resource to generate whole-genome TE annotations.

Results
We benchmark existing programs based on a carefully curated library of rice TEs. We evaluate the performance of methods annotating long terminal repeat (LTR) retrotransposons, terminal inverted repeat (TIR) transposons, short TIR transposons known as miniature inverted transposable elements (MITEs), and Helitrons. Performance metrics include sensitivity, specificity, accuracy, precision, FDR, and F1. Using the most robust programs, we create a comprehensive pipeline called Extensive de-novo TE Annotator (EDTA) that produces a filtered non-redundant TE library for annotation of structurally intact and fragmented elements. EDTA also deconvolutes nested TE insertions frequently found in highly repetitive genomic regions. Using other model species with curated TE libraries (maize and Drosophila), EDTA is shown to be robust across both plant and animal species.

Conclusions
The benchmarking results and pipeline developed here will greatly facilitate TE annotation in eukaryotic genomes. These annotations will promote a much more in-depth understanding of the diversity and evolution of TEs at both intra- and inter-species levels. EDTA is open-source and freely available: https://github.com/oushujun/EDTA.
A novel framework for horizontal and vertical data integration in cancer studies with application to survival time prediction models
Authors: Mihaylov Iliyan , Kańduła Maciej , Krachunov Milko , Vassilev Dimitar 
Published: December 2019

Abstract
Background
Recently high-throughput technologies have been massively used alongside clinical tests to study various types of cancer. Data generated in such large-scale studies are heterogeneous, of different types and formats. With lack of effective integration strategies novel models are necessary for efficient and operative data integration, where both clinical and molecular information can be effectively joined for storage, access and ease of use. Such models, combined with machine learning methods for accurate prediction of survival time in cancer studies, can yield novel insights into disease development and lead to precise personalized therapies.

Results
We developed an approach for intelligent data integration of two cancer datasets (breast cancer and neuroblastoma) − provided in the CAMDA 2018 ‘Cancer Data Integration Challenge’, and compared models for prediction of survival time. We developed a novel semantic network-based data integration framework that utilizes NoSQL databases, where we combined clinical and expression profile data, using both raw data records and external knowledge sources. Utilizing the integrated data we introduced Tumor Integrated Clinical Feature (TICF) − a new feature for accurate prediction of patient survival time. Finally, we applied and validated several machine learning models for survival time prediction.

Conclusion
We developed a framework for semantic integration of clinical and omics data that can borrow information across multiple cancer studies. By linking data with external domain knowledge sources our approach facilitates enrichment of the studied data by discovery of internal relations. The proposed and validated machine learning models for survival time prediction yielded accurate results.

Reviewers
This article was reviewed by Eran Elhaik, Wenzhong Xiao and Carlos Loucera.
Tamoxifen in Duchenne muscular dystrophy (TAMDMD): study protocol for a multicenter, randomized, placebo-controlled, double-blind phase 3 trial
Authors: Nagy Sara , Hafner Patricia , Schmidt Simone , Rubino-Nacht Daniela , Schädelin Sabine , Bieri Oliver , Fischer Dirk 
Published: December 2019

Abstract
Background
Duchenne muscular dystrophy (DMD) is an inherited neuromuscular disorder of childhood with a devastating disease course. Several targeted gene therapies and molecular approaches have been or are currently being tested in clinical trials; however, a causative therapy is still not available and best supportive care is limited to oral glucocorticoids with numerous long-term side effects. Tamoxifen is a selective estrogen receptor regulator, and shows antioxidant actions and regulatory roles in the calcium homeostasis besides its antitumor activity. In a mouse model of DMD, oral tamoxifen significantly improved muscle strength and reduced muscle fatigue. This multicenter, randomized, double-blind, placebo-controlled phase III trial aims to demonstrate safety and efficacy of tamoxifen over placebo in pediatric patients with DMD. After completion of the double-blind phase, an open-label extension of the study will be offered to all participants.

Methods/design
At least 71 ambulant and up to 20 nonambulant patients with DMD are planned to be enrolled at multiple European sites. Patients will be randomly assigned to receive either tamoxifen 20 mg or placebo daily over 48 weeks. In the open-label extension phase, all patients will be offered tamoxifen for a further 48 weeks. The primary endpoint of the double-blind phase is defined as the change of the D1 domain of the motor function measure in ambulant patients or a change of the D2 domain in nonambulant patients under tamoxifen compared to placebo. Secondary outcome measures include change in timed function tests, quantitative muscle testing, and quantitative magnetic resonance imaging of thigh muscles. Laboratory analyses including biomarkers of tamoxifen metabolism and muscle dystrophy will also be assessed.

Discussion
The aim of the study is to investigate whether tamoxifen can reduce disease progression in ambulant and nonambulant patients with DMD over 48 weeks. Motor function measures comprise the primary endpoint, whereas further clinical and radiological assessments and laboratory biomarkers are performed to provide more data on safety and efficacy. An adjacent open-label extension phase is planned to test if earlier initiation of the treatment with tamoxifen (verum arm of double-blind phase) compared to a delayed start can reduce disease progression more efficiently.

Trial registration
ClinicalTrials.gov, NCT03354039. Registered on 27 November 2017.
Promoting mental health and wellbeing in schools: examining Mindfulness, Relaxation and Strategies for Safety and Wellbeing in English primary and secondary schools: study protocol for a multi-school, cluster randomised controlled trial (INSPIRE)
Authors: Hayes Daniel , Moore Anna , Stapley Emily , Humphrey Neil , Mansfield Rosie , Santos Joao , Ashworth Emma , Patalay Praveetha , Bonin Eva-Maria , Moltrecht Bettina , Boehnke Jan R. , Deighton Jessica 
Published: December 2019

Abstract
Background
There are increasing rates of internalising difficulties, particularly anxiety and depression, being reported in children and young people in England. School-based, universal prevention programmes are thought to be one way of helping tackle such difficulties. This protocol describes a four-arm cluster randomised controlled trial, investigating the effectiveness of three different interventions when compared to usual provision, in English primary and secondary pupils. The primary outcome for Mindfulness and Relaxation interventions is a measure of internalising difficulties, while Strategies for Safety and Wellbeing will be examined in relation to intended help-seeking. In addition to the effectiveness analysis, a process and implementation evaluation and a cost-effectiveness evaluation will be undertaken.

Methods and analysis
Overall, 160 primary schools and 64 secondary schools will be recruited across England. This corresponds to 17,600 participants. Measures will be collected online at baseline, 3–6 months later, and 9–12 months after the commencement of the intervention. An economic evaluation will assess the cost-effectiveness of the interventions. Moreover, a process and implementation evaluation (including a qualitative research component) will explore several aspects of implementation (fidelity, quality, dosage, reach, participant responsiveness, adaptations), social validity (acceptability, appropriateness and feasibility), and their moderating effects on the outcomes of interest, and perceived impact.

Discussion
This trial aims to address important questions about whether schools’ practices around the promotion of mental wellbeing and the prevention of mental health problems can: (1) be formalised into feasible and effective models of school-based support and (2) whether these practices and their effects can be sustained over time. Given the focus of these interventions on mirroring popular practice in schools and on prioritising approaches that present low-burden, high-acceptability to schools, if proved effective, and cost-effective, the findings will indicate models that are not only empirically tested but also offer high potential for widespread use and, therefore, potentially widespread benefits beyond the life of the trial.

Trial registration
ISRCTN16386254. Registered on 30 August 2018.
Chemotherapy in conjunction with traditional Chinese medicine for survival of patients with early female breast cancer: protocol for a non-randomized, single center prospective cohort study
Authors: Liu Chien-Ting , Chen Yen-Hao , Huang Yu-Chuen , Chen Shih-Yu , Tsai Ming-Yen 
Published: December 2019

Abstract
Background
Chemotherapy after surgery for breast cancer plays a fundamental role in reducing the risk of distant and local recurrence. An increasing number of patients seek traditional Chinese medicine (TCM) during adjuvant chemotherapy to relieve symptom discomfort and side effects as well as to strengthen the body’s defenses. However, evidence on how concurrent TCM treatment affects prognosis is scarce. This trial aims to evaluate the association between TCM treatment and disease-free survival outcomes for patients with early breast cancer who are undergoing adjuvant chemotherapy.

Methods/design
This is a non-randomized, single center, prospective cohort study begun in November 2018 in Kaohsiung, Taiwan. A sample of 310 participants diagnosed with early breast cancer was recruited from the Breast Cancer Research Team and will be followed up every 3 to 6 months until October 2023. Detailed information of the participants, including general information, history of cancer, quality of life, side effects and safety of treatment, TCM body constitution, and meridian energy analysis, was collected face to face at baseline.

Discussion
This is the first prospective observational cohort study on TCM in patients with early breast cancer who are receiving adjuvant chemotherapy to evaluate the prognosis. Through this trial, we hope to assess the feasibility of a larger-scale clinical trial in the future and formulate an integrated TCM care program.

Trial registration
ClinicalTrials.gov, NCT03797248. Registered on 5 January 2019.
FIREVAT: finding reliable variants without artifacts in human cancer samples using etiologically relevant mutational signatures
Authors: Kim Hyunbin , Lee Andy Jinseok , Lee Jongkeun , Chun Hyonho , Ju Young Seok , Hong Dongwan 
Published: December 2019

Abstract
Background
Accurate identification of real somatic variants is a primary part of cancer genome studies and precision oncology. However, artifacts introduced in various steps of sequencing obfuscate confidence in variant calling. Current computational approaches to variant filtering involve intensive interrogation of Binary Alignment Map (BAM) files and require massive computing power, data storage, and manual labor. Recently, mutational signatures associated with sequencing artifacts have been extracted by the Pan-cancer Analysis of Whole Genomes (PCAWG) study. These spectrums can be used to evaluate refinement quality of a given set of somatic mutations.

Results
Here we introduce a novel variant refinement software, FIREVAT (FInding REliable Variants without ArTifacts), which uses known spectrums of sequencing artifacts extracted from one of the largest publicly available catalogs of human tumor samples. FIREVAT performs a quick and efficient variant refinement that accurately removes artifacts and greatly improves the precision and specificity of somatic calls. We validated FIREVAT refinement performance using orthogonal sequencing datasets totaling 384 tumor samples with respect to ground truth. Our novel method achieved the highest level of performance compared to existing filtering approaches. Application of FIREVAT on additional 308 The Cancer Genome Atlas (TCGA) samples demonstrated that FIREVAT refinement leads to identification of more biologically and clinically relevant mutational signatures as well as enrichment of sequence contexts associated with experimental errors. FIREVAT only requires a Variant Call Format file (VCF) and generates a comprehensive report of the variant refinement processes and outcomes for the user.

Conclusions
In summary, FIREVAT facilitates a novel refinement strategy using mutational signatures to distinguish artifactual point mutations called in human cancer samples. We anticipate that FIREVAT results will further contribute to precision oncology efforts that rely on accurate identification of variants, especially in the context of analyzing mutational signatures that bear prognostic and therapeutic significance. FIREVAT is freely available at https://github.com/cgab-ncc/FIREVAT
Improved RA classification among early arthritis patients with the concordant presence of three RA autoantibodies: analysis in two early arthritis clinics
Authors: Regueiro Cristina , Rodríguez-Martínez Lorena , Nuño Laura , Ortiz Ana M. , Villalba Alejandro , Pascual-Salcedo Dora , Martínez-Feito Ana , González-Alvaro Isidoro , Balsa Alejandro , Gonzalez Antonio 
Published: December 2019

Abstract
Background
The patients with RA benefit from early identification soon after the first clinical symptoms appear. The 2010 ACR/EULAR classification criteria were developed to fulfill this need and their application has been demonstrated to be effective. However, there is still room for improvement. Therefore, we aimed to evaluate the potential of the concordant presence of RF, anti-CCP and anti-carbamylated protein antibodies to improve current RA classification among early arthritis (EA) patients.

Methods
Data from the first visit of 1057 patients in two EA prospective cohorts were used. The serological scores from the 2010 ACR/EULAR criteria and the concordant presence of the three RA autoantibodies were assessed relative to a gold standard consisting of the RA classification with the 1987 ACR criteria at the 2 years of follow-up.

Results
The concordant presence of three antibodies showed predictive characteristics allowing for direct classification as RA (positive predictive value = 96.1% and OR = 80.9). They were significantly better than the corresponding to the high antibody titers defined as in the 2010 classification criteria (PPV = 88.8%, OR = 26.1). In addition, the concordant presence of two antibodies was also very informative (PPV = 82.3%, OR = 15.1). These results allowed devising a scoring system based only on antibody concordance that displayed similar overall performance as the serological scoring system of the 2010 criteria. However, the best classification was obtained combining the concordance and 2010 serological systems, a combination with a significant contribution from each of the two systems.

Discussion
The concordant presence of RA autoantibodies showed an independent contribution to the classification of EA patients that permitted increased discrimination and precision.
DNA methylation instability by BRAF-mediated TET silencing and lifestyle-exposure divides colon cancer pathways
Authors: Noreen Faiza , Küng Taya , Tornillo Luigi , Parker Hannah , Silva Miguel , Weis Stefan , Marra Giancarlo , Rad Roland , Truninger Kaspar , Schär Primo 
Published: December 2019

AbstractBackgroundAberrations in DNA methylation are widespread in colon cancer (CC). Understanding origin and progression of DNA methylation aberrations is essential to develop effective preventive and therapeutic strategies. Here, we aimed to dissect CC subtype-specific methylation instability to understand underlying mechanisms and functions.MethodsWe have assessed genome-wide DNA methylation in the healthy normal colon mucosa (HNM), precursor lesions and CCs in a first comprehensive study to delineate epigenetic change along the process of colon carcinogenesis. Mechanistically, we used stable cell lines, genetically engineered mouse model of mutant BRAFV600Eand molecular biology analysis to establish the role of BRAFV600E-mediated-TET inhibition in CpG-island methylator phenotype (CIMP) inititation.ResultsWe identified two distinct patterns of CpG methylation instability, determined either by age–lifestyle (CC-neutral CpGs) or genetically (CIMP-CpGs). CC-neutral-CpGs showed age-dependent hypermethylation in HNM, all precursors, and CCs, while CIMP-CpGs showed hypermethylation specifically in sessile serrated adenomas/polyps (SSA/Ps) and CIMP-CCs.BRAFV600E-mutated CCs and precursors showed a significant downregulation ofTET1andTET2DNA demethylases. Stable expression ofBRAFV600Ein nonCIMP CC cells and in a genetic mouse model was sufficient to repress TET1/TET2 and initiate hypermethylation at CIMP-CpGs, reversible byBRAFV600Einhibition.BRAFV600E-driven CIMP-CpG hypermethylation occurred at genes associated with established CC pathways, effecting functional changes otherwise achieved by genetic mutation in carcinogenesis.ConclusionsHence, while age–lifestyle-driven hypermethylation occurs generally in colon carcinogenesis,BRAFV600E-driven hypermethylation is specific for the “serrated” pathway. This knowledge will advance the use of epigenetic biomarkers to assess subgroup-specific CC risk and disease progression.
Molecular patterning during the development of Phoronopsis harmeri reveals similarities to rhynchonelliform brachiopods
Authors: Andrikou Carmen , Passamaneck Yale J. , Lowe Chris J. , Martindale Mark Q. , Hejnol Andreas 
Published: December 2019

AbstractBackgroundPhoronids, rhynchonelliform and linguliform brachiopods show striking similarities in their embryonic fate maps, in particular in their axis specification and regionalization. However, although brachiopod development has been studied in detail and demonstrated embryonic patterning as a causal factor of the gastrulation mode (protostomy vs deuterostomy), molecular descriptions are still missing in phoronids. To understand whether phoronids display underlying embryonic molecular mechanisms similar to those of brachiopods, here we report the expression patterns of anterior (otx,gsc,six3/6,nk2.1), posterior (cdx, bra) and endomesodermal (foxA,gata4/5/6,twist) markers during the development of the protostomic phoronidPhoronopsis harmeri.ResultsThe transcription factorsfoxA, gata4/5/6andcdxshow conserved expression in patterning the development and regionalization of the phoronid embryonic gut, withfoxAexpressed in the presumptive foregut,gata4/5/6demarcating the midgut andcdxconfined to the hindgut. Furthermore,six3/6,usually a well-conserved anterior marker, shows a remarkably dynamic expression, demarcating not only the apical organ and the oral ectoderm, but also clusters of cells of the developing midgut and the anterior mesoderm, similar to what has been reported for brachiopods, bryozoans and some deuterostome Bilateria. Surprisingly,brachyury, a transcription factor often associated with gastrulation movements and mouth and hindgut development, seems not to be involved with these patterning events in phoronids.ConclusionsOur description and comparison of gene expression patterns with other studied Bilateria reveals that the timing of axis determination and cell fate distribution of the phoronid shows highest similarity to that of rhynchonelliform brachiopods, which is likely related to their shared protostomic mode of development. Despite these similarities, the phoronidPh. harmerialso shows particularities in its development, which hint to divergences in the arrangement of gene regulatory networks responsible for germ layer formation and axis specification.