bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of luspatercept to treat ineffective erythropoiesis
Authors: Kubasch Anne Sophie , Fenaux Pierre , Platzbecker Uwe 
Published: March 2021

Abstract
Luspatercept (Reblozyl) was recently approved for treating patients with transfusion-dependent lower-risk myelodysplastic syndrome (MDS) with ring sideroblasts (RS) and/or SF3B1 mutation who were not eligible for erythropoiesis-stimulating agents (ESAs) or patients for whom those agents failed. Luspatercept acts as an activin receptor type IIB fusion protein ligand trap that targets the altered transforming growth factor beta pathway in MDS, which is associated with impaired terminal erythroid maturation. Treatment with luspatercept results in decreased SMAD signaling, which enables erythroid maturation by means of late-stage erythroblast differentiation and thus improves anemia. ESAs, the current standard first-line therapeutic option for anemic lower-risk patients with MDS, also improve red cell parameters mainly by expanding proliferation of early erythroid progenitor cells. However, erythropoietin (EPO) and its receptor (EPO-R) are also required for survival of late-stage definitive erythroid cells, and they play an essential role in promoting proliferation, survival, and appropriate timing of terminal maturation of primitive erythroid precursors. Thus, luspatercept joins the mechanism of ESAs in promoting erythroid maturation. Especially in the subgroup of MDS patients with RS, luspatercept showed high clinical activity for the treatment of anemia in the phase 2 (PACE-MDS) trial and subsequently in the phase 3 (MEDALIST) trial, which resulted in approval by both the US Food and Drug Administration and the European Medicines Agency in April 2020. Additional studies are needed to better understand the mechanism of action and pharmacodynamics of this novel agent in MDS.
Transcriptomic and genomic heterogeneity in blastic plasmacytoid dendritic cell neoplasms: from ontogeny to oncogenesis
Authors: Renosi Florian , Roggy Anne , Giguelay Ambre , Soret Lou , Viailly Pierre-Julien , Cheok Meyling , Biichle Sabeha , Angelot-Delettre Fanny , Asnafi Vahid , Macintyre Elizabeth , Geffroy Sandrine , Callanan Mary , Petrella Tony , Deconinck Eric , Daguindau Etienne , Harrivel Véronique , Bouyer Sabrina , Salaun Véronique , Saussoy Pascale , Feuillard Jean , Fuseau Pascal , Saas Philippe , Adotévi Olivier , Jardin Fabrice , Ferrand Christophe , Preudhomme Claude , Colinge Jacques , Roumier Christophe , Garnache-Ottou Francine 
Published: March 2021

Abstract
Oncogenesis and ontogeny of blastic plasmacytoid dendritic cell neoplasm (BPDCN) remain uncertain, between canonical plasmacytoid dendritic cells (pDCs) and AXL+ SIGLEC6+ DCs (AS-DCs). We compared 12 BPDCN to 164 acute leukemia by Affymetrix HG-U133 Plus 2.0 arrays: BPDCN were closer to B-cell acute lymphoblastic leukemia (ALL), with enrichment in pDC, B-cell signatures, vesicular transport, deubiquitination pathways, and AS-DC signatures, but only in some cases. Importantly, 1 T-cell ALL clustered with BPDCN, with compatible morphology, immunophenotype (cCD3+ sCD3− CD123+ cTCL1+ CD304+), and genetics. Many oncogenetic pathways are deregulated in BPDCN compared with normal pDC, such as cell-cycle kinases, and importantly, the transcription factor SOX4, involved in B ontogeny, pDC ontogeny, and cancer cell invasion. High-throughput sequencing (HaloPlex) showed myeloid mutations (TET2, 62%; ASXL1, 46%; ZRSR2, 31%) associated with lymphoid mutations (IKZF1), whereas single-nucleotide polymorphism (SNP) array (Affymetrix SNP array 6.0) revealed frequent losses (mean: 9 per patient) involving key hematological oncogenes (RB1, IKZF1/2/3, ETV6, NR3C1, CDKN2A/B, TP53) and immune response genes (IFNGR, TGFB, CLEC4C, IFNA cluster). Various markers suggest an AS-DC origin, but not in all patients, and some of these abnormalities are related to the leukemogenesis process, such as the 9p deletion, leading to decreased expression of genes encoding type I interferons. In addition, the AS-DC profile is only found in a subgroup of patients. Overall, the cellular ontogenic origin of BPDCN remains to be characterized, and these results highlight the heterogeneity of BPDCN, with a risk of a diagnostic trap.
Clinical and molecular predictors of response and survival following venetoclax therapy in relapsed/refractory AML
Authors: Stahl Maximilian , Menghrajani Kamal , Derkach Andriy , Chan Alexander , Xiao Wenbin , Glass Jacob , King Amber C. , Daniyan Anthony F. , Famulare Christopher , Cuello Bernadette M. , Horvat Troy Z. , Abdel-Wahab Omar , Levine Ross L. , Viny Aaron D. , Stein Eytan M. , Cai Sheng F. , Roshal Mikhail , Tallman Martin S. , Goldberg Aaron D. 
Published: March 2021

Abstract
Azacitidine + venetoclax, decitabine + venetoclax, and low-dose cytarabine + venetoclax are now standard treatments for newly diagnosed older or unfit patients with acute myeloid leukemia (AML). Although these combinations are also commonly used in relapsed or refractory AML (RR-AML), clinical and molecular predictors of response and survival in RR-AML are incompletely understood. We retrospectively analyzed clinical and molecular characteristics and outcomes for 86 patients with RR-AML who were treated with venetoclax combinations. The complete remission (CR) or CR with incomplete hematologic recovery (CRi) rate was 24%, and the overall response rate was 31% with the inclusion of a morphologic leukemia-free state. Azacitidine + venetoclax resulted in higher response rates compared with low-dose cytarabine + venetoclax (49% vs 15%; P = .008). Median overall survival (OS) was 6.1 months, but it was significantly longer with azacitidine + venetoclax compared with low-dose cytarabine + venetoclax (25 vs 3.9 months; P = .003). This survival advantage of azacitidine + venetoclax over low-dose cytarabine + venetoclax persisted when patients were censored for subsequent allogeneic stem cell transplantation (8.1 vs 3.9 months; P = .035). Mutations in NPM1 were associated with higher response rates, whereas adverse cytogenetics and mutations in TP53, KRAS/NRAS, and SF3B1 were associated with worse OS. Relapse was driven by diverse mechanisms, including acquisition of novel mutations and an increase in cytogenetic complexity. Venetoclax combination therapy is effective in many patients with RR-AML, and pretreatment molecular characteristics may predict outcomes. Trials that evaluate novel agents in combination with venetoclax therapy in patients with RR-AML that have adverse risk genomic features are warranted.
A low cartilage formation and repair endotype predicts radiographic progression of symptomatic knee osteoarthritis
Authors: Luo Yunyun , Samuels Jonathan , Krasnokutsky Svetlana , Byrjalsen Inger , Kraus Virginia B. , He Yi , Karsdal Morten A. , Abramson Steven B. , Attur Mukundan , Bay-Jensen Anne C. 
Published: March 2021

Abstract
Background
Osteoarthritis (OA) is a disease with multiple endotypes. A hallmark of OA is loss of cartilage; however, it is evident that the rate of cartilage loss differs among patients, which may partly be attributed to differential capacity for cartilage repair. We hypothesize that a low cartilage repair endotype exists and that such endotypes are more likely to progress radiographically. The aim of this study is to examine the associations of level of cartilage formation with OA severity and radiographic OA progression. We used the blood-based marker PRO-C2, reflecting type II collagen formation, to assess levels of cartilage formation.

Materials and methods
The type II collagen propeptide PRO-C2 was measured in the serum/plasma of knee OA subjects from New York University (NYU, n = 106) and a subcohort of the phase III oral salmon calcitonin (sCT) trial SMC021-2301 (SMC, n = 147). Risk of radiographic medial joint space narrowing (JSN) over 24 months was compared between quartiles (very low, low, moderate, and high) of PRO-C2. Associations were adjusted for age, gender, BMI, race, baseline pain levels, and baseline joint space width.

Results
In both the NYU and SMC cohorts, subjects with low PRO-C2 levels had greater JSN compared with subjects with high PRO-C2. Mean difference in JSN between subjects with very low and high levels of PRO-C2 was 0.65 mm (p = 0.002), corresponding to a 3.4 (1.4–8.6)-fold higher risk of progression. There was no significant effect of sCT treatment, compared with placebo, on JSN over 2 years before stratification based on baseline PRO-C2. However, there were proportionately fewer progressors in the sCT arm of the very low/low PRO-C2 group compared with the moderate/high group (Chi squared = 6.5, p = 0.011).

Conclusion
Serum/plasma level of type II collagen formation, PRO-C2, may be an objective indicator of a low cartilage repair endotype, displaying radiographic progression and superior response to a proanabolic drug.

Level of evidence
Level III post hoc exploratory analysis of one longitudinal cohort and a sub-study from one phase III clinical trial.
Deep active learning for classifying cancer pathology reports
Authors: De Angeli Kevin , Gao Shang , Alawad Mohammed , Yoon Hong-Jun , Schaefferkoetter Noah , Wu Xiao-Cheng , Durbin Eric B. , Doherty Jennifer , Stroup Antoinette , Coyle Linda , Penberthy Lynne , Tourassi Georgia 
Published: March 2021

AbstractBackgroundAutomated text classification has many important applications in the clinical setting; however, obtaining labelled data for training machine learning and deep learning models is often difficult and expensive. Active learning techniques may mitigate this challenge by reducing the amount of labelled data required to effectively train a model. In this study, we analyze the effectiveness of 11 active learning algorithms on classifying subsite and histology from cancer pathology reports using a Convolutional Neural Network as the text classification model.ResultsWe compare the performance of each active learning strategy using two differently sized datasets and two different classification tasks. Our results show that on all tasks and dataset sizes, all active learning strategies except diversity-sampling strategies outperformed random sampling, i.e., no active learning. On our large dataset (15K initial labelled samples, adding 15K additional labelled samples each iteration of active learning), there was no clear winner between the different active learning strategies. On our small dataset (1K initial labelled samples, adding 1K additional labelled samples each iteration of active learning), marginal and ratio uncertainty sampling performed better than all other active learning techniques. We found that compared to random sampling, active learning strongly helps performance on rare classes by focusing on underrepresented classes.ConclusionsActive learning can save annotation cost by helping human annotators efficiently and intelligently select which samples to label. Our results show that a dataset constructed using effective active learning techniques requires less than half the amount of labelled data to achieve the same performance as a dataset constructed using random sampling.
Dynamic expression of Ralstonia solanacearum virulence factors and metabolism-controlling genes during plant infection
Authors: de Pedro-Jové R. , Puigvert M. , Sebastià P. , Macho A. P. , Monteiro J. S. , Coll N. S. , Setúbal J. C. , Valls M. 
Published: March 2021

Abstract
Background
Ralstonia solanacearum is the causal agent of bacterial wilt, a devastating plant disease responsible for serious economic losses especially on potato, tomato, and other solanaceous plant species in temperate countries. In R. solanacearum, gene expression analysis has been key to unravel many virulence determinants as well as their regulatory networks. However, most of these assays have been performed using either bacteria grown in minimal medium or in planta, after symptom onset, which occurs at late stages of colonization. Thus, little is known about the genetic program that coordinates virulence gene expression and metabolic adaptation along the different stages of plant infection by R. solanacearum.

Results
We performed an RNA-sequencing analysis of the transcriptome of bacteria recovered from potato apoplast and from the xylem of asymptomatic or wilted potato plants, which correspond to three different conditions (Apoplast, Early and Late xylem). Our results show dynamic expression of metabolism-controlling genes and virulence factors during parasitic growth inside the plant. Flagellar motility genes were especially up-regulated in the apoplast and twitching motility genes showed a more sustained expression in planta regardless of the condition. Xylem-induced genes included virulence genes, such as the type III secretion system (T3SS) and most of its related effectors and nitrogen utilisation genes. The upstream regulators of the T3SS were exclusively up-regulated in the apoplast, preceding the induction of their downstream targets. Finally, a large subset of genes involved in central metabolism was exclusively down-regulated in the xylem at late infection stages.

Conclusions
This is the first report describing R. solanacearum dynamic transcriptional changes within the plant during infection. Our data define four main genetic programmes that define gene pathogen physiology during plant colonisation. The described expression of virulence genes, which might reflect bacterial states in different infection stages, provides key information on the R. solanacearum potato infection process.
Identification of 11 candidate structured noncoding RNA motifs in humans by comparative genomics
Authors: Hou Lijuan , Xie Jin , Wu Yaoyao , Wang Jiaojiao , Duan Anqi , Ao Yaqi , Liu Xuejiao , Yu Xinmei , Yan Hui , Perreault Jonathan , Li Sanshu 
Published: March 2021

Abstract
Background
Only 1.5% of the human genome encodes proteins, while large part of the remaining encodes noncoding RNAs (ncRNA). Many ncRNAs form structures and perform many important functions. Accurately identifying structured ncRNAs in the human genome and discovering their biological functions remain a major challenge.

Results
Here, we have established a pipeline (CM-line) with the following features for analyzing the large genomes of humans and other animals. First, we selected species with larger genetic distances to facilitate the discovery of covariations and compatible mutations. Second, we used CMfinder, which can generate useful alignments even with low sequence conservation. Third, we removed repetitive sequences and known structured ncRNAs to reduce the workload of CMfinder. Fourth, we used Infernal to find more representatives and refine the structure. We reported 11 classes of structured ncRNA candidates with significant covariations in humans. Functional analysis showed that these ncRNAs may have variable functions. Some may regulate circadian clock genes through poly (A) signals (PAS); some may regulate the elongation factor (EEF1A) and the T-cell receptor signaling pathway by cooperating with RNA binding proteins.

Conclusions
By searching for important features of RNA structure from large genomes, the CM-line has revealed the existence of a variety of novel structured ncRNAs. Functional analysis suggests that some newly discovered ncRNA motifs may have biological functions. The pipeline we have established for the discovery of structured ncRNAs and the identification of their functions can also be applied to analyze other large genomes.
Rust expression browser: an open source database for simultaneous analysis of host and pathogen gene expression profiles with expVIP
Authors: Adams Thomas M. , Olsson Tjelvar S. G. , Ramírez-González Ricardo H. , Bryant Ruth , Bryson Rosie , Campos Pablo Eduardo , Fenwick Paul , Feuerhelm David , Hayes Charlotte , Henriksson Tina , Hubbard Amelia , Jevtić Radivoje , Judge Christopher , Kerton Matthew , Lage Jacob , Lewis Clare M. , Lilly Christine , Meidan Udi , Novoselović Dario , Patrick Colin , Wanyera Ruth , Saunders Diane G. O. 
Published: March 2021

Abstract
Background
Transcriptomics is being increasingly applied to generate new insight into the interactions between plants and their pathogens. For the wheat yellow (stripe) rust pathogen (Puccinia striiformis f. sp. tritici, Pst) RNA-based sequencing (RNA-Seq) has proved particularly valuable, overcoming the barriers associated with its obligate biotrophic nature. This includes the application of RNA-Seq approaches to study Pst and wheat gene expression dynamics over time and the Pst population composition through the use of a novel RNA-Seq based surveillance approach called “field pathogenomics”. As a dual RNA-Seq approach, the field pathogenomics technique also provides gene expression data from the host, giving new insight into host responses. However, this has created a wealth of data for interrogation.

Results
Here, we used the field pathogenomics approach to generate 538 new RNA-Seq datasets from Pst-infected field wheat samples, doubling the amount of transcriptomics data available for this important pathosystem. We then analysed these datasets alongside 66 RNA-Seq datasets from four Pst infection time-courses and 420 Pst-infected plant field and laboratory samples that were publicly available. A database of gene expression values for Pst and wheat was generated for each of these 1024 RNA-Seq datasets and incorporated into the development of the rust expression browser (http://www.rust-expression.com). This enables for the first time simultaneous ‘point-and-click’ access to gene expression profiles for Pst and its wheat host and represents the largest database of processed RNA-Seq datasets available for any of the three Puccinia wheat rust pathogens. We also demonstrated the utility of the browser through investigation of expression of putative Pst virulence genes over time and examined the host plants response to Pst infection.

Conclusions
The rust expression browser offers immense value to the wider community, facilitating data sharing and transparency and the underlying database can be continually expanded as more datasets become publicly available.
Construction of competitive endogenous RNA network reveals regulatory role of long non-coding RNAs in intracranial aneurysm
Authors: Pan Yuan-Bo , Lu Jianan , Yang Biao , Lenahan Cameron , Zhang Jianmin , Shao Anwen 
Published: March 2021

AbstractBackgroundRupture of intracranial aneurysm (IA) is the main cause of devastating subarachnoid hemorrhage, which urges our understanding of the pathogenesis and regulatory mechanisms of IA. However, the regulatory roles of long non-coding RNAs (lncRNAs) in IA is less known.ResultsWe processed the raw SRR files of 12 superficial temporal artery (STA) samples and 6 IA samples to count files. Then the differentially expressed (DE) mRNAs, miRNAs, and lncRNAs between STAs and IAs were identified. The enrichment analyses were performed using DEmRNAs. Next, a lncRNA-miRNA-mRNA regulatory network was constructed using integrated bioinformatics analysis. In summary, 341 DElncRNAs, 234 DEmiRNAs, and 2914 DEmRNAs between the STA and IA. The lncRNA-miRNA-mRNA regulatory network of IA contains 91 nodes and 146 edges. The subnetwork of hub lncRNA PVT1 was extracted. The expression level of PVT1 was positively correlated with a majority of the mRNAs in its subnetwork. Moreover, we found that several mRNAs (CCND1, HIF1A, E2F1, CDKN1A, VEGFA, COL1A1 and COL5A2) in the PVT1 subnetwork served as essential components in the PI3K-Akt signaling pathway, and that some of the non-coding RNAs (ncRNAs) (PVT1, HOTAIR, hsa-miR-17, hsa-miR-142, hsa-miR-383 and hsa-miR-193b) interacted with these mRNAs.ConclusionOur annotations noting ncRNA’s role in the pathway may uncover novel regulatory mechanisms of ncRNAs and mRNAs in IA. These findings provide significant insights into the lncRNA regulatory network in IA.
Investigating psychometric properties of the arm activity measure – Thai version (ArmA-TH) sub‐scales using the Rasch model
Authors: Buntragulpoontawee Montana , Khunachiva Jeeranan , Euawongyarti Patreeya , Wongpakaran Nahathai , Wongpakaran Tinakon , Kaewma Atcharee , Ashford Stephen 
Published: March 2021

Abstract
Background
This study investigated the ArmA-TH sub-scale measurement properties based on item response theory using the Rasch model.

Methods
Patients with upper limb hemiplegia resulting from cerebrovascular and other brain disorders were asked to complete the ArmA-TH questionnaire. Rasch analysis was performed to test how well the ArmA-TH passive and active function sub-scales fit the Rasch model by investigating unidimensionality, response category functioning, reliability of person and item, and differential item functioning (DIF) for age, sex, and education.

Results
Participants had stroke or other acquired brain injury (n = 185), and the majority were men (126, 68.1 %), with a mean age of 55 (SD 22). Most patients (91, 49.2 %) had graduated from elementary/primary school. For the ArmA-TH passive function scale, all items had acceptable fit statistics. The scale’s unidimensionality and local independence were supported. The reliability was acceptable. A disordered threshold was found for five items, and none indicated DIF. For the ArmA-TH active function scale, one item was misfit and three were locally dependent. The reliability was good. No items showed DIF. All items had disordered thresholds, and the data fitted the Rasch model better after rescoring.

Conclusions
Both sub-scales of ArmA-TH fitted the Rasch model and were valid and reliable. The disordered thresholds should be further investigated.
Reduction in number to treat versus number needed to treat
Authors: Zhang Chenyang , Yin Guosheng 
Published: March 2021

Abstract
Background
We propose a new measure of treatment effect based on the expected reduction in the number of patients to treat (RNT) which is defined as the difference of the reciprocals of clinical measures of interest between two arms. Compared with the conventional number needed to treat (NNT), RNT shows superiority with both binary and time-to-event endpoints in randomized controlled trials (RCTs).

Methods
Five real RCTs, two with binary endpoints and three with survival endpoints, are used to illustrate the concept of RNT and compare the performances between RNT and NNT. For survival endpoints, we propose two versions of RNT: one is based on the survival rate and the other is based on the restricted mean survival time (RMST). Hypothetical scenarios are also constructed to explore the advantages and disadvantages of RNT and NNT.

Results
Because there is no baseline for computation of NNT, it fails to differentiate treatment effect in the absolute scale. In contrast, RNT conveys more information than NNT due to its reversed order of differencing and inverting. For survival endpoints, two versions of RNT calculated as the difference of the reciprocals of survival rates and RMSTs are complementary to each other. The RMST-based RNT can capture the entire follow-up profile and thus is clinically more intuitive and meaningful, as it inherits the time-to-event characteristics for survival endpoints instead of using truncated binary endpoints at a specific time point.

Conclusions
The RNT can serve as an alternative measure for quantifying treatment effect in RCTs, which complements NNT to help patients and clinicians better understand the magnitude of treatment benefit.