bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endemic Burkitt lymphoma: a complication of asymptomatic malaria in sub-Saharan Africa based on published literature and primary data from Uganda, Tanzania, and Kenya
Authors: Redmond Lawrence S. , Ogwang Martin D. , Kerchan Patrick , Reynolds Steven J. , Tenge Constance N. , Were Pamela A. , Kuremu Robert T. , Masalu Nestory , Kawira Esther , Otim Isaac , Legason Ismail D. , Dhudha Herry , Ayers Leona W. , Bhatia Kishor , Goedert James J. , Mbulaiteye Sam M. 
Published: July 2020

Abstract
Background
Endemic Burkitt lymphoma (eBL) is an aggressive B cell non-Hodgkin lymphoma associated with antigenic stimulation from Plasmodium falciparum malaria. Whether eBL risk is related to malaria parasite density is unknown. To address this issue, children with eBL, asymptomatic and clinical malaria, as a surrogate of malaria parasite density, were assessed.

Methods
Malaria-related laboratory results (parasite density, haemoglobin, platelet count, and white cell count [WBC]) count) were compiled for 4019 eBL cases and 80,532 subjects evaluated for asymptomatic malaria or clinical malaria (severe malaria anaemia, hyperparasitaemia, cerebral malaria, malaria prostration, moderate malaria, and mild malaria) in 21 representative studies published in Africa (mostly East Africa) and 850 eBL cases and 2878 controls with primary data from the Epidemiology of Burkitt Lymphoma in East African Children and Minors (EMBLEM) case–control study in Uganda, Tanzania, and Kenya. The average values of malaria-related laboratory results were computed by condition and trends across single-year age groups were assessed using regression and spline models.

Results
Overall, malaria infection or malaria was diagnosed in 37,089 of children compiled from the literature. Children with eBL and asymptomatic parasitaemia/antigenaemia, but not those with clinical malaria, were closest in their mean age (age 7.1–7.2 vs. 7.4–9.8 years), haemoglobin level (10.0–10.4 vs. 11.7–12.3 g/dL), malaria parasite density (2800 vs. 1827–7780 parasites/µL), platelet count (347,000–353,000 vs. 244,000–306,000 platelets/µL), and WBC count (8180–8890 vs. 7100–7410 cells/µL). Parasite density in these two groups peaked between four to five years, then decreased steadily thereafter; conversely, haemoglobin showed a corresponding increase with age. Children with clinical malaria were markedly different: all had an average age below 5 years, had dramatically elevated parasite density (13,905–869,000 parasites/µL) and dramatically decreased platelet count (< 159,000 platelets/µL) and haemoglobin (< 7 g/dL).

Conclusions
eBL and asymptomatic parasitaemia/antigenaemia, but not clinical malaria, were the most similar conditions with respect to mean age and malaria-related laboratory results. These results suggest that children with asymptomatic parasitaemia/antigenaemia may be the population at risk of eBL.
Prediction of hospital visits for the general inpatient care using floating catchment area methods: a reconceptualization of spatial accessibility
Authors: Bauer J. , Klingelhöfer D. , Maier W. , Schwettmann L. , Groneberg D. A. 
Published: July 2020

AbstractBackgroundThe adequate allocation of inpatient care resources requires assumptions about the need for health care and how this need will be met. However, in current practice, these assumptions are often based on outdated methods (e.g. Hill-Burton Formula). This study evaluated floating catchment area (FCA) methods, which have been applied as measures of spatial accessibility, focusing on their ability to predict the need for health care in the inpatient sector in Germany.MethodsWe tested three FCA methods (enhanced (E2SFCA), modified (M2SFCA) and integrated (iFCA)) for their accuracy in predicting hospital visits regarding six medical diagnoses (atrial flutter/fibrillation, heart failure, femoral fracture, gonarthrosis, stroke, and epilepsy) on national level in Germany. We further used the closest provider approach for benchmark purposes. The predicted visits were compared with the actual visits for all six diagnoses using a correlation analysis and a maximum error from the actual visits of ± 5%, ± 10% and ± 15%.ResultsThe analysis of 229 million distances between hospitals and population locations revealed a high and significant correlation of predicted with actual visits for all three FCA methods across all six diagnoses up to ρ = 0.79 (p < 0.001). Overall, all FCA methods showed a substantially higher correlation with actual hospital visits compared to the closest provider approach (up to ρ = 0.51; p < 0.001). Allowing a 5% error of the absolute values, the analysis revealed up to 13.4% correctly predicted hospital visits using the FCA methods (15% error: up to 32.5% correctly predicted hospital). Finally, the potential of the FCA methods could be revealed by using the actual hospital visits as the measure of hospital attractiveness, which returned very strong correlations with the actual hospital visits up to ρ = 0.99 (p < 0.001).ConclusionWe were able to demonstrate the impact of FCA measures regarding the prediction of hospital visits in non-emergency settings, and their superiority over commonly used methods (i.e. closest provider). However, hospital beds were inadequate as the measure of hospital attractiveness resulting in low accuracy of predicted hospital visits. More reliable measures must be integrated within the proposed methods. Still, this study strengthens the possibilities of FCA methods in health care planning beyond their original application in measuring spatial accessibility.
Exosomal circPACRGL promotes progression of colorectal cancer via the miR-142-3p/miR-506-3p- TGF-β1 axis
Authors: Shang Anquan , Gu Chenzheng , Wang Weiwei , Wang Xuan , Sun Junjun , Zeng Bingjie , Chen Chen , Chang Wenjing , Ping Yili , Ji Ping , Wu Junlu , Quan Wenqiang , Yao Yiwen , Zhou Yongxin , Sun Zujun , Li Dong 
Published: July 2020

Abstract
Background
Colorectal cancer (CRC) is the leading cause of cancer-related death worldwide. Exosome shave emerged as crucial regulators of intercellular communication and that abundant Circular RNAs (circRNAs) are enriched within exosomes. CircRNAs are novel members of noncoding RNAs regulating cancer proliferation and progression. However, the function and regulatory mechanism of cancer-derived exosomal circRNAs in CRC remains unclear.

Methods
CRC cells-derived exosomes were characterized using transmission electron microscopy, nanoparticle tracking analysis (NTA) and western blot. CCK-8, wound healing and transwell assays, and flow cytometry assays were conducted to assess whether exosomes would affect the proliferation, metastasis, and apoptosis of CRC cells, respectively. Moreover, we performed the RNA sequencing and RT-qPCR to identify circRNAs in exosome-stimulated CRC cells. Fluorescence in situ hybridization (FISH) assay was used to detect the cellular distribution of circPACRGL. Bioinformatic analyses (StarBase 2.0) were used to pool the miRNA targets of circPACRGL. Luciferase assays were performed to verify the direct interaction. Finally, flow cytometry was used to detect the differentiation of N1-N2 neutrophils.

Results
Our study identified a novel CRC-derived exosomal circRNA, circPACRGL. We found circPACRGL was significantly upregulated in CRC cells after tumor-derived exosomes addition. Moreover, circPACRGL serves as a sponge for miR-142-3p/miR-506-3p to facilitate the transforming growth factor-β1 (TGF-β1) expression. As a result, circPACRGL promoted CRC cell proliferation, migration and invasion, as well as differentiation of N1 to N2 neutrophils via miR-142-3p/miR-506-3p-TGF-β1 axis.

Conclusion
Our study, the first to reveal that cancer-derived exosomal circPACRGL plays an oncogenic role in CRC proliferation and metastasis, providing mechanistic insights into the roles of circRNAs in CRC progression and a valuable marker for CRC treatment.
Utility value estimates in cardiovascular disease and the effect of changing elicitation methods: a systematic literature review
Authors: Betts Marissa Blieden , Rane Pratik , Bergrath Evelien , Chitnis Madhura , Bhutani Mohit Kumar , Gulea Claudia , Qian Yi , Villa Guillermo 
Published: July 2020

AbstractObjectiveIdentify the most recent utility value estimates for cardiovascular disease (CVD) via systematic literature review (SLR) and explore trends in utility elicitation methods in the last 6 years.MethodsThis SLR was updated on January 25, 2018, and identified studies reporting utilities for myocardial infarction (MI), stroke, angina, peripheral artery disease (PAD), and any-cause revascularization by searching Embase, PubMed, Health Technology Assessment Database, and grey literature.ResultsA total of 375 studies reported CVD utilities (pre-2013 vs post-2013: MI, 38 vs 32; stroke, 86 vs 113; stable angina, 8 vs 9; undefined/unstable angina, 23 vs 8; PAD, 29 vs 13; revascularization, 54 vs 40). Median average utilities for MI, stroke, and revascularization increased over time (pre-2013 vs post-2013: MI, 0.71 vs 0.79; stroke, 0.63 vs 0.64; revascularization, 0.76 vs 0.81); angina and PAD showed a decrease in median values over time (stable angina, 0.83 vs 0.72; undefined/unstable angina, 0.70 vs 0.69; PAD, 0.76 vs 0.71). The proportion of utility estimates from trials increased across health states (pre-2013 vs post-2013: 22.5% vs 37.2%), as did the proportion of trials using the EuroQol Five Dimensions Questionnaire (EQ-5D; pre-2013 vs post-2013: 73.8% vs 91.4%). Use of methods such as the standard gamble, time trade-off, and Health Utilities Index has declined.ConclusionsHealth state utilities for cardiovascular health states have changed in the last 6 years, likely due to changes in the types of studies conducted, the patient populations evaluated, and possibly changing utility elicitation methods. The EQ-5D has been used more frequently.
Male involvement in reproductive, maternal, newborn, and child health: evaluating gaps between policy and practice in Uganda
Authors: Gopal Prerna , Fisher Duncan , Seruwagi Gloria , Taddese Henock B. 
Published: July 2020

AbstractIntroductionMale involvement in maternal and child health is a practice wherein fathers and male community members actively participate in caring for women and supporting their family to access better health services. There is positive association between male involvement and better maternal and child health outcomes. However, the practice is not always practiced optimally, especially in low- and middle-income countries, where women may not have access to economic resources and decision-making power.AimThis study investigates how key stakeholders within the health system in Uganda engage with the ‘male involvement’ agenda and implement related policies. We also analyzed men’s perceptions of male involvement initiatives, and how these are influenced by different political, economic, and organizational factors.MethodologyThis is a qualitative study utilizing data from 17 in-depth interviews and two focus group discussions conducted in Kasese and Kampala, Uganda. Study participants included men involved in a maternal health project, their wives, and individuals and organizations working to improve male involvement; all purposively selected.ResultThrough thematic analysis, four major themes were identified: ‘gaps between policy and practice’, ‘resources and skills’, ‘inadequate participation by key actors’, and ‘types of dissemination’. These themes represent the barriers to effective implementation of male involvement policies. Most health workers interviewed have not been adequately trained to provide male-friendly services or to mobilize men. Interventions are highly dependent on external aid and support, which in turn renders them unsustainable. Furthermore, community and religious leaders, and men themselves, are often left out of the design and management of male involvement interventions. Finally, communication and feedback mechanisms were found to be inadequate.ConclusionTo enable sustainable behavior change, we suggest a ‘bottom-up’ approach to male involvement that emphasizes solutions developed by or in tandem with community members, specifically, fathers and community leaders who are privy to the social norms, structures, and challenges of the community.
Stigma: how it affects the substance use disorder patient
Authors: Zwick Janet , Appleseth Hannah , Arndt Stephan 
Published: July 2020

AbstractThe stigma surrounding individuals who have substance use disorders is a pervasive phenomenon that has had detrimental effects on treatment outcomes, health care providers, treatments, research, policies, and society as a whole (Kelly JF, Dow SJ, Westerhoff C , J Drug Issues_40:805-818, Kelly JF, Westerhoff, Int J Drug Policy_21:202-207, 2010). Stigma can be cultivated by various sources, but this article specifically focuses on the impact words have. Individuals influence each other through dynamic language processes. Language, which we use to communicate, represents shared values, history, beliefs, and customs. Moreover, language can be used to promote stigma or decrease it [Snodgrass S: The Power of Words: Changing the Language of Addiction, 2920]. Language usage for addiction medical care is dated in comparison to other standards. Research and organizations are recognizing that substance use treatment, policies, and language need to evolve to aid this crisis and those affected by this disease. Language sustains the stigma surrounding substance use. The stigmatized language used to describe substance use behaviors, individuals with substance use disorders, and substance use treatment can create barriers in essential areas, such as health care, employment, insurance policies, and laws for individuals who are trying to heal and make meaningful contributions to society. There are many ways to contribute to a more accepting society, but it starts with bottom-up processes like language choices in day-to-day conversations. An effort must be made to normalize destigmatized language when referring to substance use and individuals with substance use disorders.
Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies
Authors: He Yonghan , Khan Sajid , Huo Zhiguang , Lv Dongwen , Zhang Xuan , Liu Xingui , Yuan Yaxia , Hromas Robert , Xu Mingjiang , Zheng Guangrong , Zhou Daohong 
Published: July 2020

AbstractProteolysis targeting chimeras (PROTACs) are heterobifunctional small molecules that utilize the ubiquitin proteasome system (UPS) to degrade proteins of interest (POI). PROTACs are potentially superior to conventional small molecule inhibitors (SMIs) because of their unique mechanism of action (MOA, i.e., degrading POI in a sub-stoichiometric manner), ability to target “undruggable” and mutant proteins, and improved target selectivity. Therefore, PROTACs have become an emerging technology for the development of novel targeted anticancer therapeutics. In fact, some of these reported PROTACs exhibit unprecedented efficacy and specificity in degrading various oncogenic proteins and have advanced to various stages of preclinical and clinical development for the treatment of cancer and hematologic malignancy. In this review, we systematically summarize the known PROTACs that have the potential to be used to treat various hematologic malignancies and discuss strategies to improve the safety of PROTACs for clinical application. Particularly, we propose to use the latest human pan-tissue single-cell RNA sequencing data to identify hematopoietic cell type-specific/selective E3 ligases to generate tumor-specific/selective PROTACs. These PROTACs have the potential to become safer therapeutics for hematologic malignancies because they can overcome some of the on-target toxicities of SMIs and PROTACs.
Expression of metalloproteinases MMP-2 and MMP-9 is associated to the presence of androgen receptor in epithelial ovarian tumors
Authors: Morales-Vásquez Flavia , Castillo-Sánchez Rocío , Gómora María J. , Almaraz Miguel Ángel , Pedernera Enrique , Pérez-Montiel Delia , Rendón Elizabeth , López-Basave Horacio Noé , Román-Basaure Edgar , Cuevas-Covarrubias Sergio , Maldonado-Cubas Juan , Villa Antonio , Mendez Carmen 
Published: July 2020

Abstract
Background
The current study evaluated the metalloproteinases MMP-2 and MMP-9 expression in epithelial cells and the surrounding stroma in ovarian tumors and the association of MMPs with the histological subtypes, the clinical stage and the presence of steroid hormone receptors. Tumor samples were obtained from 88 patients undergoing surgical cytoreduction of primary ovarian tumors in Instituto Nacional de Cancerología, from México City. The formalin fixed and paraffin embedded samples were processed in order to demonstrate the presence of androgen receptor,estrogen receptor alpha, progesterone receptor, MMP-2,MMP-9 and collagen IV by immunohistochemistry and/or immunofluorescence.

Results
MMP-2 and MMP-9 were differentially expressed in the epithelium and the stroma of ovarian tumors associated to histological subtype, clinical stage and sexual steroid hormone receptor expression. Based on Cox proportional hazard regression model we demonstrated that MMP-2 located in the epithelium and the stroma are independent prognostic biomarkers for overall survival in epithelial ovarian tumors. Kaplan Meir analysis of the combination of AR (+) with MMP-2 (+) in epithelium and AR (+) with MMP-2 (−) in stroma displayed a significant reduction of survival.

Conclusions
The presence of MMP-2 in the stroma of the tumor was a protective factor while the presence of MMP-2 in the epithelium indicated an adverse prognosis. The presence of AR associated with MMP-2 in the tumor cells was a risk factor for overall survival in epithelial ovarian cancer.
DNA methylation repels binding of hypoxia-inducible transcription factors to maintain tumor immunotolerance
Authors: D’Anna Flora , Van Dyck Laurien , Xiong Jieyi , Zhao Hui , Berrens Rebecca V. , Qian Junbin , Bieniasz-Krzywiec Pawel , Chandra Vikas , Schoonjans Luc , Matthews Jason , De Smedt Julie , Minnoye Liesbeth , Amorim Ricardo , Khorasanizadeh Sepideh , Yu Qian , Zhao Liyun , De Borre Marie , Savvides Savvas N. , Simon M. Celeste , Carmeliet Peter , Reik Wolf , Rastinejad Fraydoon , Mazzone Massimiliano , Thienpont Bernard , Lambrechts Diether 
Published: July 2020

Abstract
Background
Hypoxia is pervasive in cancer and other diseases. Cells sense and adapt to hypoxia by activating hypoxia-inducible transcription factors (HIFs), but it is still an outstanding question why cell types differ in their transcriptional response to hypoxia.

Results
We report that HIFs fail to bind CpG dinucleotides that are methylated in their consensus binding sequence, both in in vitro biochemical binding assays and in vivo studies of differentially methylated isogenic cell lines. Based on in silico structural modeling, we show that 5-methylcytosine indeed causes steric hindrance in the HIF binding pocket. A model wherein cell-type-specific methylation landscapes, as laid down by the differential expression and binding of other transcription factors under normoxia, control cell-type-specific hypoxia responses is observed. We also discover ectopic HIF binding sites in repeat regions which are normally methylated. Genetic and pharmacological DNA demethylation, but also cancer-associated DNA hypomethylation, expose these binding sites, inducing HIF-dependent expression of cryptic transcripts. In line with such cryptic transcripts being more prone to cause double-stranded RNA and viral mimicry, we observe low DNA methylation and high cryptic transcript expression in tumors with high immune checkpoint expression, but not in tumors with low immune checkpoint expression, where they would compromise tumor immunotolerance. In a low-immunogenic tumor model, DNA demethylation upregulates cryptic transcript expression in a HIF-dependent manner, causing immune activation and reducing tumor growth.

Conclusions
Our data elucidate the mechanism underlying cell-type-specific responses to hypoxia and suggest DNA methylation and hypoxia to underlie tumor immunotolerance.
Polymorphic mobile element insertions contribute to gene expression and alternative splicing in human tissues
Authors: Cao Xiaolong , Zhang Yeting , Payer Lindsay M. , Lords Hannah , Steranka Jared P. , Burns Kathleen H. , Xing Jinchuan 
Published: July 2020

Abstract
Background
Mobile elements are a major source of structural variants in the human genome, and some mobile elements can regulate gene expression and transcript splicing. However, the impact of polymorphic mobile element insertions (pMEIs) on gene expression and splicing in diverse human tissues has not been thoroughly studied. The multi-tissue gene expression and whole genome sequencing data generated by the Genotype-Tissue Expression (GTEx) project provide a great opportunity to systematically evaluate the role of pMEIs in regulating gene expression in human tissues.

Results
Using the GTEx whole genome sequencing data, we identify 20,545 high-quality pMEIs from 639 individuals. Coupling pMEI genotypes with gene expression profiles, we identify pMEI-associated expression quantitative trait loci (eQTLs) and splicing quantitative trait loci (sQTLs) in 48 tissues. Using joint analyses of pMEIs and other genomic variants, pMEIs are predicted to be the potential causal variant for 3522 eQTLs and 3717 sQTLs. The pMEI-associated eQTLs and sQTLs show a high level of tissue specificity, and these pMEIs are enriched in the proximity of affected genes and in regulatory elements. Using reporter assays, we confirm that several pMEIs associated with eQTLs and sQTLs can alter gene expression levels and isoform proportions, respectively.

Conclusion
Overall, our study shows that pMEIs are associated with thousands of gene expression and splicing variations, indicating that pMEIs could have a significant role in regulating tissue-specific gene expression and transcript splicing. Detailed mechanisms for the role of pMEIs in gene regulation in different tissues will be an important direction for future studies.
Bovine breed-specific augmented reference graphs facilitate accurate sequence read mapping and unbiased variant discovery
Authors: Crysnanto Danang , Pausch Hubert 
Published: July 2020

Abstract
Background
The current bovine genomic reference sequence was assembled from a Hereford cow. The resulting linear assembly lacks diversity because it does not contain allelic variation, a drawback of linear references that causes reference allele bias. High nucleotide diversity and the separation of individuals by hundreds of breeds make cattle ideally suited to investigate the optimal composition of variation-aware references.

Results
We augment the bovine linear reference sequence (ARS-UCD1.2) with variants filtered for allele frequency in dairy (Brown Swiss, Holstein) and dual-purpose (Fleckvieh, Original Braunvieh) cattle breeds to construct either breed-specific or pan-genome reference graphs using the vg toolkit. We find that read mapping is more accurate to variation-aware than linear references if pre-selected variants are used to construct the genome graphs. Graphs that contain random variants do not improve read mapping over the linear reference sequence. Breed-specific augmented and pan-genome graphs enable almost similar mapping accuracy improvements over the linear reference. We construct a whole-genome graph that contains the Hereford-based reference sequence and 14 million alleles that have alternate allele frequency greater than 0.03 in the Brown Swiss cattle breed. Our novel variation-aware reference facilitates accurate read mapping and unbiased sequence variant genotyping for SNPs and Indels.

Conclusions
We develop the first variation-aware reference graph for an agricultural animal (10.5281/zenodo.3759712). Our novel reference structure improves sequence read mapping and variant genotyping over the linear reference. Our work is a first step towards the transition from linear to variation-aware reference structures in species with high genetic diversity and many sub-populations.