bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expression Quantitative Trait Locus Analysis in Systemic Sclerosis Identifies New Candidate Genes Associated With Multiple Aspects of Disease Pathology
Authors: Kerick Martin , González‐Serna David , Carnero‐Montoro Elena , Teruel Maria , Acosta‐Herrera Marialbert , Makowska Zuzanna , Buttgereit Anne , Babaei Sepideh , Barturen Guillermo , López‐Isac Elena ,   PRECISESADS Clinical Consortium, Lesche Ralf , Beretta Lorenzo , Alarcon‐Riquelme Marta E. , Martin Javier 
Published: January 2021

ObjectiveTo identify the genetic variants that affect gene expression (expression quantitative trait loci [eQTLs]) in systemic sclerosis (SSc) and to investigate their role in the pathogenesis of the disease.MethodsWe performed an eQTL analysis using whole‐blood sequencing data from 333 SSc patients and 524 controls and integrated them with SSc genome‐wide association study (GWAS) data. We integrated our findings from expression modeling, differential expression analysis, and transcription factor binding site enrichment with key clinical features of SSc.ResultsWe detected 49,123 validated cis‐eQTLs from 4,539 SSc‐associated single‐nucleotide polymorphisms (SNPs) (PGWAS < 10−5). A total of 1,436 genes were within 1 Mb of the 4,539 SSc‐associated SNPs. Of those 1,436 genes, 565 were detected as having ≥1 eQTL with an SSc‐associated SNP. We developed a strategy to prioritize disease‐associated genes based on their expression variance explained by SSc eQTLs (r2 > 0.05). As a result, 233 candidates were identified, 134 (58%) of them associated with hallmarks of SSc and 105 (45%) of them differentially expressed in the blood cells, skin, or lung tissue of SSc patients. Transcription factor binding site analysis revealed enriched motifs of 24 transcription factors (5%) among SSc eQTLs, 5 of which were found to be differentially regulated in the blood cells (ELF1 and MGA), skin (KLF4 and ID4), and lungs (TBX4) of SSc patients. Ten candidate genes (4%) can be targeted by approved medications for immune‐mediated diseases, of which only 3 have been tested in clinical trials in patients with SSc.ConclusionThe findings of the present study indicate a new layer to the molecular complexity of SSc, contributing to a better understanding of the pathogenesis of the disease.
To sling or not to sling? Impact of intraoperative sling procedures during radical prostatectomy on postoperative continence outcomes: A systematic review and meta‐analysis
Authors: Lim Eunice , Leslie Scott , Thanigasalam Ruban , Steffens Daniel 
Published: January 2021

AbstractPurposeThis systematic review and meta‐analysis investigates the efficacy of intraoperative sling procedures in reducing postprostatectomy urinary incontinence compared to having no slings.MethodsA comprehensive search of PubMed, Medline, Embase, and the Cochrane library from inception to November 2020 was performed. Risk of bias was assessed using the Cochrane Risk of Bias tool for randomized studies and Newcastle‐Ottawa Scale for nonrandomized studies. The GRADE approach was used for critical appraisal of evidences and meta‐analyses were conducted using random‐effects models.ResultsTen studies were included (n = 1,447). Quality of evidence ranged from moderate to very low. Sling procedure was generally favorable for short‐term continence outcomes, although discrepancies exist due to variability in continence definition. Sling procedure resulted in reduced urinary pad weight at 1 month postoperatively (MD: 21.55; 95%CI: 12.58 to 30.52). Patient‐reported questionnaires were also favorable for the sling group for up to 3 months (IPSS; (MD: 1.44; 95%CI: 0.14 to 2.74), ICIQ‐SF; (MD: 2.25; 95%CI: 1.26 to 3.24), EPIC‐U; (MD: 5.30; 95%CI: 1.12 to 9.39)) postoperatively. Sling procedure improved the number of continent patients at 1 month with continence definition of zero pad use/day (RR:1.41; 95%CI: 1.10 to 1.83) but not with the definition of ≤ 1pad/day. Similarly, it reduced the time to continence with the ≤ 1 pad/day definition (MD: 0.5; 95%CI: 0.1 to 0.9) but not with the zero pad/day definition.ConclusionThe current literature suggests that intraoperative sling procedures during radical prostatectomy may promote early return of continence compared to having no sling, however, there are no long‐term differences.
Dicer‐independent snRNA/snoRNA‐derived nuclear RNA 3 regulates tumor‐associated macrophage function by epigenetically repressing inducible nitric oxide synthase transcription
Authors: Shi Yang , Shi Qingzhu , Shen Qicong , Zhang Qian , Cao Xuetao 
Published: January 2021

AbstractBackgroundSmall RNAs (sRNAs) extensively mediate gene‐specific chromatin regulation in lower organisms. As a dominant type of functional sRNAs in mature mammals, microRNAs mainly regulate gene expression at post‐transcription level in the cytoplasm. Currently, whether there exists a type of nuclear‐localized sRNAs mediating gene‐specific epigenetic regulation in mature mammalian cells remains largely unclear. Here, we profiled sRNAs enriched in the nucleus and investigated their function in mediating gene‐specific epigenetic regulation in anti‐tumor immunity.MethodsWe established cytoplasmic and nuclear transcriptomes of sRNAs of dendritic cells (DCs) using high‐throughput sequencing. Transcription abundances of sRNAs and mRNAs were analyzed by reverse transcription‐quantitative polymerase chain reaction (RT‐qPCR) assay. The associations between sRNAs and Argonaute (AGO) proteins were detected by RNA immunoprecipitation analysis. Synthesized sRNAs and locked nucleic acid (LNA) ‐modified sRNA inhibitors were used to screen the function of sRNAs in innate immune cells. The effect of sRNA on the enrichment of either chromatin remodeler or histone modification at the gene promoter was analyzed by chromatin immunoprecipitation (ChIP)‐qPCR assay. Chromatin accessibility qPCR assay was used to detect the accessibility of gene promoters. A B16 melanoma‐bearing mouse model was established to determine the function of sRNAs in tumor‐associated macrophages (TAMs) and their effect on tumor growth.ResultsWe identified a new class of nucleus‐localized sRNAs, named snRNA/snoRNA‐derived nuclear RNAs (sdnRNAs). Some sdnRNAs were Dicer‐independent and had no association with Argonaute proteins. sdnRNA‐3, the most abundant Dicer‐independent sdnRNAs identified in our analysis, was selected as a representative to examine the biological function of sdnRNAs. sdnRNA‐3 selectively inhibited the transcription of Nos2 in macrophages during innate immune response by repressing the chromatin accessibility at Nos2 gene promoter. sdnRNA‐3 promoted the enrichments of repressive chromatin‐remodeling regulator Mi‐2β and the repressive histone modification H3K27me3 at Nos2 gene promoter. In the B16 melanoma mouse model, we found higher expression of sdnRNA‐3 in M2 TAMs than M1 TAMs and DCs. Transfer of sdnRNA‐3‐silenced macrophages inhibited tumor growth with increased expression of inducible nitric oxide synthase (iNOS) in TAMs.ConclusionsOur results demonstrated that the sdnRNA‐3 repressed the transcription of Nos2 by repressing chromatin accessibility at the promoter, providing new insights into the regulation of macrophage function in tumor immunity.
Factors associated with cognitive impairment during the first year of treatment for nonmetastatic breast cancer
Authors: Rodriguez Nicole , Fawcett Jonathan M. , Rash Joshua A. , Lester Renee , Powell Erin , MacMillan Connor D. , Garland Sheila N. 
Published: January 2021

AbstractBackgroundWomen with breast cancer are more likely to develop cognitive impairment (CI), insomnia, fatigue, and mood disturbance than individuals with other cancers. The main objectives of this study were to establish the prevalence of CI and examine the relationships between CI, insomnia, fatigue, and mood over the first year of breast cancer treatment.MethodsParticipants were recruited after diagnosis and completed validated measures of insomnia, objective and perceived CI, fatigue, and mood disturbance at four time points during the first year of treatment. A random intercepts cross‐lagged panel model assessed relationships among symptoms over time.ResultsThe sample included 98 women. Prevalence of objective CI ranged from 3.1% to 8.2% throughout the year, whereas 36.7% demonstrated a clinically meaningful decline in perceived CI from baseline to 4 months, which remained relatively stable. Greater perceived CI was associated with more fatigue (β = −0.78, z = 17.48, p < .01) and symptoms of insomnia (β = −0.58, z = 5.24, p < .01). Short‐term fluctuations in perceived CI (p < .05), but not fatigue or insomnia, predicted future perceived CI. Fatigue (p < .001) was a significant predictor of future reported symptoms of fatigue and insomnia.ConclusionSubjective CI is more prevalent than objective impairments. Fatigue, insomnia, and perceived CI remain stable and are associated during the first year of treatment. Changes in insomnia and fatigue may have little effect on future perceived cognition. Women with breast cancer likely require targeted intervention for these side effects.
Association between blood pressure and BMI with bladder cancer risk and mortality in 340,000 men in three Swedish cohorts
Authors: Teleka Stanley , Jochems Sylvia H. J. , Häggström Christel , Wood Angela M. , Järvholm Bengt , Orho‐Melander Marju , Liedberg Fredrik , Stocks Tanja 
Published: January 2021

AbstractBackgroundThe relation between obesity, blood pressure (BP) and bladder cancer (BC) risk and mortality remains unclear, partially due to potential confounding by smoking, the strongest risk factor for BC, and not accounting for tumor stage and grade in such studies. We investigated body mass index (BMI) and BP in relation to BC risk by stage and grade, and BC‐specific mortality, including separately among never‐smokers aimed at minimizing confounding by smoking.MethodsWe analyzed 338,910 men from three Swedish cohorts, with 4895 incident BC's (940 among never‐smokers) during follow‐up. Cox regression was used to calculate hazard ratios (HR) and 95% confidence intervals adjusted for smoking status. HRs for BMI and BP were corrected for their regression dilution ratios, calculated from 280,456 individuals with 758,641 observations.ResultsBody mass index was positively associated with non‐muscle invasive BC (NMIBC, HR per 5 kg/m2, 1.10 [1.02–1.19]) and NMIBC grade 3 (HR 1.17 [1.01–1.34]) in the full cohort, with similar effect sizes, albeit non‐significant, among never‐smokers. Systolic BP was positively associated with muscle‐invasive BC (MIBC, HR per 10 mmHg, 1.25 [1.00–1.55]) and BC‐specific mortality (HR 1.10 [1.01–1.20]) among never‐smokers, with weaker and non‐significant associations in the full cohort.ConclusionsIn an analyses of BMI, BP and BC risk by stage and grade among men, we found modest positive associations between BMI and NMIBC and NMIBC grade 3. SBP was positively associated with MIBC and BC‐specific mortality in an analysis of never‐smokers, which may reflect the association, un‐confounded by smoking, also in a broader population.
Clinical significance of genetic alterations in endoscopically obtained pancreatic cancer specimens
Authors: Takano Shinichi , Fukasawa Mitsuharu , Shindo Hiroko , Takahashi Ei , Hirose Sumio , Fukasawa Yoshimitsu , Kawakami Satoshi , Hayakawa Hiroshi , Kuratomi Natsuhiko , Kadokura Makoto , Maekawa Shinya , Sato Tadashi , Enomoto Nobuyuki 
Published: January 2021

AbstractAlthough comprehensive gene analyses of pancreatic cancer provide new knowledge on molecular mechanisms, the usefulness and possibility of the analyses in routinely available clinical samples remain unclear. We assessed the possibility and utility of target sequencing of endoscopically obtained pancreatic cancer samples. Fifty‐eight pancreatic cancer patients who underwent EUS‐FNA or endoscopic biopsy were enrolled. The extracted DNA quantity was assessed and used for next‐generation sequencing (NGS) of 50 cancer‐related genes from which gene mutations, copy number alterations, and microsatellite instability (MSI) were extracted via secondary analysis. A median of 19.2 ng (3.8–228) of DNA was extracted from formalin‐fixed paraffin‐embedded samples. Gene alterations were detected in 55 of 58 samples (94.8%), including all samples with a DNA concentration below the detection limit (n = 11). Four frequently altered genes were KRAS (83%), TP53 (66%), SMAD4 (26%), and PTEN (17%), and molecular targetable genes were detected in 13 cases (22.4%). Five samples (8.6%) had many mutations and suspected MSI with impaired mismatch repair genes. A Cox regression analysis revealed that metastasis (p < 0.005, hazard ratio [HR] 10.1), serum CEA >5 ng/ml (p = 0.01, HR 2.86), ≤10 detected hotspot mutations (p = 0.03, HR 9.86), and intact Ras signaling (p < 0.005, HR 5.57) were associated with a poor pancreatic cancer prognosis. We performed small, targeted sequencing of pancreatic cancer using available samples from real clinical practice and determined the relationship between gene alterations and prognosis to help determine treatment choices.
Artificial neural networks and genetic algorithms: An efficient modelling and optimization methodology for active chlorine production using the electrolysis process
Authors: Gholami Shirkoohi Majid , D. Tyagi Rajeshwar , Vanrolleghem Peter A. , Drogui Patrick 
Published: January 2021

AbstractThis study evaluates the effectiveness of a modelling and optimization methodology based on artificial neural networks and genetic algorithms in the prediction of the behaviour of an electrolysis process of active chlorine production from a synthetic saline effluent. Multilayer perceptrons feedforward neural networks were developed for the active chlorine production and energy consumption based on the following inputs: electrolysis time, current intensity, hydrochloric acid concentration, and chloride ion concentration. In order to diagnose and prevent the over‐fitting problem during the learning process, learning curves and the regularization factor were utilized. The trained ANN models were able to successfully predict the active chlorine production and energy consumption of the process (R2 = 0.979 and MSE = 3.826 for active chlorine production and R2 = 0.985 and MSE = 6.952 for energy consumption). Multi‐objective optimization for maximizing active chlorine production and minimizing energy consumption was carried out by a genetic algorithm using the best derived ANN models. The Pareto front obtained led to multiple non‐dominated optimal points, which result in insights regarding the optimal operating conditions for the process.
Searching for potential surrogate endpoints of overall survival in clinical trials for patients with prostate cancer
Authors: Maeda Hideki , Takeda Kentaro , Urushihara Hisashi , Kurokawa Tatsuo 
Published: January 2021

AbstractBackgroundThe purpose of this study was to investigate the correlation between overall survival (OS) and other clinical outcomes in patients with prostate cancer. Further, we conducted subgroup analysis in the correlation of OS.AimThis study intended to investigate potential surrogate endpoints of OS for prostate cancer by examining the correlation between OS and the other endpoints.MethodsWe performed a systematic review through a literature search by computer‐based searches of the Medline database (January 1965 and May 2014).ResultsThe contents of 115 studies with endpoint as OS were analyzed in our study. Our results showed that 47.8% (55/115) of the studies used progression‐free survival as an endpoint besides OS, followed by time to progression (43.5% [50/115]) and PSA response (40.9% [47/115]). Also, the relationship between OS and each surrogate endpoint was examined using the hazard ratio (HR) by a Bayesian hybrid model for random effect multivariate meta‐analysis. Our results showed that the endpoint that had the highest correlation with OS was progression‐free survival (PFS) with an estimated marginal correlation of 0.939 (95%CI: 0.900, 0.967). Furthermore, our stratified analysis identified PFS in castration‐resistant prostate cancer patients (0.937), in sensitive patients (0.932), in none of chemotherapy patients (0.929), in first line of the chemotherapy (0.948), in patients who received no Docetaxel previously (0.942), in both symptomatic and asymptomatic patients (0.950), in patients who received only chemotherapy (0.956), and in phase III (0.960), time to progression (TTP) in castration‐resistant prostate cancer (CRPC) patients (0.942), in metastasis patients (0.948), in both symptomatic and asymptomatic patients (0.953), in patients who received only chemotherapy (0.938), and in Phase III (0.927) as endpoints, which showed a lower limit for 95% CI of estimated marginal correlation ≥0.850 with overall survival.ConclusionsOur study suggests that PFS is a potential surrogate endpoint of OS in clinical trials for patients with prostate cancer. It also suggests potential surrogate endpoints for CRPC and locally advanced prostate cancer.
Fast Computation of Orthogonal Systems with a Skew‐Symmetric Differentiation Matrix
Authors: Iserles Arieh , Webb Marcus 
Published: January 2021

AbstractOrthogonal systems in L2(ℝ), once implemented in spectral methods, enjoy a number of important advantages if their differentiation matrix is skew‐symmetric and highly structured. Such systems, where the differentiation matrix is skew‐symmetric, tridiagonal, and irreducible, have been recently fully characterised. In this paper we go a step further, imposing the extra requirement of fast computation: specifically, that the first N coefficients of the expansion can be computed to high accuracy in operations. We consider two settings, one approximating a function f directly in (−∞, ∞) and the other approximating [f(x) + f(−x)]/2 and [f(x) − f(−x)]/2 separately in [0, ∞). In each setting we prove that there is a single family, parametrised by α, β >  − 1, of orthogonal systems with a skew‐symmetric, tridiagonal, irreducible differentiation matrix and whose coefficients can be computed as Jacobi polynomial coefficients of a modified function. The four special cases where α, β =  ± 1/2 are of particular interest, since coefficients can be computed using fast sine and cosine transforms. Banded, Toeplitz‐plus‐Hankel multiplication operators are also possible for representing variable coefficients in a spectral method. In Fourier space these orthogonal systems are related to an apparently new generalisation of the Carlitz polynomials. © 2020 Wiley Periodicals, Inc.
Evaluation of the CYP3A and CYP2B6 Drug‐Drug Interaction Potential of Lemborexant
Authors: Landry Ishani , Aluri Jagadeesh , Nakai Kenya , Hall Nancy , Miyajima Yukiko , Ueno Takashi , Dayal Satish , Filippov Gleb , Lalovic Bojan , Moline Margaret , Reyderman Larisa 
Published: January 2021

AbstractLemborexant is approved for treating insomnia and is under investigation for treating irregular sleep‐wake rhythm disorder. Based on in vitro drug‐drug interaction (DDI) characteristics, phase 1, open‐label DDI studies were conducted to evaluate lemborexant's cytochrome P450 3A (CYP3A) and CYP2B6 interaction potential. Interactions between lemborexant 10 mg and strong and moderate CYP3A inhibitors (itraconazole and fluconazole), a strong CYP3A inducer (rifampin), and CYP3A (midazolam) and CYP2B6 substrates (bupropion) were evaluated. Coadministration of lemborexant with itraconazole or fluconazole resulted in 1.4‐ to 1.6‐fold and 3.7‐ to 4‐fold increases in lemborexant maximum observed concentration (Cmax) and area under the concentration‐time curve from zero time extrapolated to infinity (AUC0‐inf), respectively. Coadministration of lemborexant with rifampin resulted in >90% decreases in lemborexant Cmax and AUC0‐inf. Midazolam exposure was not affected. Coadministration of lemborexant with bupropion resulted in 49.9% and 45.5% decreases in S‐bupropion Cmax and AUC0‐inf, respectively.Comparison of estimated exposures for patients in phase 3 trials who were/were not receiving concomitant weak CYP3A inhibitors substantiated the DDI pharmacokinetic findings. Lemborexant was generally well tolerated in the phase 1 studies. In summary, lemborexant does not affect the pharmacokinetics of CYP3A substrates and has potential to induce CYP2B6. Consistent with in vitro findings, moderate and strong CYP3A inhibitors and inducers affected the pharmacokinetics of lemborexant; hence, patients taking lemborexant 5 or 10 mg should avoid coadministration with moderate and strong CYP3A inhibitors and inducers.
Kinetics of activation marker expression after in vitro polyclonal stimulation of chicken peripheralT cells
Authors: Naghizadeh Mohammad , Hatamzade Nasim , Larsen Frederik T. , Kjaerup Rikke B. , Wattrang Eva , Dalgaard Tina S. 
Published: January 2021

AbstractA comprehensive analysis of T cell activation markers in chicken is lacking. Kinetics of T cell activation markers (CD25, CD28, CD5, MHC‐II, CD44, and CD45) in response toin vitrostimulation of peripheral blood mononuclear cells with concanavalin A (Con A) were evaluated between two chicken lines selected for high and low levels of mannose‐binding lectin in serum (L10H and L10L, respectively) by flow cytometry. L10H chickens showed a stronger response to Con A based on the frequency of T cell blasts in both the CD4+and CD8+compartment. The majority of the proliferating CD4+and CD8+T cells expressed CD25. Proliferating T cells were seen both in the CD4+ MHC‐II+/−and CD8+ MHC‐II+/−population. For both CD4+and CD8+T cells, frequencies of CD25+and MHC‐II+T cells were increased 24 h after stimulation. CD28+frequencies were only increased on CD8+T cells 48 h after stimulation. An increase in the relative surface expression based on mean fluorescence intensity (MFI) upon activation was observed for most markers except CD5. For CD4+T cells, CD28 expression increased 24 h after stimulation whereas MHC‐II expression increased after 48 h. For CD8+T cells, a tendency toward an increase in CD25 expression was observed. CD28 expression started to increase 24 h after stimulation and only a transient peak in MHC‐II expression on CD8+T cells was observed after 24 h. CD44 and CD45 expressed on CD4+and CD8+T cells increased 24–72 h after stimulation. In summary, the frequency of CD25+and MHC‐II+T cells were shown to be early markers (24 h) forin vitroactivation of both CD4+and CD8+T cells. Frequency of CD28+T cells was a later marker (48 h) and only for CD8+T cells. Surface expression of all markers (MFI) increased permanently or transiently upon activation except for CD5.
Writing and Publishing Scientific Book Reviews as a Teaching Tool in Fisheries
Authors: Juanes Francis 
Published: January 2021

Abstract
Writing and publishing fisheries book reviews serves as a useful teaching tool that can provide a variety of skills, including critical thinking, scientific writing, collaboration, and the publication process. Here, I describe the process my students and I have followed over the last 25 years in publishing 19 student-oriented book reviews, and highlight some of the lessons learned.