bluuebunny/crossref_metadata_2025_split huggingface dataset:
Global DNA hypomethylation in epithelial ovarian cancer: passive demethylation and association with genomic instability
Authors: Zhang Wa , Klinkebiel David , Barger Carter J , Pandey Sanjit , Guda Chittibabu , Miller Austin , Akers Stacey N. , Odunsi Kunle , Karpf Adam R. 
Published: January 2020

AbstractA hallmark of human cancer is global DNA hypomethylation (GDHO), but the mechanisms accounting for this defect and its pathological consequences have not been defined in human epithelial ovarian cancer (EOC). In EOC, GDHO was associated with advanced disease and reduced overall and disease-free survival. GDHO(+) EOC was enriched for a proliferative gene expression signature, including CCNE1 and FOXM1 overexpression. DNA hypomethylation preferentially occurred within genomic blocks (hypomethylated blocks) overlapping late-replicating, lamina-associated domains, PRC2 binding, and H3K27me3. Increased proliferation coupled with hypomethylated block formation at late replicating regions suggested passive hypomethylation, which was further supported by the observation that cytosine DNA methyltransferases (DNMTs) and UHRF1 showed significantly reduced expression in GDHO(+) EOC, after normalization to proliferation markers. Importantly, GDHO(+) EOC showed elevated chromosomal instability (CIN), and copy number alterations (CNA) were enriched at hypomethylated blocks. Together, these findings implicate a passive demethylation mechanism for GDHO that promotes genomic instability and poor prognosis in EOC.
Bayesian hierarchical modeling of joint spatiotemporal risk patterns for Human Immunodeficiency Virus (HIV) and Tuberculosis (TB) in Kenya
Authors: Otiende Verrah A. , Achia Thomas N. , Mwambi Henry G. 
Published: January 2020

AbstractThe spatiotemporal modeling of multiple diseases simultaneously is a recent extension that advances the space-time analysis to model multiple related diseases simultaneously. This approach strengthens inferences by borrowing information between related diseases. Numerous research contributions to spatiotemporal modeling approaches exhibit their strengths differently with increasing complexity. However, contributions that combine spatiotemporal approaches to modeling of multiple diseases simultaneously are not so common. We present a full Bayesian hierarchical spatio-temporal approach to the joint modeling of Human Immunodeficiency Virus and Tuberculosis incidences in Kenya. Using case notification data for the period 2012 - 2017, we estimated the model parameters and determined the joint spatial patterns and temporal variations. Our model included specific and shared spatial and temporal effects. The specific random effects allowed for departures from the shared patterns for the different diseases. The space-time interaction term characterized the underlying spatial patterns with every temporal fluctuation. We assumed the shared random effects to be the structured effects and the disease-specific random effects to be unstructured effects. We detected the spatial congruence in the distribution of Tuberculosis and Human Immunodeficiency Virus in approximately 29 counties around the western, central and southern regions of Kenya. The distribution of the shared relative risks had minimal difference with the Human Immunodeficiency Virus disease-specific relative risk whereas that of Tuberculosis presented many more counties as high-risk areas. The flexibility and informative outputs of Bayesian Hierarchical Models enabled us to identify the similarities and differences in the distribution of the relative risks associated with each disease. Estimating the Human Immunodeficiency Virus and Tuberculosis shared relative risks provide additional insights towards collaborative monitoring of the diseases and control efforts.
microRNA-based predictor for diagnosis of frontotemporal dementia
Authors: Magen Iddo , Yacovzada Nancy-Sarah , Warren Jason D. , Heller Carolin , Swift Imogen , Bobeva Yoana , Malaspina Andrea , Rohrer Jonathan D. , Fratta Pietro , Hornstein Eran 
Published: January 2020

AbstractBACKGROUNDFrontotemporal dementia (FTD) is an early onset dementia that is diagnosed in ∼20% of the progressive dementia cases. Heterogeneity in FTD clinical presentation too often delays clinical diagnosis and calls for molecular biomarkers to assist diagnosis, including cell free microRNAs (miRNA). However, nonlinearity in the relationship of miRNAs to clinical states and underpowered cohorts has limited research in this domain.METHODSWe initially studied a training cohort of 219 subjects (135 FTD and 84 non-neurodegenerative controls) and then validated the results in a cohort of 74 subjects (33 FTD and 41 controls).RESULTSBased on cell-free plasma miRNA profiling by next generation sequencing and machine learning approaches, we develop a nonlinear prediction model that accurately distinguishes FTD from non-neurodegenerative controls in ∼90% of cases.DISCUSSIONThe fascinating potential of diagnostic miRNA biomarkers might enable early-stage detection and a cost-effective screening approach for clinical trials that can facilitate drug development.
Perceived facilitators and barriers among physical therapists and orthopedic surgeons to pre-operative home-based exercise withoneexercise-only in patients with severe knee osteoarthritis: A qualitative interview study nested in the QUADX-1 trial
Authors: Husted Rasmus Skov , Bandholm Thomas , Rathleff Michael Skovdal , Troelsen Anders , Kirk Jeanette 
Published: January 2020

AbstractAimClinical guidelines recommend non-surgical treatment before surgery is considered in patients eligible for knee replacement (KR). Surgical treatment is provided by orthopedic surgeons and exercise therapy is provided by physical therapists. This study aimed to investigate key stakeholder perspectives on pre-operative, home-based exercise therapy withoneexercise-only in patients eligible for KR.MethodsThis qualitative study is embedded within the QUADX-1 randomized trial that investigates a model of coordinated non-surgical and surgical treatment for patients eligible for KR. Physical therapists and orthopedic surgeons working with patients with knee osteoarthritis in their daily clinical work were interviewed (one focus group and four single interviews) to explore their perceived facilitators and barriers related to pre-operative home-based exercise therapy withoneexercise-only in patients eligible for KR. Interviews were analyzed using content analysis.ResultsFrom the content analysis three main themes emerged: 1)Physical therapists’ and orthopedic surgeons’ ambivalence in their professional roles, 2)Orthopedic surgeons view on exercise, and 3)Coordinated non-surgical and surgical care.ConclusionWe found that the pre-operative exercise intervention created ambivalence in the professional role of both the physical therapists and orthopedic surgeons. The physical therapists were skeptical towards over-simplified exercise therapy. The orthopedic surgeons were skeptical towards the potential lack of (long-term) effect of exercise therapy in patients eligible for KR. The consequence of these barriers and ambivalence in the professional role is important to consider when planning implementation of the model of coordinated non-surgical and surgical treatment.Trial registrationClinicalTrials.gov, ID:NCT02931058.
The modified arterial reservoir: an update with consideration of asymptotic pressure (P∞) and zero-flow pressure (Pzf)
Authors: Hughes Alun D , Parker Kim H 
Published: January 2020

AbstractThis article describes the modified arterial reservoir in detail. The modified arterial reservoir makes explicit the wave nature of both reservoir (Pres) and excess pressure (Pxs). The mathematical derivation and methods for estimatingPresin the absence of flow velocity data are described. There is also discussion of zero-flow pressure (Pzf), the pressure at which flow through the circulation ceases; its relationship to asymptotic pressure (P∞) estimated by the reservoir model; and the physiological interpretation ofPzf. A systematic review and meta-analysis provides evidence thatPzfdiffers from mean circulatory filling pressure.
Integrated genomics identify novel immunotherapy targets for malignant mesothelioma
Authors: Nastase Anca , Mandal Amit , Lu Shir Kiong , Anbunathan Hima , Morris-Rosendahl Deborah , Zhang Yu Zhi , Sun Xiao-Ming , Gennatas Spyridon , Rintoul Robert C , Edwards Matthew , Bowman Alex , Chernova Tatyana , Benepal Tim , Lim Eric , Taylor Anthony Newman , Nicholson Andrew G , Popat Sanjay , Willis Anne E , MacFarlane Marion , Lathrop Mark , Bowcock Anne M , Moffatt Miriam F , Cookson William OCM 
Published: January 2020

AbstractBackgroundMalignant pleural mesothelioma (MPM) is an aggressive malignancy with limited effective therapies.MethodsIn order to identify therapeutic targets, we integrated SNP genotyping, sequencing and transcriptomics from tumours and low-passage patient-derived cells.ResultsPreviously unrecognised losses of SUFU locus (10q24.32), observed in 21% of 118 tumours, resulted in disordered expression of transcripts from Hedgehog pathways and the T-cell synapse including VISTA. Co-deletion of Interferon Type I genes and CDKN2A was present in half of tumours and was a predictor of poor survival. We also found previously unrecognised deletions in RB1 in 26% of cases and show sub-micromolar responses to downstream PLK1, CHEK1 and Aurora Kinase inhibitors in primary MPM cells. Defects in Hippo pathways that included RASSF7 amplification and NF2 or LATS1/2 mutations were present in 50% of tumours and were accompanied by micromolar responses to the YAP1 inhibitor Verteporfin.ConclusionsOur results suggest new therapeutic avenues in MPM and provide targets and biomarkers for immunotherapy.
Targetable ERBB2 mutation status is an independent marker of adverse prognosis in estrogen receptor positive, ERBB2 non-amplified primary lobular breast carcinoma: a retrospective in silico analysis of public datasets
Authors: Kurozumi Sasagu , Alsaleem Mansour , Monteiro Cíntia J. , Bhardwaj Kartikeya , Joosten Stacey E. P. , Fujii Takaaki , Shirabe Ken , Green Andrew R. , Ellis Ian O. , Rakha Emad A. , Mongan Nigel P. , Heery David M. , Zwart Wilbert , Oesterreich Steffi , Johnston Simon J. 
Published: January 2020

AbstractBackgroundInvasive lobular carcinoma (ILC) accounts for 10-15% of primary breast cancers and is typically estrogen receptor alpha positive (ER+) and ERBB2 non-amplified. Somatic mutations in ERBB2/3 are emerging as a tractable mechanism underlying enhanced human epidermal growth factor 2 (HER2) activity. We tested the hypothesis that therapeutically targetable ERBB2/3 mutations in primary ILC of the breast associate with poor survival outcome in large public datasets.MethodsWe performed in silico comparison of ERBB2 non-amplified cases of ER+ stage I-III primary ILC (N=279) and invasive ductal carcinoma (IDC, N=1,301) using METABRIC, TCGA and MSK-IMPACT information. Activating mutations amenable to HER2-directed therapy with neratinib were identified using existing functional data from in vitro cell line and xenograft experiments. Multivariate analysis of 10-year overall survival (OS) with tumor size, grade and lymph node status was performed using a Cox regression model. Differential gene expression analyses by ERBB2 mutation and amplification status was performed using weighted average differences and an in-silico model of response to neratinib derived from breast cancer cell lines.ResultsILC tumors comprised 17.7% of all cases in the dataset but accounted for 47.1% of ERBB2-mutated cases. Mutations in ERBB2 were enriched in ILC versus IDC cases (5.7%, N=16 vs. 1.4%, N=18, p<0.0001) and clustered in the tyrosine kinase domain of HER2. ERBB3 mutations were not enriched in ILC (1.1%, N=3 vs. 1.8%, N=23; p=0.604). Median OS for patients with ERBB2-mutant ILC tumors was 66 months versus 211 months for ERBB2 wild-type (p=0.0001), and 159 vs. 166 months (p=0.733) for IDC tumors. Targetable ERBB2 mutational status was an independent prognostic marker of 10-year OS – but only in ILC (hazard ratio, HR=3.7, 95% CI 1.2–11.0; p=0.021). Findings were validated using a novel ERBB2 mutation gene enrichment score (HR for 10-year OS in ILC=2.3, 95% CI 1.04–5.05; p=0.040).ConclusionsTargetable ERBB2 mutations are enriched in primary ILC and their detection represents an actionable strategy with the potential to improve patient outcomes. Biomarker-led clinical trials of adjuvant HER-targeted therapy are warranted for patients with ERBB2-mutated primary ILC.
Unpublished clinical studies in pediatric emergence delirium – a cross sectional analysis
Authors: Meyburg Jochen , Ries Markus 
Published: January 2020

AbstractObjectivesEmergence delirium (ED) is a frequent and potentially serious complication of general anesthesia in children. Although there are various treatment strategies, no general management recommendations can be made. Selective reporting of study results may impair clinical decision making. We therefore analyzed whether the results of completed registered clinical studies in patients with pediatric ED are publically available or remain unpublished.DesignCross sectional analysis.SettingClinicalTrials.gov and ClinicalTrialsRegister.euParticipants and outcome measuresWe determined the proportion of published and unpublished studies registered at ClinicalTrials.gov and ClinicalTrialsRegister.eu that were marked as completed by September 1st 2018. The major trial and literature databases were used to search for publications. In addition, the study investigators were contacted directly.ResultsOf the 44 registered studies on pediatric ED, only 24 (54%) have been published by September 2019. Published trials contained data from n=2556 patients, whereas n=1644 patients were enrolled in unpublished trials. Median time to publication was 19 months. Studies completed in recent years were published faster, but still only 9 of 25 trials were published within 12 months after completion.ConclusionThere is a distinct publication gap in clinical research in pediatric ED that may have an impact on meta-analyses and clinical practice.Strengths and limitations of this studyThis study quantitates the amount of research waste in pediatric emergence delirium assessed as a) the number and b) sample sizes of published and unpublished completed clinical studiesThe precise reasons for non-publication of the studies included in this analysis remain unknownStrengths of findings as well as directions of individual unpublished studies remain unknownStudy registers other than ClinicalTrials.gov and ClinicalTrialsRegister.eu were not analyzedFunding statementThis research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.
Temporal selectivity declines in the aging human auditory cortex
Authors: Erb Julia , Schmitt Lea-Maria , Obleser Jonas 
Published: January 2020

AbstractCurrent models successfully describe the auditory cortical response to natural sounds with a set of spectra-temporal features. However, these models have hardly been linked to the ill-understood neurobiological changes that occur in the aging auditory cortex. Modelling the hemodynamic response to a rich natural sound mixture in N=64 listeners of varying age, we here show that in older listeners’ auditory cortex, the key feature of temporal rate is represented with a markedly broader tuning. This loss of temporal selectivity is most prominent in primary auditory cortex and planum temporale, with no such changes in adjacent auditory or other brain areas. Amongst older listeners, we observe a direct relationship between chronological age and temporal-rate tuning, unconfounded by auditory acuity or model goodness of fit. In line with senescent neural dedifferentiation more generally, our results highlight decreased selectivity to temporal information as a hallmark of the aging auditory cortex.Impact StatementAge-dependent broadening of tuning to temporal modulation rate in older humans’ cortical sound representations highlights decreased temporal selectivity as an anatomically and functionally specific hallmark of the aging auditory cortex.
Time-varying transmission dynamics of Novel Coronavirus Pneumonia in China
Authors: Liu Tao , Hu Jianxiong , Xiao Jianpeng , He Guanhao , Kang Min , Rong Zuhua , Lin Lifeng , Zhong Haojie , Huang Qiong , Deng Aiping , Zeng Weilin , Tan Xiaohua , Zeng Siqing , Zhu Zhihua , Li Jiansen , Gong Dexin , Wan Donghua , Chen Shaowei , Guo Lingchuan , Li Yan , Sun Limei , Liang Wenjia , Song Tie , He Jianfeng , Ma Wenjun 
Published: January 2020

ABSTRACTRationaleSeveral studies have estimated basic production number of novel coronavirus pneumonia (NCP). However, the time-varying transmission dynamics of NCP during the outbreak remain unclear.ObjectivesWe aimed to estimate the basic and time-varying transmission dynamics of NCP across China, and compared them with SARS.MethodsData on NCP cases by February 7, 2020 were collected from epidemiological investigations or official websites. Data on severe acute respiratory syndrome (SARS) cases in Guangdong Province, Beijing and Hong Kong during 2002-2003 were also obtained. We estimated the doubling time, basic reproduction number (R0) and time-varying reproduction number (Rt) of NCP and SARS.Measurements and main resultsAs of February 7, 2020, 34,598 NCP cases were identified in China, and daily confirmed cases decreased after February 4. The doubling time of NCP nationwide was 2.4 days which was shorter than that of SARS in Guangdong (14.3 days), Hong Kong (5.7 days) and Beijing (12.4 days). TheR0of NCP cases nationwide and in Wuhan were 4.5 and 4.4 respectively, which were higher thanR0of SARS in Guangdong (R0=2.3), Hongkong (R0=2.3), and Beijing (R0=2.6). TheRtfor NCP continuously decreased especially after January 16 nationwide and in Wuhan. TheR0for secondary NCP cases in Guangdong was 0.6, and theRtvalues were less than 1 during the epidemic.ConclusionsNCP may have a higher transmissibility than SARS, and the efforts of containing the outbreak are effective. However, the efforts are needed to persist in for reducing time-varying reproduction number below one.At a Glance CommentaryScientific Knowledge on the SubjectSince December 29, 2019, pneumonia infection with 2019-nCoV, now named as Novel Coronavirus Pneumonia (NCP), occurred in Wuhan, Hubei Province, China. The disease has rapidly spread from Wuhan to other areas. As a novel virus, the time-varying transmission dynamics of NCP remain unclear, and it is also important to compare it with SARS.What This Study Adds to the FieldWe compared the transmission dynamics of NCP with SARS, and found that NCP has a higher transmissibility than SARS. Time-varying production number indicates that rigorous control measures taken by governments are effective across China, and persistent efforts are needed to be taken for reducing instantaneous reproduction number below one.
Interleukin-11 is a Marker for Both Cancer- and Inflammation-Associated Fibroblasts that Contribute to Colorectal Cancer Progression
Authors: Nishina Takashi , Deguchi Yutaka , Takeda Wakami , Ohtsuka Masato , Ohshima Daisuke , Yamazaki Soh , Kawauchi Mika , Nakamura Eri , Nishiyama Chiharu , Kojima Yuko , Adachi-Akahane Satomi , Hasegawa Mizuho , Nakayama Mizuho , Oshima Masanobu , Yagita Hideo , Shibuya Kazutoshi , Mikami Tetuo , Inohara Naohiro , Tada Norihiro , Nakano Hiroyasu 
Published: January 2020

SUMMARYInterleukin (IL)-11 is a member of the IL-6 family of cytokines and involved in multiple cellular responses, including tumor development. However, the origin and functions of IL-11-producing (IL-11+) cells are not fully understood. To characterize IL-11+cellsin vivo, we generatedIl11reporter mice. IL-11+cells appeared in the colon of three murine tumor models, and a murine acute colitis model.Il11ra1orIl11deletion attenuated the development of colitis-associated colorectal cancer. IL-11+cells expressed fibroblast markers, and genes associated with cell proliferation and tissue repair. IL-11 induced STAT3 phosphorylation in colonic fibroblasts, suggesting the activation of IL-11+fibroblasts. Analysis using the human cancer database revealed that genes enriched in IL-11+fibroblasts were elevated in human colorectal cancer, and correlated with reduced disease-free survival. Together, our results suggested that tumor cells induced IL-11+fibroblasts, and that a feed-forward loop between IL-11 and IL-11+fibroblasts might contribute to tumor development.
Epigenetic engineering of yeast reveals dynamic molecular adaptation to methylation stress and genetic modulators of specific DNMT3 family members
Authors: Finnegan Alex I. , Kim Somang , Jin Hu , Gapinske Michael , Woods Wendy S. , Perez-Pinera Pablo , Song Jun S. 
Published: January 2020

ABSTRACTCytosine methylation is a ubiquitous modification in mammalian DNA generated and maintained by several DNA methyltransferases (DNMTs) with partially overlapping functions and genomic targets. To systematically dissect the factors specifying each DNMT’s activity, we engineered combinatorial knock-in of human DNMT genes inKomagataella phaffii, a yeast species lacking endogenous DNA methylation. Time-course expression measurements captured dynamic network-level adaptation of cells to DNMT3B1-induced DNA methylation stress and showed that coordinately modulating the availability of S-adenosyl methionine (SAM), the essential metabolite for DNMT-catalyzed methylation, is an evolutionarily conserved epigenetic stress response, also implicated in several human diseases. Convolutional neural networks trained on genome-wide CpG-methylation data learned distinct sequence preferences of DNMT3 family members. A simulated annealing interpretation method resolved these preferences into individual flanking nucleotides and periodic poly(A) tracts that rotationally position highly methylated cytosines relative to phased nucleosomes. Furthermore, the nucleosome repeat length defined the spatial unit of methylation spreading. Gene methylation patterns were similar to those in mammals, and hypo- and hypermethylation were predictive of increased and decreased transcription relative to control, respectively, in the absence of mammalian readers of DNA methylation. Introducing controlled epigenetic perturbations in yeast thus enabled characterization of fundamental genomic features directing specific DNMT3 proteins.