bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prospective Evaluation of a Breast Cancer Risk Model Integrating Classical Risk Factors and Polygenic Risk in 15 Cohorts from Six Countries
Authors: Wilcox Amber N , Choudhury Parichoy Pal , Gao Chi , Hüsing Anika , Eriksson Mikael , Shi Min , Scott Christopher , Carter Brian D , Martin Kara , Harkness Elaine , Brook Mark N , Ahearn Thomas U , Mavaddat Nasim , Antoniou Antonis C , Chang-Claude Jenny , Simard Jacques , Jones Michael E , Orr Nick , Schoemaker Minouk J , Swerdlow Anthony J , Sampson Sarah , Newman William G , van Veen Elke M , Evans D. Gareth R , MacInnis Robert J , Giles Graham G , Southey Melissa , Milne Roger L , Gapstur Susan M , Gaudet Mia M , Winham Stacey J , Brandt Kathy , Norman Aaron , Vachon Celine M , Sandler Dale P , Weinberg Clarice R , Czene Kamila , Gabrielson Marike , Hall Per , van Gils Carla H , Khaw Kay-Tee , Barrdahl Myrto , Kaaks Rudolf , Ridker Paul M , Buring Julie E , Chasman Dan I , Easton Douglas F , Schmidt Marjanka K , Kraft Peter , Garcia-Closas Montserrat , Chatterjee Nilanjan 
Published: November 2019

ABSTRACTPURPOSERisk-stratified breast cancer prevention requires accurate identification of women at sufficiently different levels of risk. We conducted a comprehensive evaluation of a model integrating classical risk factors and a recently developed 313-variant polygenic risk score (PRS) to predict breast cancer risk.METHODSFifteen prospective cohorts from six countries with 237,632 women (7,529 incident breast cancer patients) of European ancestry aged 19-75 years at baseline were included. Calibration of five-year risk was assessed by comparing predicted and observed proportions of cases overall and within risk categories. Risk stratification for women of European ancestry aged 50-70 years in those countries was evaluated by the proportion of women and future breast cancer cases crossing clinically-relevant risk thresholds.RESULTSThe model integrating classical risk factors and PRS accurately predicted five-year risk. For women younger than 50 years, median (range) expected-to-observed ratio across the cohorts was 0.94 (0.72 to 1.01) overall and 0.9 (0.7 to 1.4) at the highest risk decile. For women 50 years or older, these ratios were 1.04 (0.73 to 1.31) and 1.2 (0.7 to 1.6), respectively. The proportion of women in the general population identified above the 3% five-year risk threshold (used for recommending risk-reducing medications in the US) ranged from 7.0% in Germany (∼841,000 of 12 million) to 17.7% in the US (∼5.3 of 30 million). At this threshold, 14.7% of US women were re-classified by the addition of PRS to classical risk factors, identifying 12.2% additional future breast cancer cases.CONCLUSIONEvaluation across multiple prospective cohorts demonstrates that integrating a 313-SNP PRS into a risk model substantially improves its ability to stratify women of European ancestry for applying current breast cancer prevention guidelines.
Human regulatory T cells at the maternal-fetal interface show functional site-specific adaptation with tumor-infiltrating-like features
Authors: Wienke Judith , Brouwers Laura , van der Burg Leone , Mokry Michal , Scholman Rianne C. , Nikkels Peter G.J. , van Rijn Bas , van Wijk Femke 
Published: November 2019

AbstractObjectivesRegulatory T cells (Tregs) are crucial for maintaining immune tolerance against the semi-allogeneic fetus during pregnancy. Since their functional profile at the human maternal-fetal interface is still elusive, we investigated the transcriptional profile and functional adaptation of human uterine Tregs (uTregs) during pregnancy.MethodsBlood and uterine biopsies from the placental bed (=maternal-fetal interface) and incision site (=control), were obtained from women with uneventful pregnancies undergoing primary Caesarean section. Tregs and CD4+non-Tregs (Tconv) were isolated for transcriptomic profiling by Cel-Seq2. Results were validated on protein and single cell level by flow cytometry.ResultsPlacental bed uterine Tregs (uTregs) showed elevated expression of Treg signature markers compared to blood Tregs, including FOXP3, CTLA4 and TIGIT. The uTreg transcriptional profile was indicative of late-stage effector Treg differentiation and chronic activation with high expression of immune checkpoints GITR, TNFR2, OX-40, 4-1BB, genes associated with suppressive capacity (CTLA4, HAVCR2, IL10, IL2RA, LAYN, PDCD1), activation (HLA-DR, LRRC32), and transcription factors MAF, PRDM1, BATF, and VDR. uTregs mirrored uTconv Th1 polarization, and characteristics indicating tissue-residency, including high CD69, CCR1, and CXCR6. The particular transcriptional signature of placental bed uTregs overlapped strongly with the specialized profile of human tumor-infiltrating Tregs, and, remarkably, was more pronounced at the placental bed than uterine control site.ConclusionuTregs at the maternal-fetal interface acquire a highly differentiated effector Treg profile similar to tumor-infiltrating Tregs, which is locally enriched compared to a distant uterine site. This introduces the novel concept of site-specific transcriptional adaptation of human Tregs within one organ.
Escape from nonsense mediated decay associates with anti-tumor immunogenicity
Authors: Litchfield Kevin , Reading James , Lim Emilia , Xu Hang , Liu Po , AL-Bakir Maise , Wong Sophia , Rowan Andrew , Funt Sam , Merghoub Taha , Lauss Martin , Svane Inge Marie , Jönsson Göran , Herrero Javier , Larkin James , Quezada Sergio A. , Hellmann Matthew D. , Turajlic Samra , Swanton Charles 
Published: November 2019

AbstractFrameshift insertion/deletions (fs-indels) are an infrequent but potentially highly immunogenic mutation subtype. Although fs-indel transcripts are susceptible to degradation through the non-sense mediated decay (NMD) pathway, we hypothesise that some fs-indels escape degradation and lead to an increased abundance of tumor specific neoantigens, that are highly distinct from self. We analysed matched DNA and RNA sequencing data from TCGA, and five separate melanoma cohorts treated with immunotherapy. Using allele-specific expression analysis we show that expressed fs-indels were enriched in genomic positions predicted to escape NMD, and associated with higher protein expression, consistent with degradation escape (“NMD-escape”). Across four independent cohorts, fs-indel NMD-escape mutations were found to be significantly associated with clinical benefit to checkpoint inhibitor (CPI) therapy (Pmeta=0.0039), a stronger association than either nsSNV (Pmeta=0.073) or fs-indel (Pmeta=0.064) count. NMD-escape mutations were additionally shown to have independent predictive power in the “low-TMB” setting, and may serve as a biomarker to rescue patients judged ineligible for CPI based on overall TMB, but still with a high chance of response (low-TMB cohort: NMD-escape-positive % clinical benefit=53%, NMD-escape-negative % clinical benefit=16%, P=0.0098). Furthermore, in an adoptive cell therapy (ACT) treated cohort, NMD-escape mutation count was the most significant biomarker associated with clinical benefit (P=0.021). Analysis of functional T-cell reactivity screens from recent personalized vaccine and CPI studies shows direct evidence of fs-indel derived neoantigens eliciting patient anti-tumor immune response (n=15). We additionally observe a subset of fs-indel mutations, with highly elongated neo open reading frames, which are found to be significantly enriched for immunogenic reactivity in these patient studies (P=0.0032). Finally, consistent with the potency of NMD-escape derived neo-antigens and ongoing immune-editing, NMD-escape fs-indels appear to be under negative selective pressure in untreated TCGA cases. Given the strongly immunogenic potential, and relatively rare nature of NMD-escape fs-indels, these alterations may be attractive candidates in immunotherapy biomarker optimisation and neoantigen ACT or vaccine strategies.
An open dataset of Plasmodium falciparum genome variation in 7,000 worldwide samples
Authors: Pearson Richard D , Amato Roberto , Kwiatkowski Dominic P ,   MalariaGEN Plasmodium falciparum Community Project
Published: November 2019

AbstractMalariaGEN is a data-sharing network that enables groups around the world to work together on the genomic epidemiology of malaria. Here we describe a new release of curated genome variation data on 7,000 Plasmodium falciparum samples from MalariaGEN partner studies in 28 malaria-endemic countries. High-quality genotype calls on 3 million single nucleotide polymorphisms (SNPs) and short indels were produced using a standardised analysis pipeline. Copy number variants associated with drug resistance and structural variants that cause failure of rapid diagnostic tests were also analysed. Almost all samples showed genetic evidence of resistance to at least one antimalarial drug, and some samples from Southeast Asia carried markers of resistance to six commonly-used drugs. Genes expressed during the mosquito stage of the parasite life-cycle are prominent among loci that show strong geographic differentiation. By continuing to enlarge this open data resource we aim to facilitate research into the evolutionary processes affecting malaria control and to accelerate development of the surveillance toolkit required for malaria elimination.
Modeling adaptive therapy in non-muscle invasive bladder cancer
Authors: Ferrall-Fairbanks Meghan C. , Kimmel Gregory J. , Black Mik , Bravo Rafael , Deac Oana , Martinez Pierre , Myers Maggie , Nazari Fereshteh , Osojnik Ana , Subramanian Hemachander , Viossat Yannick , Whiting Freddie , Li Roger , Mann Karen M. , Altrock Philipp M. 
Published: November 2019

AbstractBladder cancer is the 9th most commonly diagnosed cancer. Nearly half of patients with early stage bladder cancer treated with the immune-stimulating agent BCG have disease recurrence, while 13% progress to invasive bladder cancer. Here we explored the potential of tumor mutational heterogeneity and the role of pro- and anti-inflammatory cytokines to identify different subtypes of bladder cancer that may predict therapeutic response to BCG. Further, we used mathematical modeling of dosing strategies to infer tumor response to varying doses and time schedules f BCG administration. As a proof-of-concept, present adaptive therapy scheduling of BCG as a viable strategy to control tumor size and minimize recurrence.
Microglia control small vessel calcification via TREM2
Authors: Zarb Yvette , Nassiri Sina , Utz Sebastian Guido , Schaffenrath Johanna , Rushing Elisabeth J. , Nilsson K. Peter R. , Delorenzi Mauro , Colonna Marco , Greter Melanie , Keller Annika 
Published: November 2019

AbstractMicroglia participate in CNS development and homeostasis and are often implicated in modulating disease processes in the CNS. However, less is known about the role of microglia in the biology of the neurovascular unit (NVU). In particular, data are scant on whether microglia are involved in CNS vascular pathology. In this study, we use a mouse model of primary familial brain calcification (PFBC) –Pdgfbret/retto investigate the role of microglia in calcification of the NVU. We report that microglia enclosing vessel-calcifications, coined calcification-associated microglia (CAM), display a distinct activation signature. Pharmacological ablation of microglia with the CSF1R inhibitor - PLX5622 leads to aggravated vessel calcification. Additionally, depletion of microglia in wild-type andPdgfbret/retmice causes the development of bone protein (osteocalcin, osteopontin) containing axonal spheroids in the white matter. Mechanistically, we show that microglia require functional TREM2 for controlling vessel-associated calcification. In conclusion, our results demonstrate that microglial activity in the setting of pathological vascular calcification is beneficial. In addition, we identify a new, previously unrecognized function of microglia in halting the expansion of ectopic calcification.
Complete microbial genomes for public health in Australia and Southwest Pacific
Authors: Baines Sarah L. , Gonçalves da Silva Anders , Carter Glen , Jennison Amy V. , Rathnayake Irani , Graham Rikki M. , Sintchenko Vitali , Wang Qinning , Rockett Rebecca J. , Timms Verlaine J. , Martinez Elena , Ballard Susan , Tomita Takehiro , Isles Nicole , Horan Kristy A. , Pitchers William , Stinear Timothy P. , Williamson Deborah A. , Howden Benjamin P. ,   Communicable Diseases Genomics Network (CDGN), Seemann Torsten 
Published: November 2019

AbstractComplete genomes of microbial pathogens are essential for the phylogenomic analyses that increasingly underpin core public health lab activities. Here, we present complete genomes of pathogen strains of regional importance to the Southwest Pacific and Australia. These enrich the catalogue of globally available complete genomes for public health while providing valuable strains to regional public health labs.AnnouncementWhole-genome sequence (WGS) data is increasingly important in public health microbiology (1–4). The data can be used to replicate many of the basic bacterial sub-typing approaches, as well as support epidemiological investigations, such as surveillance and outbreak investigation (5–7). The appeal of WGS data comes from the promise of a single workflow to process all microbial pathogens that can provide easily portable data that promotes deeper integration of surveillance and investigation efforts across jurisdictions. This promise is leading to a concerted effort to move microbial public health to a primarily genome-based workflow at numerous jurisdictions (8–10), including Australia (11).
Mechanosensory stimulation viaNanchungexpressing neurons can induce daytime sleep inDrosophila
Authors: Lone Shahnaz Rahman , Potdar Sheetal , Venkataraman Archana , Sheeba Vasu , Sharma Vijay Kumar 
Published: November 2019

AbstractThe neurogenetic bases of sleep, a phenomenon considered crucial for well-being of organisms has recently been under investigation using the model organismDrosophila melanogaster. Although sleep is a state where sensory threshold for arousal is enhanced, it is known that certain kinds of repetitive sensory stimuli such as rocking, can in fact promote sleep in humans. Here we report that orbital motion aided mechanosensory stimulation promotes sleep inDrosophila, independent of the circadian clock, but controlled by the homeostatic system. Mechanosensory receptornanchung(Nan) expressing neurons in the chordotonal organs mediate this sleep induction - flies where these neurons are either silenced or ablated display significantly reduced sleep induction upon mechanosensory stimulation. Transient activation of theNan-expressing neurons also enhances sleep levels confirming the role of these neurons in sleep induction. Thus, we show for the first time that mechanosensory stimulation promotes sleep even in fliesD. melanogasterand that it is mediated by proprioceptors.
Integrative analyses of the RNA modification machinery reveal tissue- and cancer-specific signatures
Authors: Begik Oguzhan , Lucas Morghan C. , Liu Huanle , Ramirez Jose Miguel , Mattick John S. , Novoa Eva Maria 
Published: November 2019

ABSTRACTBackgroundRNA modifications play central roles in cellular fate and differentiation. These features have placed the epitranscriptome in the forefront of developmental biology and cancer research. However, the machinery responsible for placing, removing and recognizing more than 170 RNA modifications remains largely uncharacterized and poorly annotated, and we currently lack integrative studies that identify which RNA modification–related proteins (RMPs) may be dysregulated in each cancer type.ResultsHere we have performed a comprehensive annotation and evolutionary analysis of human RMPs as well as an integrative analysis of their expression patterns across 32 tissues, 10 species and 13,358 paired tumor-normal human samples. Our analysis reveals an unanticipated heterogeneity of RMP expression patterns across mammalian tissues, with a vast proportion of duplicated enzymes displaying testis-specific expression, suggesting a key role for RNA modifications in sperm formation and possibly intergenerational inheritance. Moreover, through the analysis of paired tumor-normal human samples we uncover many RMPs that are dysregulated in various types of cancer, and whose expression levels are predictive of cancer progression. Surprisingly, we find that several commonly studied RNA modification enzymes such as METTL3 or FTO, are not significantly up-regulated in most cancer types, once the sample is properly scaled and normalized to the full dataset, whereas several less-characterized RMPs, such as LAGE3 and HENMT1, are dysregulated in many cancers.ConclusionsOur analyses reveal an unanticipated heterogeneity in the expression patterns of RMPs across mammalian tissues, and uncover a large proportion of dysregulated RMPs in multiple cancer types. We provide novel targets for future cancer research studies targeting the human epitranscriptome, as well as foundations to understand cell type-specific behaviours that are orchestrated by RNA modifications.
Recovering rearranged cancer chromosomes from karyotype graphs
Authors: Aganezov Sergey , Zban Ilya , Aksenov Vitaly , Alexeev Nikita , Schatz Michael C. 
Published: November 2019

AbstractMany cancer genomes are extensively rearranged with highly aberrant chromosomal karyotypes. Structural and copy number variations in cancer genomes can be determined via abnormal mapping of sequenced reads to the reference genome. Recently it became possible to reconcile both of these types of large-scale variations into a karyotype graph representation of the rearranged cancer genomes. Such a representation, however, does not directly describe the linear and/or circular structure of the underlying rearranged cancer chromosomes, thus limiting possible analysis of cancer genomes somatic evolutionary process as well as functional genomic changes brought by the large-scale genome rearrangements.Here we address the aforementioned limitation by introducing a novel methodological framework for recovering rearranged cancer chromosomes from karyotype graphs. For a cancer karyotype graph we formulate an Eulerian Decomposition Problem (EDP) of finding a collection of linear and/or circular rearranged cancer chromosomes that are determined by the graph. We derive and prove computational complexities for several variations of the EDP. We then demonstrate that Eulerian decomposition of the cancer karyotype graphs is not always unique and present the Consistent Contig Covering Problem (CCCP) of recovering unambiguous cancer contigs from the cancer karyotype graph, and describe a novel algorithmCCRcapable of solving CCCP in polynomial time.We applyCCRon a prostate cancer dataset and demonstrate that it is capable of consistently recovering large cancer contigs even when underlying cancer genomes are highly rearranged.CCRcan recover rearranged cancer contigs from karyotype graphs thereby addressing existing limitation in inferring chromosomal structures of rearranged cancer genomes and advancing our understanding of both patient/cancer-specific as well as the overall genetic instability in cancer.
Natural cryptic variation in epigenetic modulation of an embryonic gene regulatory network
Authors: Ewe Chee Kiang , Cleuren Yamila N. Torres , Flowers Sagen E. , Alok Geneva , Snell Russell G. , Rothman Joel H. 
Published: November 2019

AbstractGene regulatory networks (GRNs) that direct animal embryogenesis must respond to varying environmental and physiological conditions to ensure robust construction of organ systems. While GRNs are evolutionarily modified by natural genomic variation, the roles of epigenetic processes in shaping plasticity of GRN architecture are not well-understood. The endoderm GRN inC. elegansis initiated by the maternally supplied SKN-1/Nrf2 bZIP transcription factor; however, the requirement for SKN-1 in endoderm specification varies widely among distinctC. eleganswild isotypes owing to rapid developmental system drift driven by accumulation of cryptic genetic variants. We report here that heritable epigenetic factors that are stimulated by transient developmental diapause also underlie cryptic variation in the requirement for SKN-1 in endoderm development. This epigenetic memory is inherited from the maternal germline, apparently through a nuclear, rather than cytoplasmic, signal, resulting in a parent-of-origin effect (POE), in which the phenotype of the progeny resembles that of the maternal founder. The occurrence and persistence of POE varies between different parental pairs, perduring for at least ten generations in one pair. This long-perduring POE requires piwi-piRNA function and the germline nuclear RNAi pathway, as well as MET-2 and SET-32, which direct histone H3K9 trimethylation and drive heritable epigenetic modification. Such non-genetic cryptic variation may provide a resource of additional phenotypic diversity through which adaptation may facilitate evolutionary changes and shape developmental regulatory systems.
Skeletal and Dental Development Preserve Evidence of Energetic Stress in the Moose of Isle Royale
Authors: Brown C. , Rinaldi C.E. , Ripple W. J. , Van Valkenburgh B. 
Published: November 2019

AbstractFood shortages can leave diagnostic, and in the case of the dentition, irreversible changes in mineralized tissue that persist into historical and fossil records. Consequently, developmental defects of tooth enamel might be used to track ungulate population irruption but dental tissue’s capacity for preserving historical population density changes has yet to be investigated in wild populations. We test the ability of enamel defects, mandible and metapodial lengths to track changes in the well-known fluctuating moose population of Isle Royale National Park. Our study demonstrates that 1) a moose density threshold exists on the island above which there is a significant decrease in mandible and metatarsus length and a concomitant increase in enamel hypoplasias, 2) food limitation has a more pronounced effect on male than female skeletal growth, and 3) combined data from tooth enamel hypoplasias and bone lengths reflect the relative density of this ungulate population, and should be broadly applicable to other ungulate osteological samples. Developmental defects in dental enamel were among the highest recorded in a wild population, and even during low-density intervals the population density of Isle Royale moose has been high enough to negatively impact skeletal and dental growth, indicating the comparatively poor health of this century-old ecosystem