bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase 1 study of gefitinib combined with durvalumab in EGFR TKI-naive patients with EGFR mutation-positive locally advanced/metastatic non-small-cell lung cancer
Authors: Creelan Benjamin C. , Yeh Tammie C. , Kim Sang-We , Nogami Naoyuki , Kim Dong-Wan , Chow Laura Q. M. , Kanda Shintaro , Taylor Rosemary , Tang Weifeng , Tang Mei , Angell Helen K. , Roudier Martine P. , Marotti Marcelo , Gibbons Don L. 
Published: October 2020

AbstractBackgroundEGFR tyrosine kinase inhibitors (TKIs) induce cytolysis and release of tumour proteins, which can stimulate antigen-specific T cells. The safety and efficacy of durvalumab and gefitinib in combination for TKI-naive patients with advancedEGFRm NSCLC was evaluated.MethodsThis Phase 1 open-label, multicentre trial (NCT02088112) was conducted in 56 patients with NSCLC. Dose expansion permitted TKI-naive patients, primarily with activating L858R or Ex19delEGFRm. Arms 1 + 1a received concurrent therapy; Arm 2 received 4 weeks of gefitinib induction followed by concurrent therapy.ResultsFrom dose escalation, the recommended dose of durvalumab was 10 mg/kg Q2W with 250 mg QD gefitinib. Pharmacokinetics were as expected, consistent with inhibition of soluble PD-L1 and no treatment-emergent immunogenicity. In dose expansion, 35% of patients had elevated liver enzymes leading to drug discontinuation. In Arms 1 + 1a, objective response rate was 63.3% (95% CI: 43.9–80.1), median progression-free survival (PFS) was 10.1 months (95% CI: 5.5–15.2) and median response duration was 9.2 months (95% CI: 3.7–14.0).ConclusionsDurvalumab and gefitinib in combination had higher toxicity than either agent alone. No significant increase in PFS was detected compared with historical controls. Therefore, concurrent PD-L1 inhibitors with gefitinib should be generally avoided in TKI-naive patients withEGFRm NSCLC.
Clinically and biologically relevant subgroups of Wilms tumour defined by genomic and epigenomic analyses
Authors: Brzezinski Jack , Choufani Sanaa , Romao Rodrigo , Shuman Cheryl , Chen Haiying , Cunanan Joanna , Bagli Darius , Grant Ronald , Lorenzo Armando , Weksberg Rosanna 
Published: October 2020

Abstract
Background
Although cure rates for Wilms tumours (WT) are high, many patients receive therapy with attendant long-term complications. Our goal was to stratify WT using genome-wide analyses to identify candidate molecular features for patients who would benefit from a reduction in therapy.

Methods
We generated DNA methylation and exome sequencing data on WT–kidney pairs (n = 57) and unpaired tumours (n = 27) collected either at our centre or by the Children’s Oncology Group. Samples were divided into a discovery set (n = 32) and validation set (n = 52).

Results
Analysis of DNA methylation revealed two subgroups of WT with distinct features. Subgroup A has a similar DNA methylation profile to mature kidney, while Subgroup B has genome-wide dysregulation of DNA methylation. The rate of non-synonymous missense mutations and segmental chromosomal aberrations was higher in Subgroup B tumours, suggesting that this group has genome instability related to its epigenetic state. Subgroup A had a higher proportion of cases of bilateral disease. Tumours with high-risk histology or from patients who relapsed were only found in Subgroup B.

Conclusion
We have identified subgroup-specific molecular events that could inform future work supporting more targeted therapeutic approaches and patient stratification. We propose a novel developmental tumour model based on these findings.
Interleukin-6 trans-signaling is a candidate mechanism to drive progression of human DCCs during clinical latency
Authors: Werner-Klein Melanie , Grujovic Ana , Irlbeck Christoph , Obradović Milan , Hoffmann Martin , Koerkel-Qu Huiqin , Lu Xin , Treitschke Steffi , Köstler Cäcilia , Botteron Catherine , Weidele Kathrin , Werno Christian , Polzer Bernhard , Kirsch Stefan , Gužvić Miodrag , Warfsmann Jens , Honarnejad Kamran , Czyz Zbigniew , Feliciello Giancarlo , Blochberger Isabell , Grunewald Sandra , Schneider Elisabeth , Haunschild Gundula , Patwary Nina , Guetter Severin , Huber Sandra , Rack Brigitte , Harbeck Nadia , Buchholz Stefan , Rümmele Petra , Heine Norbert , Rose-John Stefan , Klein Christoph A. 
Published: October 2020

AbstractAlthough thousands of breast cancer cells disseminate and home to bone marrow until primary surgery, usually less than a handful will succeed in establishing manifest metastases months to years later. To identify signals that support survival or outgrowth in patients, we profile rare bone marrow-derived disseminated cancer cells (DCCs) long before manifestation of metastasis and identify IL6/PI3K-signaling as candidate pathway for DCC activation. Surprisingly, and similar to mammary epithelial cells, DCCs lack membranous IL6 receptor expression and mechanistic dissection reveals IL6 trans-signaling to regulate a stem-like state of mammary epithelial cells via gp130. Responsiveness to IL6 trans-signals is found to be niche-dependent as bone marrow stromal and endosteal cells down-regulate gp130 in premalignant mammary epithelial cells as opposed to vascular niche cells.PIK3CAactivation renders cells independent from IL6 trans-signaling. Consistent with a bottleneck function of microenvironmental DCC control, we findPIK3CAmutations highly associated with late-stage metastatic cells while being extremely rare in early DCCs. Our data suggest that the initial steps of metastasis formation are often not cancer cell-autonomous, but also depend on microenvironmental signals.
Molecular stratification of endometrioid ovarian carcinoma predicts clinical outcome
Authors: Hollis Robert L. , Thomson John P. , Stanley Barbara , Churchman Michael , Meynert Alison M. , Rye Tzyvia , Bartos Clare , Iida Yasushi , Croy Ian , Mackean Melanie , Nussey Fiona , Okamoto Aikou , Semple Colin A. , Gourley Charlie , Herrington C. Simon 
Published: October 2020

AbstractEndometrioid ovarian carcinoma (EnOC) demonstrates substantial clinical and molecular heterogeneity. Here, we report whole exome sequencing of 112 EnOC cases following rigorous pathological assessment. We detect a high frequency of mutation in CTNNB1 (43%), PIK3CA (43%), ARID1A (36%), PTEN (29%), KRAS (26%), TP53 (26%) and SOX8 (19%), a recurrently-mutated gene previously unreported in EnOC. POLE and mismatch repair protein-encoding genes were mutated at lower frequency (6%, 18%) with significant co-occurrence. A molecular taxonomy is constructed, identifying clinically distinct EnOC subtypes: cases with TP53 mutation demonstrate greater genomic complexity, are commonly FIGO stage III/IV at diagnosis (48%), are frequently incompletely debulked (44%) and demonstrate inferior survival; conversely, cases with CTNNB1 mutation, which is mutually exclusive with TP53 mutation, demonstrate low genomic complexity and excellent clinical outcome, and are predominantly stage I/II at diagnosis (89%) and completely resected (87%). Moreover, we identify the WNT, MAPK/RAS and PI3K pathways as good candidate targets for molecular therapeutics in EnOC.
A comparative study of asleep and awake deep brain stimulation robot-assisted surgery for Parkinson’s disease
Authors: Jin Hai , Gong Shun , Tao Yingqun , Huo Hua , Sun Xiao , Song Dandan , Xu Ming , Xu Zhaozhu , Liu Yang , Wang Shimiao , Yuan Lijia , Wang Tingting , Song Weilong , Pan He 
Published: October 2020

AbstractTo compare the differences between asleep and awake robot-assisted deep brain stimulation (DBS) surgery for Parkinson’s Disease (PD), we conducted this retrospective cohort study included 153 PD patients undergoing bilateral robot-assisted DBS from June 2017 to August 2019, of which 58 cases were performed under general anesthesia (GA) and 95 cases under local anesthesia (LA). Procedure duration, stimulation parameters, electrode implantation accuracy, intracranial air, intraoperative electrophysiological signal length, complications, and Unified PD Rating Scale (UPDRS) measurements were recorded and compared. The clinical evaluation was conducted by two raters who were blinded to the choice of anesthesia. Procedure duration was significantly shorter in the GA group, while on stimulation off medication motor scores (UPDRS-III) were significantly improved in both the GA and LA group. ANCOVA covariated for the baseline UPDRS-III and levodopa challenge exhibited no significant differences. In terms of amplitude, frequency, and pulse width, the stimulation parameters used for DBS power-on were similar. There were no significant differences in electrode implantation accuracy, intraoperative electrophysiological signal length, or intracerebral hemorrhage (no occurrences in either group). The pneumocephalus volume was significantly smaller in the GA group. Six patients exhibited transient throat discomfort associated with tracheal intubation in the GA group. The occurrence of surgical incision infection was similar in both groups. Compared with the awake group, the asleep group exhibited a shorter procedure duration with a similar electrode implantation accuracy and short-term motor improvement. Robot-assisted asleep DBS surgery is a promising surgical method for PD.
lncRNAKB, a knowledgebase of tissue-specific functional annotation and trait association of long noncoding RNA
Authors: Seifuddin Fayaz , Singh Komudi , Suresh Abhilash , Judy Jennifer T. , Chen Yun-Ching , Chaitankar Vijender , Tunc Ilker , Ruan Xiangbo , Li Ping , Chen Yi , Cao Haiming , Lee Richard S. , Goes Fernando S. , Zandi Peter P. , Jafri M. Saleet , Pirooznia Mehdi 
Published: October 2020

AbstractLong non-coding RNA Knowledgebase (lncRNAKB) is an integrated resource for exploring lncRNA biology in the context of tissue-specificity and disease association. A systematic integration of annotations from six independent databases resulted in 77,199 human lncRNA (224,286 transcripts). The user-friendly knowledgebase covers a comprehensive breadth and depth of lncRNA annotation. lncRNAKB is a compendium of expression patterns, derived from analysis of RNA-seq data in thousands of samples across 31 solid human normal tissues (GTEx). Thousands of co-expression modules identified via network analysis and pathway enrichment to delineate lncRNA function are also accessible. Millions of expression quantitative trait loci (cis-eQTL) computed using whole genome sequence genotype data (GTEx) can be downloaded at lncRNAKB that also includes tissue-specificity, phylogenetic conservation and coding potential scores. Tissue-specific lncRNA-trait associations encompassing 323 GWAS (UK Biobank) are also provided. LncRNAKB is accessible at http://www.lncrnakb.org/, and the data are freely available through Open Science Framework (https://doi.org/10.17605/OSF.IO/RU4D2).
Data segmentation based on the local intrinsic dimension
Authors: Allegra Michele , Facco Elena , Denti Francesco , Laio Alessandro , Mira Antonietta 
Published: October 2020

AbstractOne of the founding paradigms of machine learning is that a small number of variables is often sufficient to describe high-dimensional data. The minimum number of variables required is called the intrinsic dimension (ID) of the data. Contrary to common intuition, there are cases where the ID varies within the same data set. This fact has been highlighted in technical discussions, but seldom exploited to analyze large data sets and obtain insight into their structure. Here we develop a robust approach to discriminate regions with different local IDs and segment the points accordingly. Our approach is computationally efficient and can be proficiently used even on large data sets. We find that many real-world data sets contain regions with widely heterogeneous dimensions. These regions host points differing in core properties: folded versus unfolded configurations in a protein molecular dynamics trajectory, active versus non-active regions in brain imaging data, and firms with different financial risk in company balance sheets. A simple topological feature, the local ID, is thus sufficient to achieve an unsupervised segmentation of high-dimensional data, complementary to the one given by clustering algorithms.
The cognitive effects of a promised bonus do not depend on dopamine synthesis capacity
Authors: Hofmans Lieke , van den Bosch Ruben , Määttä Jessica I. , Verkes Robbert-Jan , Aarts Esther , Cools Roshan 
Published: October 2020

AbstractReward motivation is known to enhance cognitive control. However, detrimental effects have also been observed, which have been attributed to overdosing of already high baseline dopamine levels by further dopamine increases elicited by reward cues. Aarts et al. (2014) indeed demonstrated, in 14 individuals, that reward effects depended on striatal dopamine synthesis capacity, measured with [18F]FMT-PET: promised reward improved Stroop control in low-dopamine individuals, while impairing it in high-dopamine individuals. Here, we aimed to assess this same effect in 44 new participants, who had previously undergone an [18F]DOPA-PET scan to quantify dopamine synthesis capacity. This sample performed the exact same rewarded Stroop paradigm as in the prior study. However, we did not find any correlation between reward effects on cognitive control and striatal dopamine synthesis capacity. Critical differences between the radiotracers [18F]DOPA and [18F]FMT are discussed, as the discrepancy between the current and our previous findings might reflect the use of the potentially less sensitive [18F]DOPA radiotracer in the current study.
Disruption of NREM sleep and sleep-related spatial memory consolidation in mice lacking adult hippocampal neurogenesis
Authors: Sippel D. , Schwabedal J. , Snyder J. C. , Oyanedel C. N. , Bernas S. N. , Garthe A. , Tröndle A. , Storch A. , Kempermann G. , Brandt M. D. 
Published: October 2020

AbstractCellular plasticity at the structural level and sleep at the behavioural level are both essential for memory formation. The link between the two is not well understood. A functional connection between adult neurogenesis and hippocampus-dependent memory consolidation during NREM sleep has been hypothesized but not experimentally shown. Here, we present evidence that during a three-day learning session in the Morris water maze task a genetic knockout model of adult neurogenesis (Cyclin D2−/−) showed changes in sleep macro- and microstructure. Sleep EEG analyses revealed a lower total sleep time and NREM fraction in Cyclin D2−/− mice as well as an impairment of sleep specific neuronal oscillations that are associated with memory consolidation. Better performance in the memory task was associated with specific sleep parameters in wild-type, but not in Cyclin D2−/− mice. In wild-type animals the number of proliferating cells correlated with the amount of NREM sleep. The lack of adult neurogenesis led to changes in sleep architecture and oscillations that represent the dialog between hippocampus and neocortex during sleep. We suggest that adult neurogenesis—as a key event of hippocampal plasticity—might play an important role for sleep-dependent memory consolidation and modulates learning-induced changes of sleep macro- and microstructure.
Geophysical early warning of salt precipitation during geological carbon sequestration
Authors: Falcon-Suarez Ismael Himar , Livo Kurt , Callow Ben , Marin-Moreno Hector , Prasad Manika , Best Angus Ian 
Published: October 2020

AbstractSequestration of industrial carbon dioxide (CO2) in deep geological saline aquifers is needed to mitigate global greenhouse gas emissions; monitoring the mechanical integrity of reservoir formations is essential for effective and safe operations. Clogging of fluid transport pathways in rocks from CO2-induced salt precipitation reduces injectivity and potentially compromises the reservoir storage integrity through pore fluid pressure build-up. Here, we show that early warning of salt precipitation can be achieved through geophysical remote sensing. From elastic P- and S-wave velocity and electrical resistivity monitoring during controlled laboratory CO2 injection experiments into brine-saturated quartz-sandstone of high porosity (29%) and permeability (1660 mD), and X-ray CT imaging of pore-scale salt precipitation, we were able to observe, for the first time, how CO2-induced salt precipitation leads to detectable geophysical signatures. We inferred salt-induced rock changes from (i) strain changes, (ii) a permanent ~ 1.5% decrease in wave velocities, linking the geophysical signatures to salt volume fraction through geophysical models, and (iii) increases of porosity (by ~ 6%) and permeability (~ 7%). Despite over 10% salt saturation, no clogging effects were observed, which suggests salt precipitation could extend to large sub-surface regions without loss of CO2 injectivity into high porosity and permeability saline sandstone aquifers.
COVID-19 lockdown and its latency in Northern Italy: seismic evidence and socio-economic interpretation
Authors: Piccinini Davide , Giunchi Carlo , Olivieri Marco , Frattini Federico , Di Giovanni Matteo , Prodi Giorgio , Chiarabba Claudio 
Published: October 2020

AbstractThe Italian Government has decreed a series of progressive restrictions to delay the COVID-19 pandemic diffusion in Italy since March 10, 2020, including limitation in individual mobility and the closure of social, cultural, economic and industrial activities. Here we show the lockdown effect in Northern Italy, the COVID-19 most affected area, as revealed by noise variation at seismic stations. The reaction to lockdown was slow and not homogeneous with spots of negligible noise reduction, especially in the first week. A fresh interpretation of seismic noise variations in terms of socio-economic indicators sheds new light on the lockdown efficacy pointing to the causes of such delay: the noise reduction is significant where non strategic activities prevails, while it is small or negligible where dense population and strategic activities are present. These results are crucial for the a posteriori interpretation of the pandemic diffusion and the efficacy of differently targeted political actions.
Climatic oscillations in Quaternary have shaped the co-evolutionary patterns between the Norway spruce and its host-associated herbivore
Authors: Goczał Jakub , Oleksa Andrzej , Rossa Robert , Chybicki Igor , Meyza Katarzyna , Plewa Radosław , Landvik Matti , Gobbi Mauro , Hoch Gernot , Tamutis Vytautas , Balalaikins Maksims , Telnov Dmitry , Dascălu Maria-Magdalena , Tofilski Adam 
Published: October 2020

AbstractDuring the Last Glacial Maximum in the Northern Hemisphere, expanding ice sheets forced a large number of plants, including trees, to retreat from their primary distribution areas. Many host-associated herbivores migrated along with their host plants. Long-lasting geographic isolation between glacial refugia could have been led to the allopatric speciation in separated populations. Here, we have studied whether the migration history of the Norway sprucePicea abiesin Quaternary has affected its host-associated herbivorous beetle—Monochamus sartor. By using microsatellite markers accompanied by the geometric morphometrics analysis of wing venation, we have revealed the clear geographic structure ofM. sartorin Eurasia, encompassing two main clusters: southern (Alpine–Carpathian) and eastern (including northeastern Europe and Asia), which reflects the northern and southern ecotypes of its host. The two beetles’ lineages probably diverged during the Pleniglacial (57,000—15,000 BC) when their host tree species was undergoing significant range fragmentation and experienced secondary contact during post-glacial recolonization of spruce in the Holocene. A secondary contact of divergent lineages ofM.sartor has resulted in the formation of the hybrid zone in northeastern Europe. Our findings suggest that the climatic oscillations during the Pleistocene have driven an insect-plant co-evolutionary process, and have contributed to the formation of the unique biodiversity of Europe.
The role of cat eye narrowing movements in cat–human communication
Authors: Humphrey Tasmin , Proops Leanne , Forman Jemma , Spooner Rebecca , McComb Karen 
Published: October 2020

AbstractDomestic animals are sensitive to human cues that facilitate inter-specific communication, including cues to emotional state. The eyes are important in signalling emotions, with the act of narrowing the eyes appearing to be associated with positive emotional communication in a range of species. This study examines the communicatory significance of a widely reported cat behaviour that involves eye narrowing, referred to as the slow blink sequence. Slow blink sequences typically involve a series of half-blinks followed by either a prolonged eye narrow or an eye closure. Our first experiment revealed that cat half-blinks and eye narrowing occurred more frequently in response to owners’ slow blink stimuli towards their cats (compared to no owner–cat interaction). In a second experiment, this time where an experimenter provided the slow blink stimulus, cats had a higher propensity to approach the experimenter after a slow blink interaction than when they had adopted a neutral expression. Collectively, our results suggest that slow blink sequences may function as a form of positive emotional communication between cats and humans.
Oscillations of skyrmion clusters in Co/Pt multilayer nanodots
Authors: Tejo Felipe , Velozo Felipe , Elías Ricardo Gabriel , Escrig Juan 
Published: October 2020

AbstractIn this work we study the oscillations of the skyrmion cores in a multilayer nanodot as a function of the number of skyrmions hosted in the system. When all the skyrmions in the nanodot have the same core radius, and after applying a perpendicular spin-polarized current, a relaxation process takes place towards an equilibrium configuration that is accompanied by coherent damped oscillations of the skyrmion cores, whose frequency depends on the number of skyrmions present in the nanodot. Additionally, we found that the oscillation frequency is directly related to the total energy of the system.
The complete mitochondrial genome of medicinal fungus Taiwanofungus camphoratus reveals gene rearrangements and intron dynamics of Polyporales
Authors: Wang Xu , Jia Lihua , Wang Mingdao , Yang Hao , Chen Mingyue , Li Xiao , Liu Hanyu , Li Qiang , Liu Na 
Published: October 2020

AbstractTaiwanofungus camphoratus is a highly valued medicinal mushroom that is endemic to Taiwan, China. In the present study, the mitogenome of T. camphoratus was assembled and compared with other published Polyporales mitogenomes. The T. camphoratus mitogenome was composed of circular DNA molecules, with a total size of 114,922 bp. Genome collinearity analysis revealed large-scale gene rearrangements between the mitogenomes of Polyporales, and T. camphoratus contained a unique gene order. The number and classes of introns were highly variable in 12 Polyporales species we examined, which proved that numerous intron loss or gain events occurred in the evolution of Polyporales. The Ka/Ks values for most core protein coding genes in Polyporales species were less than 1, indicating that these genes were subject to purifying selection. However, the rps3 gene was found under positive or relaxed selection between some Polyporales species. Phylogenetic analysis based on the combined mitochondrial gene set obtained a well-supported topology, and T. camphoratus was identified as a sister species to Laetiporus sulphureus. This study served as the first report on the mitogenome in the Taiwanofungus genus, which will provide a basis for understanding the phylogeny and evolution of this important fungus.