bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of tumor immune infiltration-associated lncRNAs for improving prognosis and immunotherapy response of patients with non-small cell lung cancer
Authors: Sun Jie , Zhang Zicheng , Bao Siqi , Yan Congcong , Hou Ping , Wu Nan , Su Jianzhong , Xu Liangde , Zhou Meng 
Published: February 2020

BackgroundIncreasing evidence has demonstrated the functional relevance of long non-coding RNAs (lncRNAs) to immunity regulation and the tumor microenvironment in non-small cell lung cancer (NSCLC). However, tumor immune infiltration-associated lncRNAs and their value in improving clinical outcomes and immunotherapy remain largely unexplored.MethodsWe developed a computational approach to identify an lncRNA signature (TILSig) as an indicator of immune cell infiltration in patients with NSCLC through integrative analysis for lncRNA, immune and clinical profiles of 115 immune cell lines, 187 NSCLC cell lines and 1533 patients with NSCLC. Then the influence of the TILSig on the prognosis and immunotherapy in NSCLC was comprehensively investigated.ResultsComputational immune and lncRNA profiling analysis identified an lncRNA signature (TILSig) consisting of seven lncRNAs associated with tumor immune infiltration. The TILSig significantly stratified patients into the immune-cold group and immune-hot group in both training and validation cohorts. These immune-hot patients exhibit significantly improved survival outcome and greater immune cell infiltration compared with immune-cold patients. Multivariate analysis revealed that the TILSig is an independent predictive factor after adjusting for other clinical factors. Further analysis accounting for TILSig and immune checkpoint gene revealed that the TILSig has a discriminatory power in patients with similar expression levels of immune checkpoint genes and significantly prolonged survival was observed for patients with low TILSig and low immune checkpoint gene expression implying a better response to immune checkpoint inhibitor (ICI) immunotherapy.ConclusionsOur finding demonstrated the importance and value of lncRNAs in evaluating the immune infiltrate of the tumor and highlighted the potential of lncRNA coupled with specific immune checkpoint factors as predictive biomarkers of ICI response to enable a more precise selection of patients.
Poor outcome with anti-programmed death-ligand 1 (PD-L1) antibody due to poor pharmacokinetic properties in PD-1/PD-L1 blockade-sensitive mouse models
Authors: Kurino Taiki , Matsuda Reiko , Terui Ayu , Suzuki Hiroyuki , Kokubo Tomomi , Uehara Tomoya , Arano Yasushi , Hisaka Akihiro , Hatakeyama Hiroto 
Published: February 2020

BackgroundRecently, antiprogrammed cell death protein 1 (aPD-1) and antiprogrammed death-ligand 1 (aPD-L1) monoclonal antibodies (mAbs) have been approved. Even though aPD-1 and aPD-L1 mAbs target the same PD-1/PD-L1 axis, it is still unclear whether both mAbs exert equivalent pharmacological activity in patients who are sensitive to PD-1/PD-L1 blockade therapy, as there is no direct comparison of their pharmacokinetics (PK) and antitumor effects. Therefore, we evaluated the differences between both mAbs in PK and therapeutic effects in PD-1/PD-L1 blockade-sensitive mouse models.MethodsHerein, murine breast MM48 and colon MC38 xenografts were used to analyze the pharmacological activity of aPD-1 and aPD-L1 mAbs. The PK of the mAbs in the tumor-bearing mice was investigated at low and high doses using two radioisotopes (Indium-111 and Iodine-125) to evaluate the accumulation and degradation of the mAbs.ResultsaPD-1 mAb showed antitumor effect in a dose-dependent manner, indicating that the tumor model was sensitive to PD-1/PD-L1 blockade therapy, whereas aPD-L1 mAb failed to suppress tumor growth. The PK study showed that aPD-L1 mAb was accumulated largely in normal organs such as the spleen, liver, and kidney, resulting in low blood concentration and low distributions to tumors at a low dose, even though the tumors expressed PD-L1. Sufficient accumulation of aPD-L1 mAb in tumors was achieved by administration at a high dose owing to the saturation of target-mediated binding in healthy organs. However, degradation of aPD-L1 mAb in tumors was greater than that of aPD-1 mAb, which resulted in poor outcome presumably due to less inhibition of PD-L1 by aPD-L1 mAb than that of PD-1 by aPD-1 mAb.ConclusionAccording to the PK studies, aPD-1 mAb showed linear PK, whereas aPD-L1 mAb showed non-linear PK between low and high doses. Collectively, the poor PK characteristics of aPD-L1 mAb caused lower antitumor activity than of aPD-1 mAb. These results clearly indicated that aPD-L1 mAb required higher doses than aPD-1 mAb in clinical setting. Thus, targeting of PD-1 would be more advantageous than PD-L1 in terms of PK.
Poor prognosis associated with TERT gene alterations in meningioma is independent of the WHO classification: an individual patient data meta-analysis
Authors: Mirian Christian , Duun-Henriksen Anne Katrine , Juratli Tareq , Sahm Felix , Spiegl-Kreinecker Sabine , Peyre Matthieu , Biczok Annamaria , Tonn Jörg-Christian , Goutagny Stéphane , Bertero Luca , Maier Andrea Daniela , Møller Pedersen Maria , Law Ian , Broholm Helle , Cahill Daniel P. , Brastianos Priscilla , Poulsgaard Lars , Fugleholm Kåre , Ziebell Morten , Munch Tina , Mathiesen Tiit 
Published: February 2020

BackgroundTERT gene alterations (TERT-alt) have been linked to increased risk of recurrence in meningiomas, whereas the association to mortality largely remain incompletely investigated. As incongruence between clinical course and WHO grade exists, reliable biomarkers have been sought.MethodsWe applied the Preferred Reporting Items for Systematic Review and Meta-Analyses of individual participant data Statement. We compiled data from eight studies and allocated patients to TERT-alt (n=59) or TERT promoter wild-type (TERTp-wt; n=618). We compared the two groups stratified for WHO grades as: incidence rates, survival probabilities and cumulative recurrences. We estimated the effects of WHO grade, age at diagnosis and sex as HRs.ResultsTERT-alt occurred in 4.7%, 7.9% and 15.4% of WHO-I/WHO-II/WHO-III meningiomas, respectively. The median recurrence-free survival was 14 months for all TERT-alt patients versus 101 months for all TERTp-wt patients. The HR for TERT-alt was 3.74 in reference to TERTp-wt. For all TERT-alt patients versus all TERTp-wt patients, the median overall survival was 58 months and 160 months, respectively. The HR for TERT-alt was 2.77 compared with TERTp-wt. TERT-alt affected prognosis independent of WHO grades. Particularly, the recurrence rate was 4.8 times higher in WHO-I/-II TERT-alt patients compared with WHO-III TERTp-wt patients. The mortality rate was 2.7 times higher in the WHO-I and WHO-II TERT-alt patients compared with WHO-III TERTp-wt patients.ConclusionsTERT-alt is an important biomarker for significantly higher risk of recurrence and death in meningiomas. TERT-alt should be managed and surveilled aggressively. We propose that TERT-alt analysis should be implemented as a routine diagnostic test in meningioma and integrated into the WHO classification.Trial registration numberPROSPERO: CRD42018110566.
Patients with markedly elevated D-dimer who do not have pulmonary embolism
Authors: Lim Jeren , Cardle Calum , Isles Chris 
Published: February 2020

ABSTRACTObjectiveTo determine the cause of a markedly raised D-dimer among patients in whom a diagnosis of pulmonary embolism (PE) has been excluded by CT pulmonary angiogram (CTPA) with particular reference to new cases of cancer and aortic dissection.MethodsOne thousand consecutive patients, suspected of PE, who had undergone CTPA and for whom a D-dimer had been requested, were seen between 2012 and 2016. Retrospectively we examined the case records of all those in the top quintile of the D-dimer distribution whose CTPA was negative for PE. D-dimer in the top quintile ranged from 7.5 to 260 times upper limit normal.ResultsEighty-five patients fulfilled our inclusion criteria. The likely causes of their very high D-dimer were infection (n=35, 41.2%), cardiovascular disease (n=12, 14.1% including two patients with previously undiagnosed aortic dissection), surgery or trauma (n=12, 14.1%), new or active cancer (n=9, 10.6% comprising six new cancers and three patients with cancers diagnosed previously that were considered to be active) and miscellaneous causes (n=17, 20.0%). Thirty-five patients (43.5%) died over a 2-year follow-up. Kaplan-Meier survival analysis showed poorer outcomes for patients with new or active cancer, when compared with those with no known cancer (p&lt;0.001).ConclusionsWe have shown that a small proportion of patients suspected of PE whose D-dimers are markedly elevated have diagnoses we would not want to miss including previously unsuspected cancer and aortic dissection. Further studies will be required to define the optimal workup of patients with extremely high D-dimer who do not have venous thromboembolism
Paediatric Free Open Access Meducation (FOAM): behaviours, trends and implications
Authors: Barton Jack , Round Jonathan , Knight Katie 
Published: February 2020

AbstractIntroductionFree Open Access Meducation (FOAM) describes online resources assisting learning in medicine. Little is known about users or their behaviours.MethodsUsing Google Analytics for a popular FOAM site (www.paedatricfoam.com), we explored user demographics and patterns of behaviour. We analysed these further with descriptive and statistical tests using SPSS (version 26). Data are presented as mean (SD).ResultsThere were 181.44 (75.16) mean daily users accessing the site throughout a 4-month period during 2018/2019. 68.9% of users were female; 44% were 25–34 years; 57.3% used a mobile device. The mean session duration was 73.55 (9.41) seconds, with more time spent per session and a greater number of pages per session observed in users accessing the site from a desktop or tablet as opposed to a mobile phone. 84.3% of mobile users left the site after viewing a single page. Referral source was also associated with device used (p&lt;0.001). Age was not related to user behaviours (p&gt;0.05).DiscussionFOAM is a rapidly developing form of medical education, with large user numbers seen for a site just 2 years old. The site is being used by many beyond its intended readership. Rather than accessing multiple pages from a desktop, users have varied online behaviours, with the majority viewing a single page on a mobile phone, referred by social media or Google.ConclusionsGoogle Analytics can powerfully display usage of medical websites but has important limitations if statistical exploration is required. FOAM users are a heterogenous group, and thus content should be designed with this in mind. Further research must be prioritised focussing on the scope, curriculum coverage, accuracy of information and the effectiveness of FOAM as an educational resource.
Comprehensive overview of common e-liquid ingredients and how they can be used to predict an e-liquid’s flavour category
Authors: Krüsemann Erna J Z , Havermans Anne , Pennings Jeroen L A , de Graaf Kees , Boesveldt Sanne , Talhout Reinskje 
Published: February 2020

ObjectivesFlavours increase e-cigarette attractiveness and use and thereby exposure to potentially toxic ingredients. An overview of e-liquid ingredients is needed to select target ingredients for chemical analytical and toxicological research and for regulatory approaches aimed at reducing e-cigarette attractiveness. Using information from e-cigarette manufacturers, we aim to identify the flavouring ingredients most frequently added to e-liquids on the Dutch market. Additionally, we used flavouring compositions to automatically classify e-liquids into flavour categories, thereby generating an overview that can facilitate market surveillance.MethodsWe used a dataset containing 16 839 e-liquids that were manually classified into 16 flavour categories in our previous study. For the overall set and each flavour category, we identified flavourings present in more than 10% of the products and their median quantities. Next, quantitative and qualitative ingredient information was used to predict e-liquid flavour categories using a random forest algorithm.ResultsWe identified 219 unique ingredients that were added to more than 100 e-liquids, of which 213 were flavourings. The mean number of flavourings per e-liquid was 10±15. The most frequently used flavourings were vanillin (present in 35% of all liquids), ethyl maltol (32%) and ethyl butyrate (28%). In addition, we identified 29 category-specific flavourings. Moreover, e-liquids’ flavour categories were predicted with an overall accuracy of 70%.ConclusionsInformation from manufacturers can be used to identify frequently used and category-specific flavourings. Qualitative and quantitative ingredient information can be used to successfully predict an e-liquid’s flavour category, serving as an example for regulators that have similar datasets available.
Acute effects of JUUL and IQOS in cigarette smokers
Authors: Maloney Sarah , Eversole Alisha , Crabtree Melanie , Soule Eric , Eissenberg Thomas , Breland Alison 
Published: February 2020

BackgroundJUUL is an electronic cigarette that aerosolises a nicotine-containing liquid, while IQOS heats tobacco to produce an aerosol. Both are marketed to smokers, but their effects have seldom been examined in this population.MethodsEighteen cigarette smokers (13 men) with no JUUL or IQOS experience completed a within-subject, laboratory study assessing nicotine delivery and subjective effects after controlled (10 puffs, ~30 s interpuff interval) and ad libitum (90 min) use of JUUL, IQOS or own-brand (OB) cigarettes.ResultsJUUL increased mean plasma nicotine concentration significantly from 2.2 (SD=0.7) ng/mL to 9.8 (4.9) ng/mL after 10 puffs and to 11.5 (9.3) ng/mL after ad libitum use. IQOS increased mean plasma nicotine significantly from 2.1 (0.2) ng/mL to 12.7 (6.2) ng/mL after 10 puffs and to 11.3 (8.0) ng/mL after ad libitum use. OB increased mean plasma nicotine significantly from 2.1 (0.2) ng/mL to 20.4 (11.4) ng/mL after 10 puffs and to 21.0 (10.2) ng/mL after ad libitum use. Mean OB plasma nicotine concentration was significantly higher than JUUL and IQOS. OB increased expired carbon monoxide concentration, but IQOS and JUUL did not. ‘Craving a cigarette/nicotine’ and ‘Urges to smoke’ were reduced significantly for all products following the directed bout.ConclusionsAmong smokers, JUUL and IQOS delivered less nicotine than cigarettes. Also, in this sample, IQOS and OB reduced abstinence symptoms more effectively than JUUL. Additional work with experienced JUUL and IQOS users is needed, as their nicotine delivery profiles and subjective experiences may differ.
Shadow of a Schwarzschild black hole surrounded by a Bach–Weyl ring
Authors: Wang Mingzhi , Chen Songbai , Wang Jieci , Jing Jiliang 
Published: February 2020

AbstractWe have studied the shadows of a Schwarzschild black hole surrounded by a Bach–Weyl ring through the backward ray-tracing method. The presence of Bach–Weyl ring leads to that the photon dynamical system is non-integrable and then chaos would appear in the photon motion, which affects sharply the black hole shadow. The size and shape the black hole shadow depend on the black hole parameter, the Bach–Weyl ring mass and the Weyl radius between black hole and ring. Some self-similar fractal structures also appear in the black hole shadow, which originates from the chaotic lensing. We also study the change of the image of Bach–Weyl ring with the ring mass and the Weyl radius. Finally, we analyze the invariant manifolds of Lyapunov orbits near the fixed points and discuss further the formation of the shadow of a Schwarzschild black hole with Bach–Weyl ring.
Optical excitation of atomic force microscopy cantilever for accurate spectroscopic measurements
Authors: Miyahara Yoichi , Griffin Harrisonn , Roy-Gobeil Antoine , Belyansky Ron , Bergeron Hadallia , Bustamante José , Grutter Peter 
Published: February 2020

AbstractReliable operation of frequency modulation mode atomic force microscopy (FM-AFM) depends on a clean resonance of an AFM cantilever. It is recognized that the spurious mechanical resonances which originate from various mechanical components in the microscope body are excited by a piezoelectric elemen that is intended for exciting the AFM cantilever oscillation and these spurious resonance modes cause the serious undesirable signal artifacts in both frequency shift and dissipation signals. We present an experimental setup to excite only the oscillation of the AFM cantilever in a fiber-optic interferometer system using optical excitation force. While the optical excitation force is provided by a separate laser light source with a different wavelength (excitation laser : λ=1310 nm), the excitation laser light is still guided through the same single-mode optical fiber that guides the laser light (detection laser : λ=1550 nm) used for the interferometric detection of the cantilever deflection. We present the details of the instrumentation and its performance. This setup allows us to eliminate the problems associated with the spurious mechanical resonances such as the apparent dissipation signal and the inaccuracy in the resonance frequency measurement.
Fast, Accurate and Provable Triangle Counting in Fully Dynamic Graph Streams
Authors: Shin Kijung , Oh Sejoon , Kim Jisu , Hooi Bryan , Faloutsos Christos 
Published: February 2020

Given a stream of edge additions and deletions, how can we estimate the count of triangles in it? If we can store only a subset of the edges, how can we obtain unbiased estimates with small variances?
Counting triangles (i.e., cliques of size three) in a graph is a classical problem with applications in a wide range of research areas, including social network analysis, data mining, and databases. Recently, streaming algorithms for triangle counting have been extensively studied since they can naturally be used for large dynamic graphs. However, existing algorithms cannot handle edge deletions or suffer from low accuracy.

Can we handle edge deletions while achieving high accuracy? We propose T
hink
D, which accurately estimates the counts of global triangles (i.e., all triangles) and local triangles associated with each node in a fully dynamic graph stream with additions and deletions of edges. Compared to its best competitors, T
hink
D is
(a) Accurate:
up to
4.3
×
more accurate
within the same memory budget,
(b) Fast:
up to
2.2
×
faster
for the same accuracy requirements, and
(c) Theoretically sound:
always maintaining estimates with zero bias (i.e., the difference between the true triangle count and the expected value of its estimate) and small variance. As an application, we use T
hink
D to detect suddenly emerging dense subgraphs, and we show its advantages over state-of-the-art methods.
Secretin effects on gastric functions, hormones and symptoms in functional dyspepsia and health: randomized crossover trial
Authors: Brandler Justin , Miller Laurence J. , Wang Xiao Jing , Burton Duane , Busciglio Irene , Arndt Kayla , Harmsen William S. , Camilleri Michael 
Published: February 2020

Abnormal gastric accommodation (GA) and gastric emptying contribute to pathophysiology in functional dyspepsia (FD). Secretin is a key regulator of GA in animal studies. Our aim was to study the effects of secretin on gastric motility, satiation, postprandial symptoms, and key hormones. We performed two double-blind, randomized, saline-controlled crossover trials in 10 healthy volunteers and 10 patients with FD by Rome IV criteria. We used measured GA (by validated SPECT method) after a 111In radiolabeled Ensure 300-mL meal and quantified gastric emptying for 30 min by scintigraphy. Satiation was measured by volume to fullness (VTF) and maximum tolerated volume (MTV) on an Ensure nutrient drink test and postprandial symptoms 30 min post-MTV. Fasting and postprandial GLP-1, GIP, and HPP were measured. The ages and sex distribution of healthy controls and patients with FD were similar. Compared with placebo, secretin delayed gastric emptying at 30 min in both health [−11% (−16, −4), P = 0.004]; and FD [−8% (−9, 0), P = 0.03]. Satiation (VTF and MTV), GA, and plasma levels of GLP-1, GIP, and HPP did not differ between treatment arms in health or FD. On ANCOVA analysis (adjusting for age and sex), secretin did not consistently increase postprandial symptoms in health or FD. Secretin delayed gastric emptying in both health and FD without significantly altering GA, VTF, or MTV or selected hormones. Thus, secretin receptor activation may provide a novel therapeutic mechanism for patients with FD and rapid gastric emptying. NEW & NOTEWORTHY The naturally occurring hormone secretin retards gastric emptying of solids without deleteriously affecting gastric accommodation, satiation, other upper gastrointestinal hormones, or postprandial symptoms. Given these findings, a subset of patients with rapid gastric emptying (e.g., the estimated 20% of patients with functional dyspepsia) could be candidates for treatments that stimulate a secretin receptor such as sacubitril, which inhibits neprilysin, an enzyme that degrades secretin.
In SilicoModels Accurately PredictIn VivoResponse for IL6 Blockade in Head and Neck Cancer
Authors: Nazari Fereshteh , Oklejas Alexandra E. , Nör Jacques E. , Pearson Alexander T. , Jackson Trachette L. 
Published: February 2020

AbstractMalignant features of head and neck squamous cell carcinoma (HNSCC) may be derived from the presence of stem-like cells that are characterized by uniquely high tumorigenic potential. These cancer stem cells (CSC) function as putative drivers of tumor initiation, therapeutic evasion, metastasis, and recurrence. Although they are an appealing conceptual target, CSC-directed cancer therapies remain scarce. One promising CSC target is the IL6 pathway, which is strongly correlated with poor patient survival. In this study we created and validated a multiscale mathematical model to investigate the impact of cross-talk between tumor cell- and endothelial cell (EC)-secreted IL6 on HNSCC growth and the CSC fraction. We then predicted and analyzed the responses of HNSCC to tocilizumab (TCZ) and cisplatin combination therapy. The model was validated with in vivo experiments involving human ECs coimplanted with HNSCC cell line xenografts. Without artificial tuning to the laboratory data, the model showed excellent predictive agreement with the decrease in tumor volumes observed in TCZ-treated mice, as well as a decrease in the CSC fraction. This computational platform provides a framework for preclinical cisplatin and TCZ dose and frequency evaluation to be tested in future clinical studies.Significance:A mathematical model is used to rapidly evaluate dosing strategies for IL6 pathway modulation. These results may lead to nonintuitive dosing or timing treatment schedules to optimize synergism between drugs.