bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cooperation of dominant oncogenes with regulatory germline variants shapes clinical outcomes in childhood cancer
Authors: Musa Julian , Cidre-Aranaz Florencia , Aynaud Marie-Ming , Orth Martin F. , Mirabeau Olivier , Varon Mor , Grossetête Sandrine , Surdez Didier , Ohmura Shunya , Gerke Julia S. , Marchetto Aruna , Dallmayer Marlene , Baldauf Michaela C. , Gartlgruber Moritz , Westermann Frank , Stein Stefanie , Hölting Tilman L. B. , Knott Maximilian M. L. , Sannino Giuseppina , Li Jing , Romero-Pérez Laura , Hartmann Wolfgang , Dirksen Uta , Gymrek Melissa , Anderson Nathaniel D. , Shlien Adam , Rotblat Barak , Kirchner Thomas , Delattre Olivier , Grünewald Thomas G. P. 
Published: December 2018

INTRODUCTORY PARAGRAPHDeciphering principles of inter-individual tumor heterogeneity is essential for refinement of personalized anti-cancer therapy. Unlike cancers of adulthood, pediatric malignancies including Ewing sarcoma (EwS) feature a striking paucity of somatic alterations except for pathognomonic driver-mutations that cannot explain overt variations in clinical outcome.Here we demonstrate in the EwS model how cooperation of a dominant oncogene and regulatory variants determine tumor growth, patient survival and drug response.We show that binding of the oncogenic EWSR1-FLI1 fusion transcription factor to a polymorphic enhancer-like DNA element controls expression of the transcription factor MYBL2, whose high expression promotes poor patient outcome via activation of pro-proliferative signatures. Analysis of paired germline and tumor whole-genome sequencing data revealed that regulatory variability at this locus is inherited via the germline. CRISPR-mediated interference with this regulatory element almost abolished MYBL2 transcription, and MYBL2 knockdown decreased cell proliferation, cell survival and tumorigenicity of EwS cells. Combined RNA- and ChIP-seq analyses as well as functional experiments and clinical data identified CCNF, BIRC5 and AURKB as direct MYBL2 targets and critical mediators of its phenotype. In drug-response experiments, high MYBL2 levels sensitized EwS cells for inhibition of its activating cyclin dependent kinase CDK2 in vitro and in vivo, suggesting MYBL2 as a predictive biomarker for targeted anti-CDK2-therapy.Collectively, our findings establish cooperation of somatic mutations and regulatory germline variants as a major determinant of tumor progression and indicate the importance of integrating the regulatory genome in the process of developing new diagnostic and/or therapeutic strategies to fully harness the potential of precision medicine.
Neocortical layer 4 in adult mouse differs in major cell types and circuit organization between primary sensory areas
Authors: Scala F. , Kobak D. , Shan S. , Bernaerts Y. , Laturnus S. , Cadwell C.R. , Hartmanis L. , Froudarakis E. , Castro J. , Tan Z.H. , Papadopoulos S. , Patel S. , Sandberg R. , Berens P. , Jiang X. , Tolias A.S. 
Published: December 2018

AbstractLayer 4 (L4) of mammalian neocortex plays a crucial role in cortical information processing, yet a complete census of its cell types and connectivity remains elusive. Using whole-cell recordings with morphological recovery, we identified one major excitatory and seven inhibitory types of neurons in L4 of adult mouse visual cortex (V1). Nearly all excitatory neurons were pyramidal and all somatostatin-positive (SOM+) non-fast-spiking neurons were Martinotti cells. In contrast, in somatosensory cortex (S1), excitatory neurons were mostly stellate and SOM+ neurons were non-Martinotti. These morphologically distinct SOM+ interneurons corresponded to different transcriptomic cell types and were differentially integrated into the local circuit with only S1 neurons receiving local excitatory input. We propose that cell-type specific circuit motifs, such as the Martinotti/pyramidal and non-Martinotti/stellate pairs, are optionally used across the cortex as building blocks to assemble cortical circuits.
Altered crosstalk of estradiol and progesterone with Myeloid‐derived suppressor cells and Th1/Th2 cytokines in early miscarriage is associated with early breakdown of maternal‐fetal tolerance
Authors: Verma Priyanka , Verma Rachna , Nair Rohini R. , Budhwar Snehil , Khanna Anuradha , Agrawal Nisha Rani , Sinha Ruchi , Birendra Ruchi , Rajender Singh , Singh Kiran 
Published: December 2018

ProblemDecline in myeloid‐derived suppressor cells (MDSCs) and Th2 cytokines levels lead to early miscarriage (EM) but how the hormonal milieu of the body regulates MDSCs and Th1/Th2 cytokine balance is still a matter of investigation.Method of studyPeripheral blood and decidua samples were collected from 20 EM patients, and 20 healthy pregnant women opted for elective abortion. MDSCs and G‐MDSCs levels were analyzed in peripheral blood mononuclear cells, and Th1/Th2 cytokines levels were determined in serum via flow cytometry. Estrogen (E2), Progesterone (P4), and Testosterone levels were measured via ELISA. Further, proliferation and apoptosis in decidual samples were checked via immunoblot/immunohistochemistry of estrogen receptor ‐α (ER‐α), STAT‐3/pSTAT‐3, and caspase‐3, respectively.ResultsOur results clearly indicate that in EM patients; decline in E2 and P4 significantly correlates with decline in MDSCs, particularly with subtype granulocytic MDSCs (G‐MDSCs) and skewness of the Th1/Th2 cytokines balance toward Th1 response. Downregulation of ER‐ α and increased caspase‐3 expression in endometrium decidua signifies poor endometrial receptivity in EM. STAT‐3 activation regulates proliferation, differentiation and suppressive potency of MDSCs. In decidua of EM, significantly lower expression of pSTAT‐3 indicates that these processes pertaining to MDSCs are compromised.ConclusionAltogether, this unfavorable systemic milieu may drive toward early breakdown of maternal‐fetal tolerance in EM. Therefore, regulated crosstalk of E2, P4 with MDSCs and balanced Th1/Th2 cytokines is prerequisite for successful pregnancy.
Ultrafiltration and reinfusion of residual cardiopulmonary bypass pump blood: A prospective non‐randomized controlled study
Authors: Yan Shujie , Zhao Yu , Lou Song 
Published: December 2018

AbstractThe aim of the study was to investigate whether processing residual pump blood with ultrafiltration could increase the increment of hemoglobin after residual pump blood reinfusion and evaluate its influence on plasma‐free hemoglobin (pFHb) level and postoperative renal function. Sixty adult patients undergoing elective cardiac surgery with cardiopulmonary bypass were assigned to 2 groups, based on pump blood processing strategy: ultrafiltration plus reinfusion (n = 30) or reinfusion (control; n = 30). Increment in hemoglobin and pFHb after reinfusion (ΔHgb, ΔpFHb), reinfusion volume, postoperative chest drainage volume (first 24 h), duration of mechanical ventilation, changes in serum creatinine, and prevalence of AKI were compared between the 2 groups. Higher levels of both ΔHgb and ΔpFHb were observed after reinfusion in the ultrafiltration group [ΔHgb 1.8 ± 1.1 g/dL vs. 1.2 ± 0.6 g/dL, P = 0.03, ΔpFHb 100 (0, 200) mg/L vs. 0 (−100, 0) mg/L, P = 0.03]. The reinfusion volume was lower in the ultrafiltration group [550 (325, 615) mL vs. 1000 (900, 1180) mL, P < 0.001]. No differences were found in postoperative chest drainage volume (first 24 h), duration of mechanical ventilation, changes in serum creatinine, and prevalence of AKI. Compared to the unprocessed group, ultrafiltration before reinfusion of residual pump blood improved the hemoglobin level and reduced volume loading. Despite an increase in pFHb, the processing procedure was not related to postoperative kidney injury.
Evaluation of energy dissipation rate as a predictor of mechanical blood damage
Authors: Faghih Mohammad M. , Sharp Michael Keith 
Published: December 2018

AbstractA long‐standing goal in the field of biofluid mechanics has been to reliably predict hemolysis across the wide range of flows that can occur in prosthetic cardiovascular devices. A scalar representation of the complex three‐dimensional fluid stresses that are exerted on cells is an attractive alternative for the simplicity that it lends to the computations. The appropriateness of the commonly used von‐Mises‐like scalar stress as a universal hemolysis scaling parameter was previously evaluated, finding that erythrocyte membrane tensions calculated for laminar shear and extensional flows and for three cases of turbulent flow were widely divergent for the same value of scalar stress. The same techniques are applied in this study to laminar and turbulent flows that each have the same energy dissipation rate. Results showed that agreement of membrane tension between laminar shear and turbulent shear inside an eddy was improved relative to the common scalar stress cases, but disagreement between laminar shear and laminar extension remained the same and disagreement between laminar shear and other turbulent flows increased. It is therefore concluded that energy dissipation rate alone is also likely not sufficient to universally scale blood damage across the range of different flows that can be encountered clinically.
Human/robotic interaction: vision limits performance in simulated vitreoretinal surgery
Authors: de Smet Marc D. , de Jonge Nicky , Iannetta Danilo , Faridpooya Koorosh , van Oosterhout Eric , Naus Gerrit , Meenink Thijs C.M. , Mura Marco , Beelen Maarten J. 
Published: December 2018

AbstractPurposeCompare accuracy and precision in XYZ of stationary and dynamic tasks performed by surgeons with and without the use of a tele‐operated robotic micromanipulator in a simulated vitreoretinal environment. The tasks were performed using a surgical microscope or while observing a video monitor.MethodTwo experienced and two novice surgeons performed tracking and static tasks at a fixed depth with hand‐held instruments on a Preceyes Surgical System R0.4. Visualization was through a standard microscope or a video display. The distances between the instrument tip and the targets (in μm) determined tracking errors in accuracy and precision.ResultsUsing a microscope, dynamic or static accuracy and precision in XY (planar) movements were similar among test subjects. In Z (depth) movements, experience lead to more precision in both dynamic and static tasks (dynamic 35 ± 14 versus 60 ± 37 μm; static 27 ± 8 versus 36 ± 10 μm), and more accuracy in dynamic tasks (58 ± 35 versus 109 ± 79 μm). Robotic assistance improved both precision and accuracy in Z (1–3 ± 1 μm) in both groups. Using a video screen in combination with robotic assistance improved all performance measurements and reduced any differences due to experience.ConclusionsRobotics increases precision and accuracy, with greater benefit observed in less experienced surgeons. However, human control was a limiting factor in the achieved improvement. A major limitation was visualization of the target surface, in particular in depth. To maximize the benefit of robotic assistance, visualization must be optimized.
Predictors of relapse following infliximab de‐escalation in patients with inflammatory bowel disease: the value of a strategy based on therapeutic drug monitoring
Authors: Lucidarme Camille , Petitcollin Antoine , Brochard Charlène , Siproudhis Laurent , Dewitte Marie , Landemaine Amandine , Bellissant Eric , Bouguen Guillaume 
Published: December 2018

SummaryBackgroundThere are limited data concerning infliximab drug monitoring during de‐escalation of the treatment of inflammatory bowel disease (IBD).AimTo define the rate and the predictors of relapse following infliximab de‐escalation in IBD patients in remission.MethodsAll IBD patients at a single referral centre in clinical and biological remission and in whom the dose of infliximab had been de‐escalated were included. Patients in remission with a high trough level of infliximab (>7 mg/L) were considered to be trough level‐based de‐escalation patients. The data were retrieved from a prospective IBD database. Actuarial analysis was performed for statistical purposes.ResultsA total of 146 de‐escalations were performed in 96 patients (Crohn's disease/ulcerative colitis: 68%/32%); 54 (37%) were based on clinical remission only, and 92 (63%) were based on clinical remission associated with a trough level above 7 mg/L. The cumulative probabilities of relapse following infliximab de‐escalation were 16% and 47% at 1 and 2 years, respectively. Ulcerative colitis was associated with an increased risk of relapse (HR = 3.2, P = 0.005). Conversely, combination therapy at infliximab initiation (HR = 0.39, P = 0.0110) and trough level‐based de‐escalation were associated with decreased risk of relapse (HR = 0.45, P = 0.024). Trough levels before and after de‐escalation were well correlated; a decrease by half was observed following a 2‐week interval increase or a half‐dose decrease.ConclusionThe use of trough levels to assess the feasibility of dose de‐escalation seems to be a prerequisite for decreasing the risk of relapse.
Randomised clinical trial: vonoprazan versus lansoprazole for the initial relief of heartburn in patients with erosive oesophagitis
Authors: Oshima Tadayuki , Arai Eitatsu , Taki Masato , Kondo Takashi , Tomita Toshihiko , Fukui Hirokazu , Watari Jiro , Miwa Hiroto 
Published: December 2018

SummaryBackgroundProton pump inhibitors (PPIs) are widely used to treat gastro‐oesophageal reflux disease (GORD). However, the onset of action is considered slow and PPIs cannot completely block acid secretion at night. A new potassium‐competitive acid blocker (P‐CAB) can rapidly block acid secretion. However, whether this P‐CAB can relieve GORD symptoms quickly and adequately soon after starting treatment is unknown.AimTo determine how rapidly vonoprazan and lansoprazole provide heartburn relief.MethodsPatients (n = 32) with endoscopically confirmed erosive oesophagitis who experienced heartburn at least once a week were randomised in a double‐blind manner to receive either daily vonoprazan (20 mg) or lansoprazole (30 mg) before breakfast for 14 days. Day time and night time heartburn were assessed daily throughout the study using a five‐point Likert scale. The primary endpoint was the first day of complete day and night heartburn relief for at least seven consecutive days. The ethics committees of the participating institutions approved the study protocol.ResultsHeartburn was relieved sooner with vonoprazan than with lansoprazole (P < 0.05, log‐rank test). Heartburn was completely relieved in 31.3% and 12.5% of patients on day 1 with vonoprazan and lansoprazole, respectively. Significantly more patients achieved complete nocturnal heartburn relief with vonoprazan than lansoprazole (P < 0.01). Both regimens were well tolerated.ConclusionsComplete sustained heartburn relief was achieved sooner with vonoprazan than with lansoprazole during the first week of therapy. (UMIN000018776)
Review article: implementation of a diet low in FODMAPs for patients with irritable bowel syndrome—directions for future research
Authors: Mitchell Hannah , Porter Judi , Gibson Peter R. , Barrett Jacqueline , Garg Mayur 
Published: December 2018

SummaryBackgroundDespite the efficacy of a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) for patients with irritable bowel syndrome, many questions remain unanswered with respect to its clinical implementation.AimTo review literature to identify, synthesise, and provide direction for future research in the implementation and evaluation of the low FODMAP diet.MethodsBibliographical searches were performed in Ovid Medline, CINAHL, Scopus and PubMed from database commencement until September 2018, with search terms focused on the population (irritable bowel syndrome) and intervention of interest (FODMAP).ResultsPredictors of response to a low FODMAP diet remain under investigation, with preliminary data supporting faecal microbiota or faecal volatile organic compound profiling. Training of clinicians, and standards for the education of patients about the phases of a low FODMAP diet, as well as the role of Apps, require formal evaluation. There are limited data on the longer term efficacy and safety of the low FODMAP diet with respect to sustained symptom control, effect on quality of life and healthcare utilisation, nutritional adequacy, precipitation of disordered eating behaviours, effects on faecal microbiota and metabolomic markers, and subsequent translation to clinical effects.ConclusionsMany gaps in implementation of the low FODMAP diet in clinical practice, as well as long‐term safety and efficacy, remain for further investigation.
Flaws in design, execution and interpretation limit CLARITY‐BPA’s value for risk assessments of bisphenol A
Authors: vom Saal Frederick S. 
Published: December 2018

AbstractThe Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY‐BPA) involved the Food and Drug Administration, the National Toxicology Program and 14 academic investigators funded by the National Institute of Environmental Health Sciences. Two key questions to be answered by CLARITY‐BPA were as follows: (1) Would the academic investigator studies show effects at low doses of bisphenol A (BPA) while the core guideline study conducted by the FDA only showed toxic effects at high doses? (2) Would the academic investigators be able to replicate their numerous prior studies with animals raised and treated in the FDA's toxicology centre? Several flaws in the design and execution of CLARITY‐BPA biased the experiment towards not finding significant results (Type 2 error): (1) use of the oestrogen‐insensitive NCTR CD‐SD rat, (2) use of a stressful daily gavage BPA administration procedure throughout life, (3) lack of inclusion of non‐gavaged negative controls and (4) lack of a comprehensive examination of animals for BPA contamination. In spite of these flaws, in some of the experiments conducted by CLARITY‐BPA academic investigators, and also in the FDA's core study, there were significant low‐dose effects, but these were ignored by the FDA. Thus, immediately after releasing the results from their core portion of CLARITY‐BPA, the FDA issued a statement concluding BPA was “safe,” and they ignored non‐monotonic dose‐response relationships. The FDA should not base its BPA risk assessment only on outdated guideline studies, but instead on the vast (~8000) number of publications documenting the similar health hazards BPA poses to animals and humans.
Pharmacokinetics, pharmacodynamics, tolerability and prediction of clinically effective dose of ACT‐774312: A novel CRTH2 antagonist
Authors: Géhin Martine , Lott Dominik , Farine Hervé , Issac Milena , Strasser Daniel , Sidharta Patricia , Dingemanse Jasper 
Published: December 2018

AbstractACT‐774312 is an antagonist of the chemoattractant receptor‐homologous molecule expressed on T helper (Th) 2 cells (CRTH2), in development for the treatment of nasal polyposis or other allergic and type‐2 inflammatory diseases. Placebo, single doses of 1‐1000 mg, or multiple doses of 30‐500 mg either once or twice daily for 4 days of ACT‐774312 were administered orally to healthy subjects. The single‐ and multiple‐dose pharmacokinetics (PK) of ACT‐774312 were dose proportional and characterized by a time to attainment of maximum plasma concentrations between 1 and 3 hours and a terminal elimination half‐life of about 12 hours In the presence of food, tmax was delayed by 1 hour and exposure to ACT‐774312 slightly decreased. Full blockade (>90% of the maximum effect, Emax) of CRTH2 as measured in a whole blood internalization assay was observed after 50 mg ACT‐774312 twice daily and lasted for at least 9 hours The relationship between ACT‐774312 concentration and CRTH2 blockade was described by a Emax model. The estimated twice‐daily dose of ACT‐774312 at which full blockade of CRTH2 is achieved at trough in at least 80% of subjects was estimated at 109 mg. Administration of ACT‐774312 was safe and well tolerated at all doses. For none of the recorded adverse events, a relationship to dose was discerned, and there were no clinically relevant findings on the measured ECG, clinical laboratory and vital signs variables. The observed PK, pharmacodynamics and safety profile warrant further development of ACT‐774312.
Neurotoxic effects of mercury exposure in dental personnel
Authors: Bjørklund Geir , Hilt Bjørn , Dadar Maryam , Lindh Ulf , Aaseth Jan 
Published: December 2018

AbstractNumerous studies have reported neurobehavioural effects in dental personnel occupationally exposed to chronic low levels of mercury (Hg). Hg exposure from dental work may also induce various chronic conditions such as elevation of amyloid protein expression, deterioration of microtubules and increase or inhibition of transmitter release at motor nerve terminal endings. Therefore, clinical studies of Hg toxicity in dentistry may provide new knowledge about disturbed metal homeostasis in neurodegenerative diseases such as Alzheimer's disease, multiple sclerosis and mood disorders. The purpose of this MiniReview is to evaluate the evidence of possible relevance between Hg exposure in dentistry and idiopathic disturbances in motor functions, cognitive skills and affective reactions, as well as dose‐response relationships.
Effectiveness of a web‐based treatment decision aid for men with lower urinary tract symptoms due to benign prostatic hyperplasia
Authors: van der Wijden Fieke C. , de Angst Isabel B. , Lamers Romy E.D. , Cuypers Maarten , de Vries Marieke , van Melick Harm H.E. , de Beij Jeltje S. , Oerlemans Dennis J.A.J. , van de Beek Kees , Kil Paul J.M. 
Published: December 2018

ObjectivesTo evaluate the effectiveness of a web‐based decision aid (DA), with values clarification exercises compared with usual care, for men with lower urinary tract symptoms due to benign prostatic hyperplasia (LUTS/BPH).Patients and MethodsBetween July 2016 and January 2017, all new patients with LUTS/BPH who consulted the urologist were invited to use the DA and participate in this prospective questionnaire study. Patients who consulted the urologist between December 2015 and February 2016 served as controls. The DA was designed to support patients in making a well‐informed treatment decision, corresponding with their personal preferences and values. Well‐informed decision was measured by using a knowledge questionnaire. Value congruent decision was measured by the correspondence between responses on nine value statements and chosen treatment. The primary outcome, decision quality, was defined as the combination of well‐informed decision and value congruent decision. Secondary outcomes were decisional conflict, involvement and received role in shared decision‐making, decisional regret, and treatment choice.ResultsA total of 109 DA‐users and 108 controls were included. DA‐users were younger (68.4 vs 71.5 years; P = 0.003) and their education level was higher (P = 0.047) compared with the controls. Patients who used the DA made a well‐informed and value congruent decision more often than the control group (43% vs 21%; P = 0.028). DA‐users had less decisional conflict (score 33.2 vs 46.6; P = 0.003), experienced a less passive role in decision‐making (22% vs 41%; P = 0.038), and reported less process regret (score 2.4 vs 2.8; P = 0.034). Furthermore, DA‐users who had not used prior medication chose lifestyle advices more often than the control group (43% vs 11%; P = 0.002). Outcomes were adjusted for significantly different baseline characteristics.ConclusionThe LUTS/BPH DA seems to improve the decision quality by supporting patients in making more well‐informed and value congruent treatment decisions. Therefore, further implementation of this DA into routine care is suggested.