bluuebunny/crossref_metadata_2025_split huggingface dataset:
Age at disease onset of inflammatory bowel disease is associated with later extraintestinal manifestations and complications
Authors: Herzog Denise , Fournier Nicolas , Buehr Patrick , Rueger Vanessa , Koller Rebekka , Heyland Klaas , Nydegger Andreas , Spalinger Johannes , Schibli Susanne , Petit Laetitia-Marie , Braegger Christian P. 
Published: January 2018

Introduction
A small but increasing number of patients with inflammatory bowel disease are diagnosed during childhood or adolescence, and disease distribution and severity at onset vary according to the age at diagnosis. Clinical factors present at the time of diagnosis can be predictive of the disease course.

Aim
The aim of this study was to characterize disease behavior and the cumulative complications and extraintestinal manifestations 10 years after the diagnosis and to assess their association with age at diagnosis.

Patients and methods
Data of patients participating with the Swiss IBD cohort study registry, a disease duration of 10 years and a complete data set were analyzed. The outcome was defined as the cumulative change of disease behavior, the occurrence of extra-intestinal manifestations or complications, and the necessity for medical or surgical interventions.

Results
A total of 481 patients with Crohn’s disease (CD) and 386 patients with ulcerative colitis (UC), grouped according to disease onset before 10, 17, 40, or after 40 years of age, were analyzed. Despite differences in sex, initial disease location, and smoking habits, at 10 years after the diagnosis, no difference was found regarding disease behavior in CD or regarding progression of disease extension in UC. Similarly, no age-of-onset-dependent cumulative need for medical or surgical therapies was found. However, higher rates of anemia and lower rates of arthralgia and osteopenia were found in both pediatric-onset CD and UC, and a tendency toward higher rates of stomatitis in pediatric-onset CD, and of primary sclerosing cholangitis and ankylosing spondylitis in pediatric-onset UC.

Conclusion
After 10 years of disease evolution, age at disease onset is not anymore associated with disease behavior but only with a small difference in the occurrence of specific extraintestinal manifestations and complications.
Toxicities Associated With PD-1/PD-L1 Blockade
Authors: Wang Daniel Y. , Johnson Douglas B. , Davis Elizabeth J. 
Published: January 2018

Abstract
Immune checkpoint inhibitors, particularly those targeting PD-1/PD-L1, produce durable responses in a subset of patients across cancer types. Although often well tolerated, these agents can induce a broad spectrum of autoimmune-like complications that may affect any organ system. Treatment of these toxicities primarily consists of immune suppression with corticosteroids and other agents. This review briefly discusses the mechanisms of immune-related adverse events, overviews the clinical and pathologic features of major toxicities caused by PD-1/PD-L1 blockade, and reviews their management.
Clinical Development of PD-1 Blockade in Hematologic Malignancies
Authors: Pianko Matthew J. , Goldberg Aaron D. , Lesokhin Alexander M. 
Published: January 2018

Abstract
Clinical development of immune checkpoint inhibitors targeting the PD-1 pathway has led to clinical benefits for patients with multiple solid tumor and hematologic malignancies and has revolutionized modern oncology. High response rates to PD-1 blockade in patients with classical Hodgkin lymphoma and certain subtypes of non-Hodgkin lymphoma highlight an intrinsic biologic sensitivity to this strategy of treatment. Despite early success of checkpoint inhibitor and immunomodulatory drug combinations in phase 2 studies in multiple myeloma, safety concerns in patients treated with the combination of immunomodulatory drugs and checkpoint inhibitors in myeloma have stalled drug development in this space. Novel combination approaches exploring PD-1 inhibitors with epigenetic modifiers in leukemia are underway.
Mechanisms of Resistance to PD-1 and PD-L1 Blockade
Authors: Nowicki Theodore S. , Hu-Lieskovan Siwen , Ribas Antoni 
Published: January 2018

Abstract
Cancer immunotherapy utilizing blockade of the PD-1/PD-L1 checkpoint has revolutionized the treatment of a wide variety of malignancies, leading to durable therapeutic responses not typically seen with traditional cytotoxic anticancer agents. However, these therapies are ineffective in a significant percentage of patients, and some initial responders eventually develop resistance to these therapies with relapsed disease. The mechanisms leading to both primary and acquired resistance to PD-1/PD-L1 inhibition are varied and can be both multifactorial and overlapping in an individual patient. As the mechanisms of resistance to PD-1/PD-L1 blockade continue to be further characterized, new strategies are being developed to prevent or reverse resistance to therapy, leading to improved patient outcomes.
First evidence that intrinsic fetal heart rate variability exists and is affected by hypoxic pregnancy
Authors: Frasch Martin G. , Herry Christophe L. , Niu Youguo , Giussani Dino A. 
Published: January 2018

AbstractFetal heart rate variability (FHRV) emerges from influences of the autonomic nervous system, fetal body and breathing movements, and from baroreflex and circadian processes. We tested whether intrinsic HRV exists in the fetal period and whether it is affected by chronic fetal hypoxia. Chronically catheterized ewes carrying male singleton fetuses were exposed to normoxia (n=6) or hypoxia (10% inspired O2, n=9) for the last third of gestation (105-138 dG; term~145 dG) in isobaric chambers. At 138dG, isolated hearts were studied using a Langendorff preparation. We calculated basal iFHRV matrix indices across five signal-analytical domains from the systolic peaks within 15 min segments in each heart. Significance was assumed at p<0.05. Maternal hypoxia yielded chronic fetal PaO2 values of 11.5±0.6 (mean+SEM) relative to controls of 20.9±0.5 mmHg. Hearts of fetuses isolated from hypoxic pregnancy showed approximately 4-fold increases in the Grid transformation as well as the AND similarity index (sgridAND, informational domain) and a 4-fold reduction in the Scale dependent Lyapunov exponent slope (invariant domain). We also detected a 2-fold reduction in the Recurrence quantification analysis, percentage of laminarity and recurrences and maximum diagonal line (dlmax, geometric domain) and in the Multiscale time irreversibility asymmetry index (energetic domain). dlmax and sgridAND correlated with left ventricular end-diastolic pressure across both groups (R2=0.32 and R2=0.63, respectively). This is the first evidence that iHRV originates in fetal life and that chronic fetal hypoxia significantly alters it. Isolated fetal hearts from hypoxic pregnancy exhibit a lower complexity in iFHRV.Key points summaryWe introduce a technique to test whether intrinsic fetal heart rate variability (iFHRV) exists and we show the utility of the technique by testing the hypothesis that iFHRV is affected by chronic fetal hypoxia, one of the most common adverse outcomes of human pregnancy complicated by fetal growth restriction.Using an established late gestation ovine model of fetal development under chronic hypoxic conditions, we identify iFHRV in isolated fetal hearts and show that it is markedly affected by hypoxic pregnancy.Therefore, the isolated fetal heart carries a memory of adverse intrauterine conditions experienced during the last third of pregnancy.Indices of iFHRV may improve fetal health surveillance by helping to diagnose prediction of fetal hypoxia and acidaemia during antenatal or intra-partum fetal compromise.
A framework for large-scale dynamic metabolome drug profiling in mammalian cells: a case study analysis of the anti-cancer drug dichloroacetate
Authors: Dubuis Sébastien , Ortmayr Karin , Zampieri Mattia 
Published: January 2018

AbstractMetabolic profiling of cell line collections have become an invaluable tool to study disease etiology, drug modes of action and personalized medicine. However, large-scalein vitrodynamic metabolic profiling is limited by time-consuming sampling and complex measurement procedures. By adapting an MS-based metabolomics workflow for high-throughput profiling of diverse adherent mammalian cells, we establish a technique for the rapid measurement and analysis of drug-induced dynamic changes in intracellular metabolites. This methodology is scalable to large compound libraries and is here applied to study the mechanism underlying the toxic effect of dichloroacetate in ovarian cancer cell lines. System-level analysis of the metabolic responses revealed a key and unexpected role of CoA imbalance in dichloroacetate toxicity. The herein proposed strategy for large-scale drug metabolic profiling is complementary to other molecular profiling techniques, opening new scientific and drug-discovery opportunities.
Comparative analysis of molecular signatures suggests the use of gabapentin for the management of endometriosis-associated pain
Authors: Bellessort Brice , Bachelot Anne , Grouthier Virginie , Lombares Camille de , Narboux-Neme Nicolas , Garagnani Paolo , Pirazzini Chiara , Astigiano Simonetta , Mastracci Luca , Fontaine Anastasia , Alfama Gladys , Duvernois-Berthet Evelyne , Levi Giovanni 
Published: January 2018

CapsuleComparative analysis of gene expression signatures from endometriosis and mouse models shows that CACNAα2δs calcium-channel components involved in nociception are targets for the treatment of endometriosis-associated pain.ContextDifferential gene expression analyses comparing endometriotic lesions to eutopic endometrium have shown that the transcription factors DLX5 and DLX6 are drastically down-regulated in the ectopic implants. These finding suggests that regulatory cascades involving DLX5/6 might be involved in the origin of endometriosis symptoms such as chronic pelvic pain. We have shown that mice in which Dlx5 and Dlx6 are selectively inactivated in the uterus present an endometrial phenotype reminiscent of endometriosis implants.ObjectiveIdentify new targets for the treatment of endometriosis.DesignTo better focus the search for endometriosis targets we have compared the profile of genes deregulated in normal and ectopic women endometrium to those deregulated in the uterus of normal and Dlx5/Dlx6-null mice.SettingsAcademic research unit and University Hospital research laboratoryAnimalsMice carrying a uterus-specific deletion of Dlx5/Dlx6.InterventionsAnalysis of archive sections from normal endometrium and endometriosis implants.Main OutcomeA novel endometriosis signature suggests that α2δs subunits of voltage-gated calcium channel are targets for the management of endometriosis-associated pain.ResultsWe identify a signature of 30 genes similarly deregulated in human endometriosis implants and in Dlx5/6-null mouse uteri reinforcing the notion that the down-regulation of Dlx5/6 is an early event in the progress of endometriosis. CACNA2D3, a component of the voltage-dependent calcium channel complex is strongly overexpressed both in endometriosis implants and in mutant mouse uteri; other members of the alfa2delta family, CACNA2D1 and CACNA2D2, are also overexpressed in endometriosis.ConclusionCACNA2D1, CACNA2D2 and CACNA2D3 are directly involved in pain perception. In particular, CACNA2D3 has been associated to pain sensitization and heat nociception in animal models while, in patients, variants of this gene are associated to reduced sensitivity to acute noxious stimuli. As CACNA2Ds are targets of gabapentinoids analgesics, our results suggest to consider the use of these drugs for the treatment of endometriosis-associated pain. Indeed, recent small-scale clinical studies have shown that gabapentin can be effective in the treatment of women chronic pelvic pain. Our findings reinforce the need for a large definitive trial.
The Neural Architecture of Executive Functions Is Established by Middle Childhood
Authors: Engelhardt Laura E. , Harden K. Paige , Tucker-Drob Elliot M. , Church Jessica A. 
Published: January 2018

AbstractExecutive functions (EFs) are regulatory cognitive processes that support goal-directed thoughts and behaviors and that involve two primary networks of functional brain activity in adulthood. The current study assessed whether the same networks identified in adulthood underlie child EFs. Using task-based fMRI data from a diverse sample of N = 117 children and early adolescents (M age = 10.17 years), we assessed the extent to which neural activity was shared across three EF domains and whether these patterns reflected quantitative or qualitative differences relative to previously reported adult findings. Brain regions that were consistently engaged across switching, updating, and inhibition tasks closely corresponded to the cingulo-opercular and fronto-parietal networks identified in studies of adults. Isolating brain activity during more demanding task periods highlighted contributions of the dACC and anterior insular regions of the cingulo-opercular network. Results were independent of age and time-on-task effects. These results indicate that the two core brain networks that support EFs are in place by middle childhood. Improvement in EFs from middle childhood to adulthood, therefore, are likely due to quantitative changes in activity within these networks, rather than qualitative changes in the organization of the networks themselves. Improved knowledge of how the brain’s functional organization supports EF in childhood has critical implications for understanding the maturation of cognitive abilities.
The soft explosive model of placental mammal evolution
Authors: Phillips Matthew J , Fruciano Carmelo 
Published: January 2018

AbstractRecent molecular dating estimates for placental mammals echo fossil inferences for an explosive interordinal diversification, but typically place this event some 10-20 million years earlier than the Paleocene fossils, among apparently more “primitive” mammal faunas. However, current models of molecular evolution do not adequately account for parallel rate changes, and result in dramatic divergence underestimates for large, long-lived mammals such as whales and hominids. Calibrating among these taxa shifts the rate model errors deeper in the tree, inflating interordinal divergence estimates. We employ simulations based on empirical rate variation, which show that this “error-shift inflation” can explain previous molecular dating overestimates relative to fossil inferences. Molecular dating accuracy is substantially improved in the simulations by focusing on calibrations for taxa that retain plesiomorphic life-history characteristics. Applying this strategy to the empirical data favours the soft explosive model of placental evolution, in line with traditional palaeontological interpretations – a few Cretaceous placental lineages give rise to a rapid interordinal diversification following the 66 Ma Cretaceous-Paleogene boundary mass extinction. Our soft explosive model for the diversification of placental mammals brings into agreement previously incongruous molecular, fossil, and ancestral life history estimates, and closely aligns with a growing consensus for a similar model for bird evolution. We show that recent criticism of the soft explosive model relies on ignoring both experimental controls and statistical confidence, as well as misrepresentation, and inconsistent interpretations of morphological phylogeny. More generally, we suggest that the evolutionary properties of adaptive radiations may leave current molecular dating methods susceptible to overestimating the timing of major diversification events.
New mining concessions will severely decrease biodiversity and ecosystem services in Ecuador
Authors: Roy Bitty , Zorrilla Martin , Endara Lorena , Thomas Dan , Vandegrift Roo , Rubenstein Jesse M. , Policha Tobias , Rios-Touma Blanca 
Published: January 2018

AbstractEcuador has the world’s highest biodiversity, despite being a tiny fraction of the world’s land area. The threat of extinction for much of this biodiversity has dramatically increased since April 2016, during which time the Ecuadorian government has opened approximately 2.9 million hectares of land for mining exploration, with many of the concessions in previously protected forests. Herein, we describe the system of protected lands in Ecuador, their mining laws, and outline the scale of threat by comparing the mammals, amphibians, reptiles, birds, and orchids from several now threatened protected areas, classed as “Bosques Protectores” (BPs), in the NW montane cloud forests. We examine two large (>5,000 ha) BPs, Los Cedros and El Chontal, and two medium BPs, Mashpi (1,178 ha) and Maquipucuna (2,474 ha). Since BP El Chontal is so poorly explored, we used several other small reserves (<500 hectares) in the Intag Valley to gain an idea of its biodiversity. Together, these BPs and reserves form a buffer and a southern corridor for the still-protected Cotacachi-Cayapas Ecological Reserve, which is otherwise now surrounded by mining concessions. We gathered published literature, “gray literature”, information from reserve records and websites, and our previously unpublished observations to make comparative species tables for each reserve. Our results from these still incompletely known reserves reveal the astonishing losses that mining will incur: eight critically endangered species, including two primates (brown-headed spider monkey and white-fronted capuchin), 37 endangered species, 149 vulnerable and 85 near threatened and a large number of less threatened species Our data show that each of the reserves protects a unique subset of taxa in this land of highly localized endemics. Each of the reserves also generates sustainable income for the local people. The short-term national profits from mining will not compensate for the permanent biodiversity losses, and the long-term ecosystem service and economic losses at the local and regional level.
A label-free approach to detect ligand binding to cell surface proteins in real time
Authors: Burtscher Verena , Hotka Matej , Li Yang , Freissmuth Michael , Sandtner Walter 
Published: January 2018

AbstractElectrophysiological recordings allow for monitoring the operation of proteins with high temporal resolution down to the single molecule level. This technique has been exploited to track either ion flow arising from channel opening or the synchronized movement of charged residues and/or ions within the membrane electric field. Here, we describe a novel type of current by using the serotonin transporter (SERT) as a model. We examined transient currents elicited on rapid application of specific SERT inhibitors. Our analysis shows that these currents originate from ligand binding and not from a conformational change. The Gouy-Chapman model predicts that a ligand-induced elimination/neutralization of surface charge must produce a displacement current and related apparent changes in membrane capacitance. Here we verified these predictions with SERT. Our observations demonstrate that ligand binding to a protein can be monitored in real time and in a label-free manner by recording the membrane capacitance.
Bovine mammary gland development: new insights into the epithelial hierarchy
Authors: Finot Laurence , Chanat Eric , Dessauge Frederic 
Published: January 2018

AbstractMilk production is highly dependent on the extensive development of the mammary epithelium, which occurs during puberty. It is therefore essential to distinguish the epithelial cells committed to development during this key stage from the related epithelial hierarchy. Using cell phenotyping and sorting, we highlighted three sub-populations that we assume to be progenitors. The CD49fhighCD24negcells expressingKRT14,vimentinandPROCRcorresponded to basal progenitors whereas the CD49flowCD24negcells expressing luminal KRT, progesterone and prolactin receptors, were of luminal lineage. The CD49flowCD24poscells had features of a dual lineage, with luminal and basal characteristics (CD10, ALDH1 andKRT7expression) and were considered to be early common (bipotent) progenitors. The mammary stem cell (MaSC) fraction was recovered in a fourth sub-population of CD49fhighCD24poscells that expressed CD10/KRT14andKRT7. The differential ALDH1 activities observed within the MaSC fraction allowed to discriminate between two states: quiescent MaSCs and lineage-restricted “activated” MaSCs. The in-depth characterization of these epithelial sub-populations provides new insights into the epithelial cell hierarchy in the bovine mammary gland and suggests a common developmental hierarchy in mammals.
Severely impaired bone material quality in Chihuahua zebrafish resembles classical dominant human osteogenesis imperfecta
Authors: Fiedler Imke A.K. , Schmidt Felix N. , Plumeyer Christine , Milovanovic Petar , Gioia Roberta , Tonelli Francesca , Forlino Antonella , Busse Björn 
Published: January 2018

AbstractExcessive skeletal deformations and brittle fractures in the vast majority of patients suffering from osteogenesis imperfecta (OI) are a result of substantially reduced bone quality. Since the mechanical competence of bone is dependent on the tissue characteristics at small length scales, it is of crucial importance to assess how osteogenesis imperfecta manifests at the micro- and nanoscale of bone. In this context, the Chihuahua (Chi/+) zebrafish, carrying a heterozygous glycine substitution in the α1 chain of collagen type I, has recently been proposed as suitable animal model of dominant OI. Similar to human severe OI type III, Chi/+ show skeletal deformities, altered mineralization patterns and a smaller body size. Using a multimodal approach targeting bone quality parameters, this study aims at quantifying the changes in bone morphology, structure and tissue composition of Chi/+ at multiple length scales. Morphological changes were assessed with high-resolution micro-CT imaging and showed that the vertebrae in Chi/+ had a significantly smaller size, thinner cortical shell and distorted shape. Tissue composition in vertebrae was investigated with quantitative backscattered electron microscopy and Fourier-transform infrared spectroscopy, showing higher mean calcium content, greater matrix porosity, as well as lower mineral crystallinity and collagen maturity in comparison to controls. This study provides comprehensive quantitative data on bone quality indices in Chi/+ and thus further validates this mutant as an important model reflecting osseous characteristics associated with human classical dominant osteogenesis imperfecta, both at the whole bone level and the tissue level.