bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Time Machine for Information
Authors: Dong Xin Luna , Kementsietsidis Anastasios , Tan Wang-Chiew 
Published: September 2016

Historical data (also called long data) holds the key to understanding when facts are true. It is through long data that one can understand the trends that have developed in the past, form the audit trails needed for justification, and make predictions about the future. For searching, there is also increasing interest to develop search capabilities over long data.
In this article, we first motivate the need to develop a time machine for information that will help people "look back" so as to "look forward". We will overview key ideas on three components (extraction, linking, and cleaning) that we believe are central to the development of any time machine for information. Finally, we conclude with our thoughts on what we believe are some interesting open research problems. This article is based on the material presented in a tutorial at VLDB 2015.
State-dependent and -independent effects of dialyzing excitatory neuromodulator receptor antagonists into the ventral respiratory column
Authors: Langer Thomas M. , Neumueller Suzanne E. , Crumley Emma , Burgraff Nicholas J. , Talwar Sawan , Hodges Matthew R. , Pan Lawrence , Forster Hubert V. 
Published: September 2016

Unilateral dialysis of the broad-spectrum muscarinic receptor antagonist atropine (50 mM) into the ventral respiratory column [(VRC) including the pre-Bötzinger complex region] of awake goats increased pulmonary ventilation (V̇i) and breathing frequency (f), conceivably due to local compensatory increases in serotonin (5-HT) and substance P (SP) measured in effluent mock cerebral spinal fluid (mCSF). In contrast, unilateral dialysis of a triple cocktail of antagonists to muscarinic (atropine; 5 mM), neurokinin-1, and 5-HT receptors does not alter V̇i or f, but increases local SP. Herein, we tested hypotheses that 1) local compensatory 5-HT and SP responses to 50 mM atropine dialyzed into the VRC of goats will not differ between anesthetized and awake states; and 2) bilateral dialysis of the triple cocktail of antagonists into the VRC of awake goats will not alter V̇i or f, but will increase local excitatory neuromodulators. Through microtubules implanted into the VRC of goats, probes were inserted to dialyze mCSF alone (time control), 50 mM atropine, or the triple cocktail of antagonists. We found 1) equivalent increases in local 5-HT and SP with 50 mM atropine dialysis during wakefulness compared with isoflurane anesthesia, but V̇i and f only increased while awake; and 2) dialyses of the triple cocktail of antagonists increased V̇i, f, 5-HT, and SP (<0.05) during both day and night studies. We conclude that the mechanisms governing local neuromodulator levels are state independent, and that bilateral excitatory receptor blockade elicits an increase in breathing, presumably due to a local, (over)compensatory neuromodulator response. NEW & NOTEWORTHY The two major findings are as follows: 1) during unilateral dialysis of 50 mM atropine into the ventral respiratory column to block excitatory muscarinic receptor activity, a compensatory increase in other neuromodulators was state independent, but the ventilatory response appears to be state dependent; and 2) the hypothesis that absence of decreased V̇i and f during unilateral dialysis of excitatory receptor antagonists was due to compensation by the contralateral VRC was not supported by findings herein.
Preclinical Validation of a Single-Treatment Infusion Modality That Can Eradicate Extremity Melanomas
Authors: Kim Minhyung , Neznanov Nickolay , Wilfong Chandler D. , Fleyshman Daria I. , Purmal Andrei A. , Haderski Gary , Stanhope-Baker Patricia , Burkhart Catherine A. , Gurova Katerina V. , Gudkov Andrei V. , Skitzki Joseph J. 
Published: September 2016

Abstract
Isolated limb perfusion (ILP) with the chemotherapeutic agent melphalan is an effective treatment option for extremity in-transit melanoma but is toxic and technically challenging to deliver locoregionally. CBL0137 is an experimental clinical drug with broad anticancer activity in animal models, owing to its ability to bind DNA in a nongenotoxic manner and inactivate the FACT chromatin modulator essential for tumor cell viability. Here, we report that CBL0137 delivered by ILP in a murine melanoma model is as efficacious as melphalan, displaying antitumor activity at doses corresponding to only a fraction of the systemic MTD of CBL0137. The ability to bind DNA quickly combined with a favorable safety profile made it possible to substitute CBL0137 in the ILP protocol, using an intra-arterial infusion method, to safely achieve effective tumor suppression. Our findings of a preclinical proof of concept for CBL0137 and its administration via intra-arterial infusion as a superior treatment compared with melphalan ILP allows for locoregional treatment anywhere a catheter can be placed. Cancer Res; 76(22); 6620–30. ©2016 AACR.
α3β1 Integrin Suppresses Prostate Cancer Metastasis via Regulation of the Hippo Pathway
Authors: Varzavand Afshin , Hacker Will , Ma Deqin , Gibson-Corley Katherine , Hawayek Maria , Tayh Omar J. , Brown James A. , Henry Michael D. , Stipp Christopher S. 
Published: September 2016

Abstract
Existing anticancer strategies focused on disrupting integrin functions in tumor cells or tumor-involved endothelial cells have met limited success. An alternative strategy is to augment integrin-mediated pathways that suppress tumor progression, but how integrins can signal to restrain malignant behavior remains unclear. To address this issue, we generated an in vivo model of prostate cancer metastasis via depletion of α3β1 integrin, a correlation observed in a significant proportion of prostate cancers. Our data describe a mechanism whereby α3β1 signals through Abl family kinases to restrain Rho GTPase activity, support Hippo pathway suppressor functions, and restrain prostate cancer migration, invasion, and anchorage-independent growth. This α3β1-Abl kinase-Hippo suppressor pathway identified α3 integrin–deficient prostate cancers as potential candidates for Hippo-targeted therapies currently under development, suggesting new strategies for targeting metastatic prostate cancer based on integrin expression. Our data also revealed paradoxical tumor suppressor functions for Abl kinases in prostate cancer that may help to explain the failure of Abl kinase inhibitor imatinib in prostate cancer clinical trials. Cancer Res; 76(22); 6577–87. ©2016 AACR.
Liver Microvascular Injury and Thrombocytopenia of Antibody–Calicheamicin Conjugates in Cynomolgus Monkeys—Mechanism and Monitoring
Authors: Guffroy Magali , Falahatpisheh Hadi , Biddle Kathleen , Kreeger John , Obert Leslie , Walters Karen , Goldstein Richard , Boucher Germaine , Coskran Timothy , Reagan William , Sullivan Danielle , Huang Chunli , Sokolowski Sharon , Giovanelli Richard , Gerber Hans-Peter , Finkelstein Martin , Khan Nasir 
Published: September 2016

Abstract
Purpose: Adverse reactions reported in patients treated with antibody–calicheamicin conjugates such as gemtuzumab ozogamicin (Mylotarg) and inotuzumab ozogamicin include thrombocytopenia and sinusoidal obstruction syndrome (SOS). The objective of this experimental work was to investigate the mechanism for thrombocytopenia, characterize the liver injury, and identify potential safety biomarkers.
Experimental Design: Cynomolgus monkeys were dosed intravenously at 6 mg/m2/dose once every 3 weeks with a nonbinding antibody–calicheamicin conjugate (PF-0259) containing the same linker-payload as gemtuzumab ozogamicin and inotuzumab ozogamicin. Monkeys were necropsied 48 hours after the first administration (day 3) or 3 weeks after the third administration (day 63).
Results: PF-0259 induced acute thrombocytopenia (up to 86% platelet reduction) with nadirs on days 3 to 4. There was no indication of effects on megakaryocytes in bone marrow or activation of platelets in peripheral blood. Microscopic evaluation of liver from animals necropsied on day 3 demonstrated midzonal degeneration and loss of sinusoidal endothelial cells (SECs) associated with marked platelet accumulation in sinusoids. Liver histopathology on day 63 showed variable endothelial recovery and progression to a combination of sinusoidal capillarization and sinusoidal dilation/hepatocellular atrophy, consistent with early SOS. Among biomarkers evaluated, there were early and sustained increases in serum hyaluronic acid (HA) that correlated well with serum aspartate aminotransferase and liver microscopic changes, suggesting that HA may be a sensitive diagnostic marker of the liver microvascular injury.
Conclusions: These data support the conclusion that target-independent damage to liver SECs may be responsible for acute thrombocytopenia (through platelet sequestration in liver sinusoids) and development of SOS. Clin Cancer Res; 23(7); 1760–70. ©2016 AACR.
A Potent In Vivo Antitumor Efficacy of Novel Recombinant Type I Interferon
Authors: Zhang Kang-Jian , Yin Xiao-Fei , Yang Yuan-Qin , Li Hui-Ling , Xu Yan-Ni , Chen Lie-Yang , Liu Xi-Jun , Yuan Su-Jing , Fang Xian-Long , Xiao Jing , Wu Shuai , Xu Hai-Neng , Chu Liang , Katlinski Kanstantsin V. , Katlinskaya Yuliya V. , Guo Rong-Bing , Wei Guang-Wen , Wang Da-Cheng , Liu Xin-Yuan , Fuchs Serge Y. 
Published: September 2016

Abstract
Purpose: Antiproliferative, antiviral, and immunomodulatory activities of endogenous type I IFNs (IFN1) prompt the design of recombinant IFN1 for therapeutic purposes. However, most of the designed IFNs exhibited suboptimal therapeutic efficacies against solid tumors. Here, we report evaluation of the in vitro and in vivo antitumorigenic activities of a novel recombinant IFN termed sIFN-I.
Experimental Design: We compared primary and tertiary structures of sIFN-I with its parental human IFNα-2b, as well as affinities of these ligands for IFN1 receptor chains and pharmacokinetics. These IFN1 species were also compared for their ability to induce JAK–STAT signaling and expression of the IFN1-stimulated genes and to elicit antitumorigenic effects. Effects of sIFN-I on tumor angiogenesis and immune infiltration were also tested in transplanted and genetically engineered immunocompetent mouse models.
Results: sIFN-I displayed greater affinity for IFNAR1 (over IFNAR2) chain of the IFN1 receptor and elicited a greater extent of IFN1 signaling and expression of IFN-inducible genes in human cells. Unlike IFNα-2b, sIFN-I induced JAK–STAT signaling in mouse cells and exhibited an extended half-life in mice. Treatment with sIFN-I inhibited intratumoral angiogenesis, increased CD8+ T-cell infiltration, and robustly suppressed growth of transplantable and genetically engineered tumors in immunodeficient and immunocompetent mice.
Conclusions: These findings define sIFN-I as a novel recombinant IFN1 with potent preclinical antitumorigenic effects against solid tumor, thereby prompting the assessment of sIFN-I clinical efficacy in humans. Clin Cancer Res; 23(8); 2038–49. ©2016 AACR.
TGFβ1-Mediated SMAD3 Enhances PD-1 Expression on Antigen-Specific T Cells in Cancer
Authors: Park Benjamin V. , Freeman Zachary T. , Ghasemzadeh Ali , Chattergoon Michael A. , Rutebemberwa Alleluiah , Steigner Jordana , Winter Matthew E. , Huynh Thanh V. , Sebald Suzanne M. , Lee Se-Jin , Pan Fan , Pardoll Drew M. , Cox Andrea L. 
Published: September 2016

Abstract
Programmed death-1 (PD-1) is a coinhibitory receptor that downregulates the activity of tumor-infiltrating lymphocytes (TIL) in cancer and of virus-specific T cells in chronic infection. The molecular mechanisms driving high PD-1 expression on TILs have not been fully investigated. We demonstrate that TGFβ1 enhances antigen-induced PD-1 expression through SMAD3-dependent, SMAD2-independent transcriptional activation in T cells in vitro and in TILs in vivo. The PD-1hi subset seen in CD8+ TILs is absent in Smad3-deficient tumor-specific CD8+ TILs, resulting in enhanced cytokine production by TILs and in draining lymph nodes and antitumor activity. In addition to TGFβ1′s previously known effects on T-cell function, our findings suggest that TGFβ1 mediates T-cell suppression via PD-1 upregulation in the tumor microenvironment (TME). They highlight bidirectional cross-talk between effector TILs and TGFβ-producing cells that upregulates multiple components of the PD-1 signaling pathway to inhibit antitumor immunity.
Significance: Engagement of the coinhibitory receptor PD-1 or its ligand, PD-L1, dramatically inhibits the antitumor function of TILs within the TME. Our findings represent a novel immunosuppressive function of TGFβ and demonstrate that TGFβ1 allows tumors to evade host immune responses in part through enhanced SMAD3-mediated PD-1 expression on TILs. Cancer Discov; 6(12); 1366–81. ©2016 AACR.
This article is highlighted in the In This Issue feature, p. 1293
Pathophysiological relevance of macrophage subsets in atherogenesis
Authors: Liberale Luca , Dallegri Franco , Carbone Federico , Montecucco Fabrizio 
Published: September 2016

SummaryMacrophages are highly heterogeneous and plastic cells. They were shown to play a critical role in all stages of atherogenesis, from the initiation to the necrotic core formation and plaque rupture. Lesional macrophages primarily derive from blood monocyte, but local macrophage proliferation as well as differentiation from smooth muscle cells have also been described. Within atherosclerotic plaques, macrophages rapidly respond to changes in the microenvironment, shifting between pro- (M1) or anti-inflammatory (M2) functional phenotypes. Furthermore, different stimuli have been associated with differentiation of newly discovered M2 subtypes: IL-4/IL-13 (M2a), immunecomplex (M2b), IL-10/glucocorticoids (M2c), and adenosine receptor agonist (M2d). More recently, additional intraplaque macrophage phenotypes were also recognized in response to CXCL4 (M4), oxidized phospholipids (Mox), haemoglobin/haptoglobin complexes (HAmac/M(Hb)), and heme (Mhem). Such macrophage polarization was described as a progression among multiple phenotypes, which reflect the activity of different transcriptional factors and the cross-talk between intracellular signalling. Finally, the distribution of macrophage subsets within different plaque areas was markedly associated with cardiovascular (CV) vulnerability. The aim of this review is to update the current knowledge on the role of macrophage subsets in atherogenesis. In addition, the molecular mechanisms underlying macrophage phenotypic shift will be summarised and discussed. Finally, the role of intraplaque macrophages as predictors of CV events and the therapeutic potential of these cells will be discussed.
Applications, Prospects and Challenges of Silicon Carbide Junction Field Effect Transistor (SIC JFET)
Authors: Ehiagwina Frederick Ojiemhende , Kehinde Olufemi Oluseye , Afolabi Lateef Olashile , Onawola Hassan Jimoh , Iromini Nurudeen Ajibola 
Published: September 2016

Properties of Silicon Carbide Junction Field Effect Transistor (SiC JFET) such as high switching speed, low forward voltage drop and high temperature operation have attracted the interest of power electronic researchers and technologists, who for many years developed devices based on Silicon (Si). A number of power system Engineers have made efforts to develop more robust equipment including circuits or modules with higher power density. However, it was realized that several available power semiconductor devices were approaching theoretical limits offered by Si material with respect to capability to block high voltage, provide low on-state voltage drop and switch at high frequencies. This paper presents an overview of the current applications of SiC JFET in circuits such as inverters, rectifiers and amplifiers. Other areas of application reviewed include; usage of the SiC JFET in pulse signal circuits and boost converters. Efforts directed toward mitigating the observed increase in electromagnetic interference were also discussed. It also presented some areas for further research, such as having more applications of SiC JFET in harsh, high temperature environment. More work is needed with regards to SiC JFET drivers so as to ensure stable and reliable operation, and reduction in the prices of SiC JFETs through mass production by industries.
Left Atrial Appendage Closure Under Intracardiac Echocardiographic Guidance: Feasibility and Comparison With Transesophageal Echocardiography
Authors: Matsuo Yae , Neuzil Petr , Petru Jan , Chovanec Milan , Janotka Marek , Choudry Subbarao , Skoda Jan , Sediva Lucie , Kurabayashi Masahiko , Reddy Vivek Y. 
Published: September 2016

Background

Transcatheter left atrial appendage closure is an alternative therapy for stroke prevention in atrial fibrillation patients. These procedures are currently guided with transesophageal echocardiography and fluoroscopy in most centers. As intracardiac echocardiography (
ICE
) is commonly used in other catheter‐based procedures, we sought to determine the safety and effectiveness of intracardiac echocardiography–guided left atrial appendage closure with the Watchman device.

Methods and Results
A total of 27 patients (11 males, 77.0±8.5 years) with atrial fibrillation receiving Watchman left atrial appendage closure under intracardiac echocardiography guidance at a single center were investigated. All patients were implanted successfully. There were no major procedural complications. The overall procedure‐related complication rate was 14.8%, mainly due to access site hematoma. Transesophageal echocardiography demonstrated successful closure of the left atrial appendage in all patients at 45 days after device implant.

Conclusions
Transcatheter left atrial appendage closure with intracardiac echocardiography guidance is safe and feasible.
À propos d’ acte sans paroles I
Authors: Dupuy Dominique 
Published: September 2016

Act without Words I is a play about gravity, whose mechanisms are on display. In Worstward Ho, the image of an old man and a child holding hands suddenly appears out of the nothingness. This image, with all its implications, has given rise to our recent production of Act without Words I, in which the same sequence of movements is performed twice, first by a young circus artist, and then by myself, an eighty-year-old dancer.
Response Time Characteristics of the Fast-2D Optical Array Probe Detector Board
Authors: Hayman Matthew , McMenamin Katie J. , Jensen Jørgen B. 
Published: September 2016

AbstractTwo-dimensional optical array probes are commonly used for imaging raindrops and ice particles on research aircraft. The ability of these probes to accurately measure particle concentration and size partly depends on the response characteristics of the detection system. If the response characteristics are too slow, then small particles are less likely to be detected and the associated effective sample volume decreases. In an effort to better understand the sample volumes of optical array probes at the National Center for Atmospheric Research, the temporal response of the Fast-2D optical array probe detector board from optical input on the detector to digitization was characterized. The analysis suggests that the board electronics have a response time constant consistently near 50 ns. However, there is also a slow decay term that conforms to a decay rate. The amplitude of this slow function can impact the probe response, varying the minimum detectable pulse width between 60 and 150 ns. Also, the amplitude of the slow function is largely dictated by the illumination angle of incidence. The effects of the response time characteristics are analyzed using a simulator for a 2D cloud (2D-C) probe with 25-μm photodiode spacing. The results show the greatest sensitivity to response time characteristics when particles are smaller than 150 μm, where 10% uncertainty in the slow fraction is likely to produce sample volume uncertainties near 10%. Ignoring response time effects may bias sample volume estimates in the small size regime by as much as 25%.
Pediatric Intestinal Failure–Associated Liver Disease: Challenges in Identifying Clinically Relevant Biomarkers
Authors: Gura Kathleen M. , Mulberg Andrew E. , Mitchell Paul D. , Yap John , Kim Clara Y. , Chen Minjun , Potemkin Alexis , Puder Mark 
Published: September 2016

AbstractBackground: Intestinal failure–associated liver disease (IFALD) is complex and diagnosed by concurrent use of parenteral nutrition, clinical presentation, and alterations in hepatic biomarkers exclusive of other causes of liver disease. In comparison with individual measures, composite biomarkers may provide a more effective means for assessing disease progression and response to treatment than single parameters. Since IFALD is considered by some to be a type of drug‐induced liver injury (DILI), those diagnostic criteria could potentially be used in this population. Using a preexisting database of children treated for IFALD, our aim was to determine if a similar composite biomarker could be applied to this population. Study Design: Adult DILI criteria were applied at baseline, when treatment for IFALD (ie, direct bilirubin ≥2.0 mg/dL) was initiated. Results: A total of 214 patients with IFALD treated at Boston Children’s Hospital were identified; 168 patients were eligible for analysis. Most patients analyzed were male (61%) and preterm (87%). Alkaline phosphatase (ALP) ≥2× upper limit of normal (ULN) captured the least amount of DILI (11%), while γ‐glutamyltransferase (GGT) ≥1× ULN accounted for the most (62%). Using adult DILI criteria, 60 (39%) patients with IFALD were found to have DILI. Substituting GGT ≥1× ULN for ALP ≥2× ULN improved the sensitivity, with 105 (69%) of patients meeting at least 1 criterion for DILI. Conclusion: Numerous challenges made it difficult to apply the DILI criteria to children with IFALD. Direct bilirubin, fractionated ALP, and perhaps GGT may be more suitable. Given its complex etiology and the age‐based differences due to hepatic immaturity and growth, a more suitable composite marker needs to be developed to assess IFALD in this population.
Occupational therapy home programmes for children with unilateral cerebral palsy using bimanual and modified constraint induced movement therapies: A critical review
Authors: Milton Yvonne , Roe Sarah 
Published: September 2016

Introduction The home context is considered a good location for children with cerebral palsy to practise meaningful occupations. The aim of this critical review was to gain a deeper understanding of how bimanual therapy and modified constraint induced movement therapy or constraint induced movement therapy methods are used within occupational therapy home programmes from an occupational perspective. Method A literature search was conducted using electronic databases for health research; five studies met the inclusion criteria. These were critically appraised and were analysed according to the relevant supports and barriers of the person–environment–occupation conceptual model of practice. Findings Family collaboration, strategic use of outcome measures, construction of the programme within the home environment and occupation-focused goals and activities emerged as commonly used methods. Enhanced descriptions of intervention context, the child’s voice in defining goals and challenges in optimising occupational balance surfaced as gaps in the programmes. Conclusion The methods used in implementing these approaches within occupational therapy home programmes requires combining motor and non-motor approaches, core occupational therapy skills, working within individual contexts and valuing family preferences. Using child-specific goal-setting instruments would strengthen the child’s voice and promote participation within a wider range of occupations.