bluuebunny/crossref_metadata_2025_split huggingface dataset:
BAI1 Orchestrates Macrophage Inflammatory Response to HSV Infection—Implications for Oncolytic Viral Therapy
Authors: Bolyard Chelsea , Meisen W. Hans , Banasavadi-Siddegowda Yeshavanth , Hardcastle Jayson , Yoo Ji Young , Wohleb Eric S. , Wojton Jeffrey , Yu Jun-Ge , Dubin Samuel , Khosla Maninder , Xu Bo , Smith Jonathan , Alvarez-Breckenridge Christopher , Pow-anpongkul Pete , Pichiorri Flavia , Zhang Jianying , Old Matthew , Zhu Dan , Van Meir Erwin G. , Godbout Jonathan P. , Caligiuri Michael A. , Yu Jianhua , Kaur Balveen 
Published: November 2016

Abstract
Purpose: Brain angiogenesis inhibitor (BAI1) facilitates phagocytosis and bacterial pathogen clearance by macrophages; however, its role in viral infections is unknown. Here, we examined the role of BAI1, and its N-terminal cleavage fragment (Vstat120) in antiviral macrophage responses to oncolytic herpes simplex virus (oHSV).
Experimental Design: Changes in infiltration and activation of monocytic and microglial cells after treatment of glioma-bearing mice brains with a control (rHSVQ1) or Vstat120-expressing (RAMBO) oHSV was analyzed using flow cytometry. Co-culture of infected glioma cells with macrophages or microglia was used to examine antiviral signaling. Cytokine array gene expression and Ingenuity Pathway Analysis (IPA) helped evaluate changes in macrophage signaling in response to viral infection. TNFα-blocking antibodies and macrophages derived from Bai1−/− mice were used.
Results: RAMBO treatment of mice reduced recruitment and activation of macrophages/microglia in mice with brain tumors, and showed increased virus replication compared with rHSVQ1. Cytokine gene expression array revealed that RAMBO significantly altered the macrophage inflammatory response to infected glioma cells via altered secretion of TNFα. Furthermore, we showed that BAI1 mediated macrophage TNFα induction in response to oHSV therapy. Intracranial inoculation of wild-type/RAMBO virus in Bai1−/− or wild-type non–tumor-bearing mice revealed the safety of this approach.
Conclusions: We have uncovered a new role for BAI1 in facilitating macrophage anti-viral responses. We show that arming oHSV with antiangiogenic Vstat120 also shields them from inflammatory macrophage antiviral response, without reducing safety. Clin Cancer Res; 23(7); 1809–19. ©2016 AACR.
Optimization of a PEGylated Glucuronide-Monomethylauristatin E Linker for Antibody–Drug Conjugates
Authors: Burke Patrick J. , Hamilton Joseph Z. , Jeffrey Scott C. , Hunter Joshua H. , Doronina Svetlana O. , Okeley Nicole M. , Miyamoto Jamie B. , Anderson Martha E. , Stone Ivan J. , Ulrich Michelle L. , Simmons Jessica K. , McKinney Erica E. , Senter Peter D. , Lyon Robert P. 
Published: November 2016

Abstract
The emergence of antibody–drug conjugates (ADC), such as brentuximab vedotin and ado-trastuzumab emtansine, has led to increased efforts to identify new payloads and develop improved drug-linker technologies. Most antibody payloads impart significant hydrophobicity to the ADC, resulting in accelerated plasma clearance and suboptimal in vivo activity, particularly for conjugates with high drug-to-antibody ratios (DAR). We recently reported on the incorporation of a discrete PEG24 polymer as a side chain in a β-glucuronidase-cleavable monomethylauristatin E (MMAE) linker to provide homogeneous DAR 8 conjugates with decreased plasma clearance and increased antitumor activity in xenograft models relative to a non-PEGylated control. In this work, we optimized the drug-linker by minimizing the size of the PEG side chain and incorporating a self-stabilizing maleimide to prevent payload de-conjugation in vivo. Multiple PEG-glucuronide-MMAE linkers were prepared with PEG size up to 24 ethylene oxide units, and homogeneous DAR 8 ADCs were evaluated. A clear relationship was observed between PEG length and conjugate pharmacology when tested in vivo. Longer PEG chains resulted in slower clearance, with a threshold length of PEG8 beyond which clearance was not impacted. Conjugates bearing PEG of sufficient length to minimize plasma clearance provided a wider therapeutic window relative to faster clearing conjugates bearing shorter PEGs. A lead PEGylated glucuronide-MMAE linker was identified incorporating a self-stabilizing maleimide and a PEG12 side chain emerged from these efforts, enabling highly potent, homogeneous DAR 8 conjugates and is under consideration for future ADC programs. Mol Cancer Ther; 16(1); 116–23. ©2016 AACR.
Adherence to oral anticoagulant therapy in patients with atrial fibrillation
Authors: Raparelli Valeria , Proietti Marco , Cangemi Roberto , Lip Gregory Y. H. , Lane Deirdre A. , Basili Stefania 
Published: November 2016

SummaryOral anticoagulation is pivotal in the management of thromboembolic risk in non-valvular atrial fibrillation (NVAF) patients. Effective anticoagulation is important to avoid major adverse events and medication adherence is central to achieve good anticoagulation control. Non-vitamin K antagonist oral anticoagulants (NOACs) are as effective and safe as vitamin K antagonist (VKAs) in NVAF patients. Due to the absence of routine anticoagulation monitoring with NOACs treatment, concerns have been raised about patient’s adherence to NOACs and real-life data demonstrates variability in adherence and persistence. A multi-level approach, including patients’ preferences, factors determining physicians’ prescribing habits and healthcare system infrastructure and support, is warranted to improve initiation and adherence of anticoagulants. Adherence to NOACs is paramount to achieve a clinical benefit. Implementation of educational programs and easy-to-use tools to identify patients most likely to be non-adherent to NOACs, are central issues in improving the quality of NVAF anticoagulation management.Note: The review process for this manuscript was fully handled by C. Weber, Editor in Chief.
The effect of the amount of peritumoral adipose tissue in the detection of additional tumors with digital breast tomosynthesis and ultrasound
Authors: García-Barquín Paula , Páramo María , Elizalde Arlette , Pina Luis , Etxano Jon , Fernandez-Montero Alejandro , Caballeros Meylin 
Published: November 2016

Background Digital breast tomosynthesis (DBT) and ultrasound (US) can detect additional cancers after negative mammography. However, not all cancers are visible by both techniques. Purpose To study the role of the amount of peritumoral fat in the detection of additional cancers with DBT or US. Material and Methods One reader retrospectively reviewed 142 breast cancers in 109 women who underwent mammography, DBT, US, and magnetic resonance imaging (MRI). Two readers in consensus evaluated the additional cancers detected by US, DBT, or MRI, and classified them into four groups according to the amount of peritumoral adipose tissue: group I, >75% of peritumoral fat; group II, 50–74%; group III, 25–49%, and group IV, 0–24%. The detection of additional cancers by US and DBT with respect to the other imaging techniques was evaluated. Results Seventy-eight cancers were detected by mammography and the remaining 64 cancers were detected by DBT, US, or MRI. US and DBT detected 46 (71.8%) and 25 (39.06%) additional tumors, respectively. Statistical significance was only found in group IV ( P < 0.01). Conclusion US detected more tumors than DBT in lesions surrounded by a small amount of fat. No significant differences were found between US and DBT in the detection of additional cancers in the other groups.
Trigeminal nervous system sensitization by infraorbital nerve injury enhances responses in a migraine model
Authors: Toyama Midori , Kudo Chiho , Mukai Chikako , Inoue Mika , Oyamaguchi Aiko , Hanamoto Hiroshi , Sugimura Mitsutaka , Niwa Hitoshi 
Published: November 2016

Background Although the peripheral and central sensitizations of trigeminal nervous system may be one of the important factors of migraine, the precise mechanism is not fully understood. In this study, we examined the influence of the sensitization of the second division of the trigeminal nerve (V2) by chronic constriction injury (CCI) of the infraorbital nerve (ION) on migraine headache, using the capsaicin-induced migraine model. Methods Male Sprague-Dawley rats were assigned to four groups: (a) sham surgery and topical-dural vehicle application (Sham + Vehicle) group, (b) CCI-ION and topical-dural vehicle application (CCI-ION + Vehicle) group, (c) sham surgery and topical-dural capsaicin application (Sham + Capsaicin) group, (d) CCI-ION and topical-dural capsaicin application (CCI-ION + Capsaicin) group. Behavioral testing and immunohistochemical staining were performed. Results In the behavioral test, the Sham + Capsaicin group showed significantly longer duration of immobilization and shorter duration of exploration compared with the Sham + Vehicle group, which is similar to clinical features of migraine patients. Moreover, CCI-ION enhanced these effects in the CCI-ION + Capsaicin group. Immunohistochemical staining for phospho-extracellular signal-related kinase (pERK) in the trigeminal ganglion (TG) containing first and second divisions of the trigeminal nerve and the trigeminocervical complex (TCC) revealed that pERK expression was significantly increased in the CCI-ION + Capsaicin group compared with the other groups. However, comparing between effects of the peripheral and central sensitizations (in the TG and TCC), from our results, peripheral sensitization would play a much less or not significant role. Conclusions These data demonstrate that the sensitization of V2 could influence the activation and the sensitization of the first division of the trigeminal nerve in the TCC, subsequently exacerbating pain sensation and pain-related behaviors. We have shown for the first time that the existence of the central sensitization of V2 can be an exacerbating factor for migraine related nociceptive thresholds/activation.
Autoantibodies persist in relatives to systemic lupus erythematosus patients during 12 years follow-up
Authors: Langkilde H , Voss A , Heegaard N , Laustrup H 
Published: November 2016

Background Systemic lupus erythematosus (SLE) is an autoimmune disease with presence of autoantibodies and characteristic multi-organ involvement. Relatives of SLE patients have an increased risk of autoantibody production and autoimmune diseases. Methods In 2001, 226 first degree relatives (FDRs) of a population-based cohort of SLE patients were examined for the prevalence of autoantibodies and self-reported health complaints. In 2013, 143 FDRs were re-investigated and deceased’s medical records were examined. Results Participants and non-participants were comparable regarding baseline characteristics, while deceased FDRs were older than participants, but with comparable ANA status. ANA status at baseline correlated to ANA status at follow-up. At follow-up, two FDRs reported SLE and 15 FDRs other autoimmune diseases. No observation at baseline alone could predict self-reported health. During follow-up 33 died at median age 76 years. Three deceased FDRs were diagnosed with an autoimmune disease. Conclusion The study showed that FDRs of SLE patients have an increased prevalence of ANA compared to healthy controls. The prevalence increased during follow-up, and ANA positive FDRs at baseline were prone to be ANA positive at follow-up. ANA positive FDRs had more self-reported autoimmune diseases, including SLE and rheumatoid arthritis, than reported from other population-based investigations.
Time trend and risk factors of avascular bone necrosis in patients with systemic lupus erythematosus
Authors: Tse Sau Mei , Mok Chi Chiu 
Published: November 2016

Objectives The objective of this paper is to study the time trend and risk factors of avascular bone necrosis (AVN) in patients with systemic lupus erythematosus (SLE). Methods Between 1999 and 2014, patients who fulfilled the ACR criteria for SLE and developed symptomatic AVN were identified from our cohort database and compared with those without AVN, matched for age, sex and SLE duration. The standardized incidence ratios (SIRs) of AVN in different SLE age groups were calculated from data derived from our hospital registry and population census. Risk factors for AVN were studied by logistic regression, adjusted by a propensity score for ever use of high-dose glucocorticoids (GCs). Results Fifty-five SLE patients with AVN and 220 SLE patients without AVN were studied. There were 104 AVN sites involved, with the hips being most commonly affected (82%). The point prevalence of AVN in our SLE cohort was 7.4%. The SIRs of AVN in our SLE patients were 131 (86.6–199; p < 0.001) and 56.0 (34.3–91.4; p < 0.001), respectively, in the periods 1995–2004 and 2005–2014. In both decades, the age-stratified SIR was highest in the youngest age group (<19 years). AVN patients were more likely to be treated with GCs and had received a significantly higher cumulative dose of prednisolone since SLE diagnosis (16.5 vs 10.7 grams; p = 0.001). The SLE damage score (excluding AVN) was also significantly higher in AVN than non-AVN patients (2.5 vs 0.4; p < 0.001). Logistic regression revealed that preceding septic arthritis of the involved joint (odds ratio (OR) 17.7 (1.5–205); p = 0.02), cushingoid body habitus (OR 2.4 (1.1–5.2); p = 0.04), LDL cholesterol level (OR 1.4 (1.0–1.9); p = 0.04), maximum daily dose of prednisolone (OR 6.4 (1.2–33.3); p = 0.03) and cumulative dose of prednisolone received in the first six months of the first lupus flare (OR 1.3 (1.0–1.8); p = 0.046) were independently associated with AVN. Conclusions AVN is prevalent in SLE, particularly in younger patients. The use of GCs remains the strongest independent risk factor. A trend of reduction in the SIR of AVN in our SLE patients is observed over the past two decades.
Temporal quantitative phosphoproteomics of ADP stimulation reveals novel central nodes in platelet activation and inhibition
Authors: Beck Florian , Geiger Jörg , Gambaryan Stepan , Solari Fiorella A. , Dell’Aica Margherita , Loroch Stefan , Mattheij Nadine J. , Mindukshev Igor , Pötz Oliver , Jurk Kerstin , Burkhart Julia M. , Fufezan Christian , Heemskerk Johan W. M. , Walter Ulrich , Zahedi René P. , Sickmann Albert 
Published: November 2016

Key Points
Temporal profiles of >4000 phosphopeptides after stimulating human platelets (a) with ADP and (b) consecutively with ADP and Iloprost. Reciprocal phosphorylation profiles of ADP and Iloprost point to central players of platelet homeostasis.
Psychological, behavioral and social effects of disclosing Alzheimer’s disease biomarkers to research participants: a systematic review
Authors: Bemelmans S. A. S. A. , Tromp K. , Bunnik E. M. , Milne R. J. , Badger S. , Brayne C. , Schermer M. H. , Richard E. 
Published: November 2016

Abstract
Background
Current Alzheimer’s disease (AD) research initiatives focus on cognitively healthy individuals with biomarkers that are associated with the development of AD. It is unclear whether biomarker results should be returned to research participants and what the psychological, behavioral and social effects of disclosure are. This systematic review therefore examines the psychological, behavioral and social effects of disclosing genetic and nongenetic AD-related biomarkers to cognitively healthy research participants.

Methods
We performed a systematic literature search in eight scientific databases. Three independent reviewers screened the identified records and selected relevant articles. Results extracted from the included articles were aggregated and presented per effect group.

Results
Fourteen studies met the inclusion criteria and were included in the data synthesis. None of the identified studies examined the effects of disclosing nongenetic biomarkers. All studies but one concerned the disclosure of APOE genotype and were conducted in the USA. Study populations consisted largely of cognitively healthy first-degree relatives of AD patients. In this group, disclosure of an increased risk was not associated with anxiety, depression or changes in perceived risk in relation to family history. Disclosure of an increased risk did lead to an increase in specific test-related distress levels, health-related behavior changes and long-term care insurance uptake and possibly diminished memory functioning.

Conclusion
In cognitively healthy research participants with a first-degree relative with AD, disclosure of APOE ε4-positivity does not lead to elevated anxiety and depression levels, but does increase test-related distress and results in behavior changes concerning insurance and health. We did not find studies reporting the effects of disclosing nongenetic biomarkers and only one study included people without a family history of AD. Empirical studies on the effects of disclosing nongenetic biomarkers and of disclosure to persons without a family history of AD are urgently needed.

Trial registration
PROSPERO international prospective register for systematic reviews CRD42016035388. Registered 19 February 2016.
Effect of steroidal saponins-loaded nano-bioglass/phosphatidylserine/collagen bone substitute on bone healing
Authors: Yang Chunrong , Wu Huazhong , Wang Jianhua 
Published: November 2016

Abstract
The objective of this study was to investigate the therapeutic potential of nano-bioglass/phosphatidylserine/collagen (nBG/PS/COL) scaffolds loaded with steroidal saponins as an inducer factor for skeletal defects. The drugs-encapsulated bone substitute was prepared by loading steroidal saponins-collagen microsphere suspension in nano-bioglass and phosphatidylserine (PS) composite. The scaffolds possess an interconnected porous structure with a porosity of about 82.3%. The pore size ranges from several micrometers up to about 400 μm. The drug release assays showed the long-term sustained release of steroidal saponins from the scaffolds with effective and safe bioactivity. Moreover, in vitro and in vivo studies showed that the involvement of steroidal saponins contributed to the secretion of nerve growth factor (NGF) in MC3T3-E1 cells, which may be the possible factor that greatly enhanced bone healing. The results suggest that the bone substitute is an effective implantable drug-delivery system for use in bone repair.
Language norms and language use: Hypercorrections in the Independence period of Chilean Spanish
Authors: Rojas Darío , Avilés Tania 
Published: November 2016

AbstractIn this study we analyze ego-documents and metalinguistic texts from nineteenth century and early twentieth century Chilean Spanish showing a number of cases of phonetic-phonological hypercorrections. Our focus is the interaction between language-normative discourses and language use. We work with the assumption that hypercorrections are a symptom of the speakers’ linguistic consciousness regarding the norm and the (overt) prestige associated with certain variants, and thus they reveal the influence that normative ideas exert over language use. At the beginning of the nineteenth century, Chilean Spanish underwent a process of linguistic standardization, which manifested itself through a number of ‘disciplinary texts’ (grammars, dictionaries) that offered an exoglossic normative model. Chilean Spanish differed from this normative model in a number of features which were subject to overt condemnation and also were precisely those affected by hypercorrection in our data.
Why we need a token-based typology: A case study of analytic and lexical causatives in fifteen European languages
Authors: Levshina Natalia 
Published: November 2016

AbstractThis paper investigates variation of lexical and analytic causatives in 15 European languages from the Germanic, Romance, and Slavic genera based on a multilingual parallel corpus of film subtitles. Using typological parameters of variation of causatives from the literature, this study tests which parameters are relevant for the choice between analytic and lexical causatives in the sample of languages. The main research question is whether the variation is constrained by one semantic dimension, namely, the conceptual integration of the causing and caused events, as suggested by previous research on iconicity in language, or whether several different semantic and syntactic factors are at play. To answer this question, I use an exploratory multivariate technique for categorical data (Multiple Correspondence Analysis with supplementary points) and conditional random forests, a nonparametric regression and classification method. The study demonstrates the importance of corpus data in testing typological hypotheses.
Joint Model for Mortality and Hospitalization
Authors: Chen Yuqi , Guo Wensheng , Kotanko Peter , Usvyat Len , Wang Yuedong 
Published: November 2016

Abstract:
Modeling hospitalization is complicated because the follow-up time can be censored due to death. In this paper, we propose a shared frailty joint model for survival time and hospitalization. A random effect semi-parametric proportional hazard model is assumed for the survival time and conditional on the follow-up time, hospital admissions or total length of stay is modeled by a generalized linear model with a nonparametric offset function of the follow-up time. We assume that the hospitalization and the survival time are correlated through a latent subject-specific random frailty. The proposed model can be implemented using existing software such as SAS Proc NLMIXED. We demonstrate the feasibility through simulations. We apply our methods to study hospital admissions and total length of stay in a cohort of patients on hemodialysis. We identify age, albumin, neutrophil to lymphocyte ratio (NLR) and vintage as significant risk factors for mortality, and age, gender, race, albumin, NLR, pre-dialysis systolic blood pressure (preSBP), interdialytic weight gain (IDWG) and equilibrated Kt/V (eKt/V) as significant risk factors for both hospital admissions and total length of stay. In addition, hospitalization admissions is positively associated with vintage.
Perinatal death associated with umbilical cord prolapse
Authors: Hehir Mark P. , Hartigan Lucia , Mahony Rhona 
Published: November 2016

AbstractObjective:Umbilical cord prolapse occurs when the cord prolapses ahead of or alongside the presenting part. It is an acute obstetric emergency with potential catastrophic effects. We set out to assess incidence of cord prolapse, as well as rates and characteristics of perinatal death associated with the condition.Study design:This was a retrospective cohort study. All recorded cases of cord prolapse were included, and rates of perinatal death and encephalopathy, as well as intrapartum and maternal characteristics were examined.Results:There were 156,130 deliveries at the hospital over the 20-year study period. Three hundred and seven cases of cord prolapse were identified (1.9/1000 deliveries). There was a decrease in the incidence of cord prolapse over the course of the study. The rate peaked in 1999 at 3.9/1000 and was just 0.8/1000 of all deliveries in 2007. The majority of cases (216/307, 70%) occurred in multiparas; however, nulliparous parturients were more likely to have a perinatal death [12% (11/91) vs. 4.6% (10/216)]. The rate of perinatal death in cases of cord prolapse was 6.8% (21/307). Over half of perinatal deaths (11/21) occurred in infants of mothers who presented with ruptured membranes, seven of these infants were already dead on reaching hospital. There was just one case of neonatal encephalopathy associated with cord prolapse, giving an incidence of 0.32%.Conclusion:Cord prolapse carries a significant risk of perinatal death, approximately 7%. The corresponding rate of encephalopathy is low. A significant number of deaths were diagnosed on presentation to hospital and were not deemed preventable.