bluuebunny/crossref_metadata_2025_split huggingface dataset:
HIV Blocks Interferon Induction in Human Dendritic Cells and Macrophages by Dysregulation of TBK1
Authors: Harman Andrew N. , Nasr Najla , Feetham Alexandra , Galoyan Ani , Alshehri Abdullateef A. , Rambukwelle Dharshini , Botting Rachel A. , Hiener Bonnie M. , Diefenbach Eve , Diefenbach Russell J. , Kim Min , Mansell Ashley , Cunningham Anthony L. 
Published: April 2015

ABSTRACT
Dendritic cells (DCs) and macrophages are present in the tissues of the anogenital tract, where HIV-1 transmission occurs in almost all cases. These cells are both target cells for HIV-1 and represent the first opportunity for the virus to interfere with innate recognition. Previously we have shown that both cell types fail to produce type I interferons (IFNs) in response to HIV-1 but that, unlike T cells, the virus does not block IFN induction by targeting IFN regulatory factor 3 (IRF3) for cellular degradation. Thus, either HIV-1 inhibits IFN induction by an alternate mechanism or, less likely, these cells fail to sense HIV-1. Here we show that HIV-1 (but not herpes simplex virus 2 [HSV-2] or Sendai virus)-exposed DCs and macrophages fail to induce the expression of all known type I and III IFN genes. These cells do sense the virus, and pattern recognition receptor (PRR)-induced signaling pathways are triggered. The precise stage in the IFN-inducing signaling pathway that HIV-1 targets to block IFN induction was identified; phosphorylation but not K63 polyubiquitination of TANK-binding kinase 1 (TBK1) was completely inhibited. Two HIV-1 accessory proteins, Vpr and Vif, were shown to bind to TBK1, and their individual deletion partly restored IFN-β expression. Thus, the inhibition of TBK1 autophosphorylation by binding of these proteins appears to be the principal mechanism by which HIV-1 blocks type I and III IFN induction in myeloid cells.

IMPORTANCE
Dendritic cells (DCs) and macrophages are key HIV target cells. Therefore, definition of how HIV impairs innate immune responses to initially establish infection is essential to design preventative interventions, especially by restoring initial interferon production. Here we demonstrate how HIV-1 blocks interferon induction by inhibiting the function of a key kinase in the interferon signaling pathway, TBK1, via two different viral accessory proteins. Other viral proteins have been shown to target the general effects of TBK1, but this precise targeting between ubiquitination and phosphorylation of TBK1 is novel.
A Single Amino Acid Deletion in the Matrix Protein of Porcine Reproductive and Respiratory Syndrome Virus Confers Resistance to a Polyclonal Swine Antibody with Broadly Neutralizing Activity
Authors: Trible Benjamin R. , Popescu Luca N. , Monday Nicholas , Calvert Jay G. , Rowland Raymond R. R. 
Published: April 2015

ABSTRACT
Assessment of virus neutralization (VN) activity in 176 pigs infected with porcine reproductive and respiratory syndrome virus (PRRSV) identified one pig with broadly neutralizing activity. A Tyr-10 deletion in the matrix protein provided escape from broad neutralization without affecting homologous neutralizing activity. The role of the Tyr-10 deletion was confirmed through an infectious clone with a Tyr-10 deletion. The results demonstrate differences in the properties and specificities of VN responses elicited during PRRSV infection.
Transformation with Oncogenic Ras and the Simian Virus 40 T Antigens Induces Caspase-Dependent Sensitivity to Fatty Acid Biosynthetic Inhibition
Authors: Xu Shihao , Spencer Cody M. , Munger Joshua 
Published: April 2015

ABSTRACT

Oncogenesis is frequently accompanied by the activation of specific metabolic pathways. One such pathway is fatty acid biosynthesis, whose induction is observed upon transformation of a wide variety of cell types. Here, we explored how defined oncogenic alleles, specifically the simian virus 40 (SV40) T antigens and oncogenic Ras
12V
, affect fatty acid metabolism. Our results indicate that SV40/Ras
12V
-mediated transformation of fibroblasts induces fatty acid biosynthesis in the absence of significant changes in the concentration of fatty acid biosynthetic enzymes. This oncogene-induced activation of fatty acid biosynthesis was found to be mammalian target of rapamycin (mTOR) dependent, as it was attenuated by rapamycin treatment. Furthermore, SV40/Ras
12V
-mediated transformation induced sensitivity to treatment with fatty acid biosynthetic inhibitors. Pharmaceutical inhibition of acetyl-coenzyme A (CoA) carboxylase (ACC), a key fatty acid biosynthetic enzyme, induced caspase-dependent cell death in oncogene-transduced cells. In contrast, isogenic nontransformed cells were resistant to fatty acid biosynthetic inhibition. This oncogene-induced sensitivity to fatty acid biosynthetic inhibition was independent of the cells' growth rates and could be attenuated by supplementing the medium with unsaturated fatty acids. Both the activation of fatty acid biosynthesis and the sensitivity to fatty acid biosynthetic inhibition could be conveyed to nontransformed breast epithelial cells through transduction with oncogenic Ras
12V
. Similar to what was observed in the transformed fibroblasts, the Ras
12V
-induced sensitivity to fatty acid biosynthetic inhibition was independent of the proliferative status and could be attenuated by supplementing the medium with unsaturated fatty acids. Combined, our results indicate that specific oncogenic alleles can directly confer sensitivity to inhibitors of fatty acid biosynthesis.

IMPORTANCE
Viral oncoproteins and cellular mutations drive the transformation of normal cells to the cancerous state. These oncogenic alterations induce metabolic changes and dependencies that can be targeted to kill cancerous cells. Here, we find that the cellular transformation resulting from combined expression of the SV40 early region with an oncogenic Ras allele is sufficient to induce cellular susceptibility to fatty acid biosynthetic inhibition. Inhibition of fatty acid biosynthesis in these cells resulted in programmed cell death, which could be rescued by supplementing the medium with nonsaturated fatty acids. Similar results were observed with the expression of oncogenic Ras in nontransformed breast epithelial cells. Combined, our results suggest that specific oncogenic alleles induce metabolic dependencies that can be exploited to selectively kill cancerous cells.
Systematic review: unmet supportive care needs in people diagnosed with chronic liver disease
Authors: Valery Patricia C , Powell Elizabeth , Moses Neta , Volk Michael L , McPhail Steven M , Clark Paul J , Martin Jennifer 
Published: April 2015

ObjectivePeople with chronic liver disease, particularly those with decompensated cirrhosis, experience several potentially debilitating complications that can have a significant impact on activities of daily living and quality of life. These impairments combined with the associated complex treatment mean that they are faced with specific and high levels of supportive care needs. We aimed to review reported perspectives, experiences and concerns of people with chronic liver disease worldwide. This information is necessary to guide development of policies around supportive needs screening tools and to enable prioritisation of support services for these patients.DesignSystematic searches of PubMed, MEDLINE, CINAHL and PsycINFO from the earliest records until 19 September 2014. Data were extracted using standardised forms. A qualitative, descriptive approach was utilised to analyse and synthesise data.ResultsThe initial search yielded 2598 reports: 26 studies reporting supportive care needs among patients with chronic liver disease were included, but few of them werepatient-reportedneeds, none used a validated liver disease-specific supportive care need assessment instrument, and only three included patients with cirrhosis. Five key domains of supportive care needs were identified: informational or educational (eg, educational material, educational sessions), practical (eg, daily living), physical (eg, controlling pruritus and fatigue), patient care and support (eg, support groups), and psychological (eg, anxiety, sadness).ConclusionsWhile several key domains of supportive care needs were identified, most studies included hepatitis patients. There is a paucity of literature describing the supportive care needs of the chronic liver disease population likely to have the most needs—namely those with cirrhosis. Assessing the supportive care needs of people with chronic liver disease have potential utility in clinical practice for facilitating timely referrals to support services.
Secondhand smoke in outdoor settings: smokers’ consumption, non-smokers’ perceptions, and attitudes towards smoke-free legislation in Spain
Authors: Sureda Xisca , Fernández Esteve , Martínez-Sánchez Jose M , Fu Marcela , López María J , Martínez Cristina , Saltó Esteve 
Published: April 2015

ObjectiveTo describe where smokers smoke outdoors, where non-smokers are exposed outdoors to secondhand smoke (SHS), and attitudes towards smoke-free outdoor areas after the implementation of national smoke-free legislation.DesignThis cross-sectional study was conducted between June 2011 and March 2012 (n=1307 participants).SettingBarcelona, Spain.ParticipantsRepresentative, random sample of the adult (≥16 years) population.Primary and secondary outcomesProportion of smoking and prevalence of exposure to SHS in the various settings according to type of enclosure. Percentages of support for outdoor smoke-free policies according to smoking status.ResultsSmokers reported smoking outdoors most in bars and restaurants (54.8%), followed by outdoor places at work (46.8%). According to non-smokers, outdoor SHS exposure was highest at home (42.5%) and in bars and restaurants (33.5%). Among non-smoking adult students, 90% claimed exposure to SHS on university campuses. There was great support for banning smoking in the majority of outdoor areas, which was stronger among non-smokers than smokers. Over 70% of participants supported smoke-free playgrounds, school and high school courtyards, and the grounds of healthcare centres.ConclusionsExtending smoking bans to selected outdoor settings should be considered in further tobacco control interventions to protect non-smokers from SHS exposure and to establish a positive model for youth. The majority of public support for some outdoor smoke-free areas suggests that it is feasible to extend smoking bans to additional outdoor settings.
Pipeline embolization for definitive endoluminal reconstruction of blister-type carotid aneurysms after clip wrapping
Authors: Kalani M Yashar S , Albuquerque Felipe C , Levitt Michael , Nakaji Peter , Spetzler Robert F , McDougall Cameron 
Published: April 2015

BackgroundRuptured blister aneurysms of the carotid artery are difficult to safely treat. We present a novel strategy of microsurgical clip wrapping of internal carotid artery blister aneurysms in the setting of acute rupture, followed by delayed placement of a pipeline embolization device for definitive treatment.Clinical presentationWe present two cases of ruptured blister aneurysms of the internal carotid artery treated by wrapping of the diseased segment of the vessel, followed by delayed deployment of a flow diverting stent once the patient was out of the vasospasm window but during the same hospitalization.ResultsClip wrapping followed by flow diversion in a delayed fashion results in anatomic remodeling of the diseased artery without a high morbidity.ConclusionsA combined approach of acute surgical stabilization followed by definitive endovascular reconstruction may reduce hemorrhagic complications while improving long term treatment durability.
Venous sinus stenting for idiopathic intracranial hypertension is not associated with cortical venous occlusion
Authors: Levitt Michael R , Albuquerque Felipe C , Ducruet Andrew F , Kalani M Yashar S , Mulholland Celene B , McDougall Cameron G 
Published: April 2015

BackgroundThe effect of dural venous sinus stenting has been investigated for the treatment of idiopathic intracranial hypertension (IIH) but the effect of stenting on the long-term patency of the cortical draining veins, especially the vein of Labbé (VOL), remains unknown.MethodsWe reviewed our database of 38 patients with IIH with 41 stented dural venous sinuses between October 2006 and December 2014. Demographic, clinical, and radiological data were reviewed. Follow-up catheter angiographic data were included when available.ResultsStent placement spanned the ostium of the VOL in 35 patients (92.1%), with no immediate effect on the drainage of the VOL. Follow-up angiography (mean 35.1 months, range 1.7–80.7 months) was available in 24 patients, 21 of whom had stents spanning the VOL ostium. The VOL remained patent without occlusion or drainage alteration in all 21 patients. There were no immediate or long-term intracranial complications.ConclusionsDural venous sinus stenting for patients with IIH does not affect the immediate or long-term patency of the VOL and is not associated with intracranial complications.
Prosthetic aortic valve selection: current patient experience, preferences and knowledge
Authors: Korteland Nelleke M , Bras Frans J , van Hout Fabienne M A , Kluin Jolanda , Klautz Robert J M , Bogers Ad J J C , Takkenberg Johanna J M 
Published: April 2015

ObjectiveCurrent clinical practice guidelines advocate shared decision-making (SDM) in prosthetic valve selection. This study assesses among adult patients accepted for aortic valve replacement (AVR): (1) experience with current clinical decision-making regarding prosthetic valve selection, (2) preferences for SDM and risk presentation and (3) prosthetic valve knowledge and numeracy.MethodsIn a prospective multicentre cohort study, AVR patients were surveyed preoperatively and 3 months postoperatively.Results132 patients (89 males/43 females; mean age 67 years (range 23–86)) responded preoperatively. Decisional conflict was observed in 56% of patients, and in 25% to such an extent that it made them feel unsure about the decision. 68% wanted to be involved in decision-making, whereas 53% agreed that they actually were. 69% were able to answer three basic knowledge questions concerning prosthetic valves correctly. 56% were able to answer three basic numeracy questions correctly. Three months postsurgery, 90% (n=110) were satisfied with their aortic valve prosthesis, with no difference between mechanical and bioprosthetic valve recipients.ConclusionsIn current clinical practice, many AVR patients experience decisional conflict and suboptimal involvement in prosthetic valve selection, and exhibit impaired knowledge concerning prosthetic valves and numeracy. Given the broad support for SDM among AVR patients and the obvious need for understandable information, to-be-developed tools to support SDM in the setting of prosthetic valve selection will help to improve quality of decision-making, better inform and actively involve patients, and reduce decisional conflict.Trial registration numberNTR3618.
Development of Lung Adenocarcinomas with Exclusive Dependence on Oncogene Fusions
Authors: Saito Motonobu , Shimada Yoko , Shiraishi Kouya , Sakamoto Hiromi , Tsuta Koji , Totsuka Hirohiko , Chiku Suenori , Ichikawa Hitoshi , Kato Mamoru , Watanabe Shun-ichi , Yoshida Teruhiko , Yokota Jun , Kohno Takashi 
Published: April 2015

Abstract
This report delivers a comprehensive genetic alteration profile of lung adenocarcinomas (LADC) driven by ALK, RET, and ROS1 oncogene fusions. These tumors are difficult to study because of their rarity. Each drives only a low percentage of LADCs. Whole-exome sequencing and copy-number variation analyses were performed on a Japanese LADC cohort (n = 200) enriched in patients with fusions (n = 31, 15.5%), followed by deep resequencing for validation. The driver fusion cases showed a distinct profile with smaller numbers of nonsynonymous mutations in cancer-related genes or truncating mutations in SWI/SNF chromatin remodeling complex genes than in other LADCs (P &lt; 0.0001). This lower mutation rate was independent of age, gender, smoking status, pathologic stage, and tumor differentiation (P &lt; 0.0001) and was validated in nine fusion-positive cases from a U.S. LADCs cohort (n = 230). In conclusion, our findings indicate that LADCs with ALK, RET, and ROS1 fusions develop exclusively via their dependence on these oncogene fusions. The presence of such few alterations beyond the fusions supports the use of monotherapy with tyrosine kinase inhibitors targeting the fusion products in fusion-positive LADCs. Cancer Res; 75(11); 2264–71. ©2015 AACR.
Cell–Cell Adhesion and Cytoskeleton Tension Oppose Each Other in Regulating Tumor Cell Aggregation
Authors: Saias Laure , Gomes Aurélie , Cazales Martine , Ducommun Bernard , Lobjois Valérie 
Published: April 2015

Abstract
Cell aggregation is frequently impaired during the growth of primary tumors and the formation of metastatic lesions. Cell aggregation depends on cell–cell adhesion; however, no rigorous approach exists to monitor and quantify it accurately in the absence of the confounding factors of cell–substrate adhesion and the resulting cell motility on the substrate. We report here a highly reproducible, automated, microscopy-based quantification of tumor-cell spheroid formation in the absence of cell–substrate adhesion and use it to characterize cell aggregation dynamics in the early steps of this process. This method is based on fluorescence and bright-field microscopy and on a custom MATLAB program to quantify automatically the cells' aggregation kinetics. We demonstrate that the cell–cell adhesion protein E-cadherin and the desmosome proteins DSG2 and DSC2 are important for aggregation. Furthermore, we show that inhibition or silencing of myosin IIa enhances aggregation, suggesting that cytoskeleton tension inhibits tumor cell aggregation. This work opens new avenues to study the principles that govern multicellular aggregation, to characterize the aggregation properties of various tumor cell types, as well as to screen for drugs that inhibit or promote aggregation. Cancer Res; 75(12); 2426–33. ©2015 AACR.
CC-223, a Potent and Selective Inhibitor of mTOR Kinase: In Vitro and In Vivo Characterization
Authors: Mortensen Deborah S. , Fultz Kimberly E. , Xu Shuichan , Xu Weiming , Packard Garrick , Khambatta Godrej , Gamez James C. , Leisten Jim , Zhao Jingjing , Apuy Julius , Ghoreishi Kamran , Hickman Matt , Narla Rama Krishna , Bissonette Rene , Richardson Samantha , Peng Sophie X. , Perrin-Ninkovic Sophie , Tran Tam , Shi Tao , Yang Wen Qing , Tong Zeen , Cathers Brian E. , Moghaddam Mehran F. , Canan Stacie S. , Worland Peter , Sankar Sabita , Raymon Heather K. 
Published: April 2015

Abstract
mTOR is a serine/threonine kinase that regulates cell growth, metabolism, proliferation, and survival. mTOR complex-1 (mTORC1) and mTOR complex-2 (mTORC2) are critical mediators of the PI3K–AKT pathway, which is frequently mutated in many cancers, leading to hyperactivation of mTOR signaling. Although rapamycin analogues, allosteric inhibitors that target only the mTORC1 complex, have shown some clinical activity, it is hypothesized that mTOR kinase inhibitors, blocking both mTORC1 and mTORC2 signaling, will have expanded therapeutic potential. Here, we describe the preclinical characterization of CC-223. CC-223 is a potent, selective, and orally bioavailable inhibitor of mTOR kinase, demonstrating inhibition of mTORC1 (pS6RP and p4EBP1) and mTORC2 [pAKT(S473)] in cellular systems. Growth inhibitory activity was demonstrated in hematologic and solid tumor cell lines. mTOR kinase inhibition in cells, by CC-223, resulted in more complete inhibition of the mTOR pathway biomarkers and improved antiproliferative activity as compared with rapamycin. Growth inhibitory activity and apoptosis was demonstrated in a panel of hematologic cancer cell lines. Correlative analysis revealed that IRF4 expression level associates with resistance, whereas mTOR pathway activation seems to associate with sensitivity. Treatment with CC-223 afforded in vivo tumor biomarker inhibition in tumor-bearing mice, after a single oral dose. CC-223 exhibited dose-dependent tumor growth inhibition in multiple solid tumor xenografts. Significant inhibition of mTOR pathway markers pS6RP and pAKT in CC-223–treated tumors suggests that the observed antitumor activity of CC-223 was mediated through inhibition of both mTORC1 and mTORC2. CC-223 is currently in phase I clinical trials. Mol Cancer Ther; 14(6); 1295–305. ©2015 AACR.
Superensemble Regional Climate Modeling for the Western United States
Authors: Mote Philip W. , Allen Myles R. , Jones Richard G. , Li Sihan , Mera Roberto , Rupp David E. , Salahuddin Ahmed , Vickers Dean 
Published: April 2015

AbstractComputing resources donated by volunteers have generated the first superensemble of regional climate model results, in which the Hadley Centre Regional Model, version 3P (HadRM3P), and Hadley Centre Atmosphere Model, version 3P (HadAM3P), were implemented for the western United States at 25-km resolution. Over 136,000 valid and complete 1-yr runs have been generated to date: about 126,000 for 1960–2009 using observed sea surface temperatures (SSTs) and 10,000 for 2030–49 using projected SSTs from a global model simulation. Ensemble members differ in initial conditions, model physics, and (potentially, for future runs) SSTs. This unprecedented confluence of high spatial resolution and large ensemble size allows high signal-to-noise ratio and more robust estimates of uncertainty. This paper describes the experiment, compares model output with observations, shows select results for climate change simulations, and gives examples of the strength of the large ensemble size.
Pasientinformasjon i forkant av undersøkelser ved en medisinsk poliklinikk: Ulike betingelser for at polikliniske og inneliggende pasienter skal være godt nok forberedt
Authors: Pedersen Karen Louise , Sørheim Anne Margrethe , Giske Tove 
Published: April 2015

Aim To describe and discuss factors contributing to information preparation of hospitalized and outpatient patients coming for investigations at a medical outpatient ward. Background Information and practical preparation before medical investigations aids patients to prepare accurately for the investigation. Hospitalized and outpatient patients have different conditions for information access prior to investigations. Clinical experience raised questions to how well these two groups of patients were prepared for medical investigations. Method Both groups of patients; 127 hospitalized patients and 163 outpatients, were surveyed at the outpatient ward just before the investigation was performed. Descriptive and correlation analyses were carried out. Findings The outpatients report being prepared to a much greater extent for medical investigations than hospitalized patients. In total, 94% of the outpatients report having received information, however, just 54% of the hospitalized patients indicate that they have received any information at all about the investigation. Conclusion The results indicate that information to hospitalized patients ahead of medical investigations must be improved. Increased focus on providing information to patients from health care professionals is required. Brochures providing information about the individual investigation is one helpful way forward.