bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction of Viral, 7-Methyl-Guanosine Cap-Independent Translation and Oncolysis by Mitogen-Activated Protein Kinase-Interacting Kinase-Mediated Effects on the Serine/Arginine-Rich Protein Kinase
Authors: Brown Michael C. , Bryant Jeffrey D. , Dobrikova Elena Y. , Shveygert Mayya , Bradrick Shelton S. , Chandramohan Vidyalakshmi , Bigner Darell D. , Gromeier Matthias 
Published: September 2014

ABSTRACT

Protein synthesis, the most energy-consuming process in cells, responds to changing physiologic priorities, e.g., upon mitogen- or stress-induced adaptations signaled through the mitogen-activated protein kinases (MAPKs). The prevailing status of protein synthesis machinery is a viral pathogenesis factor, particularly for plus-strand RNA viruses, where immediate translation of incoming viral RNAs shapes host-virus interactions. In this study, we unraveled signaling pathways centered on the ERK1/2 and p38α MAPK-interacting kinases MNK1/2 and their role in controlling 7-methyl-guanosine (m
7
G) “cap”-independent translation at enterovirus type 1 internal ribosomal entry sites (IRESs). Activation of Raf-MEK-ERK1/2 signals induced viral IRES-mediated translation in a manner dependent on MNK1/2. This effect was not due to MNK's known functions as eukaryotic initiation factor (eIF) 4G binding partner or eIF4E(S209) kinase. Rather, MNK catalytic activity enabled viral IRES-mediated translation/host cell cytotoxicity through negative regulation of the Ser/Arg (SR)-rich protein kinase (SRPK). Our investigations suggest that SRPK activity is a major determinant of type 1 IRES competency, host cell cytotoxicity, and viral proliferation in infected cells.

IMPORTANCE
We are targeting unfettered enterovirus IRES activity in cancer with PVSRIPO, the type 1 live-attenuated poliovirus (PV) (Sabin) vaccine containing a human rhinovirus type 2 (HRV2) IRES. A phase I clinical trial of PVSRIPO with intratumoral inoculation in patients with recurrent glioblastoma (GBM) is showing early promise. Viral translation proficiency in infected GBM cells is a core requirement for the antineoplastic efficacy of PVSRIPO. Therefore, it is critically important to understand the mechanisms controlling viral cap-independent translation in infected host cells.
On the Laws of Virus Spread through Cell Populations
Authors: Wodarz Dominik , Chan Chi N. , Trinité Benjamin , Komarova Natalia L. , Levy David N. 
Published: September 2014

ABSTRACTThe dynamics of viral infections have been investigated extensively, often with a combination of experimental and mathematical approaches. Mathematical descriptions of virus spread through cell populations are well established in the literature and have yielded important insights, yet the formulation of certain fundamental aspects of virus dynamics models remains uncertain and untested. Here, we investigate the process of infection and, in particular, the effect of varying the target cell population size on the number of productively infected cells generated. Using anin vitrosingle-round HIV-1 infection system, we find that the established modeling framework cannot accurately fit the data. If the model is fit to data with the lowest number of cells and is used to predict data generated with larger cell populations, the model significantly overestimates the number of productively infected cells generated. Interestingly, this deviation becomes stronger under experimental conditions that promote mixing of cells and viruses. The reason for the deviation is that the standard model makes certain oversimplifying assumptions about the fate of viruses that fail to find a cell in their immediate proximity. We derive from stochastic processes a different model that assumes simultaneous access of the virus to multiple target cells. In this scenario, if no cell is available to the virus at its location, it has a chance to interact with other cells, a process that can be promoted by mixing of the populations. This model can accurately fit the experimental data and suggests a new interpretation of mass action in virus dynamics models.IMPORTANCEUnderstanding the principles of virus growth through cell populations is of fundamental importance to virology. It helps us make informed decisions about intervention strategies aimed at preventing virus growth, such as drug treatment or vaccination approaches, e.g., in HIV infection, yet considerable uncertainty remains in this respect. An important variable in this context is the number of susceptible cells available for virus replication. How does the number of susceptible cells influence the growth potential of the virus? Besides the importance of such information for clinical responses, a thorough understanding of this is also important for the prediction of virus levels in patients and the estimation of crucial patient parameters through the use of mathematical models. This paper investigates the relationship between target cell availability and the virus growth potential with a combination of experimental and mathematical approaches and provides significant new insights.
Chemical Induction of Unfolded Protein Response Enhances Cancer Cell Killing through Lytic Virus Infection
Authors: Prasad Vibhu , Suomalainen Maarit , Pennauer Mirjam , Yakimovich Artur , Andriasyan Vardan , Hemmi Silvio , Greber Urs F. 
Published: September 2014

ABSTRACT
Cancer cells are susceptible to oncolytic viruses, albeit variably. Human adenoviruses (HAdVs) are widely used oncolytic agents that have been engineered to produce progeny within the tumor and elicit bystander effects. We searched for host factors enhancing bystander effects and conducted a targeted RNA interference screen against guanine nucleotide exchange factors (GEFs) of small GTPases. We show that the unfolded protein response (UPR), which is readily inducible in aggressive tumor cells, enhances melanoma or epithelial cancer cell killing upon HAdV infection. UPR was triggered by knockdown of Golgi-specific brefeldin A-resistant guanine nucleotide exchange factor 1 (GBF-1) or the GBF-1 inhibitor golgicide A (GCA) and stimulated HAdV infection. GBF-1 is a GEF for ADP ribosylation factors (Arfs) regulating endoplasmic reticulum (ER)-to-Golgi apparatus and intra-Golgi apparatus membrane transport. Cells treated with GCA enhanced HAdV-induced cytopathic effects in epithelial and melanoma cancer cells but not normal cells, if the drug was applied several hours prior to HAdV inoculation. This was shown by real-time label-free impedance measurements using the xCELLigence system. GCA-treated cells contained fewer incoming HAdVs than control cells, but GCA treatment boosted HAdV titers and spreading in cancer cells. GCA enhanced viral gene expression or transgene expression from the cytomegalovirus promoter of B- or C-species HAdVs but did not enhance viral early region 1A (E1A) expression in uninfected cell lines or cells transfected with plasmid reporter DNA. The UPR-enhanced cell killing required the nuclease activity of the UPR sensor inositol-requiring enzyme 1 (IRE-1) and X box binding protein 1 (XBP-1), which alleviate ER stress. The collective results show that chemical UPR induction and viruses boost tumor cell killing by enhancing oncolytic viral efficacy.

IMPORTANCE
Cancer is difficult to combat. A wide range of oncolytic viruses show promise for killing cancer cells, yet the efficacy of oncolytic killing is low. We searched for host factors enhancing adenovirus cancer cell killing and found that the knockdown of Golgi-specific brefeldin A-resistant guanine nucleotide exchange factor 1 (GBF-1) or chemical inhibition of GBF-1 enhanced adenovirus infection by triggering the IRE-1/XBP-1 branch of the unfolded protein response (UPR). IRE-1/XBP-1 promote cell survival and enhanced the levels of the adenoviral immediate early gene product E1A, virus spreading, and killing of cancer cells. Aggressive tumor cells depend on a readily inducible UPR and, hence, present prime targets for a combined strategy involving adenoviruses and small chemicals inducing UPR.
Multi-institution case–control and cohort study of risk factors for the development and mortality ofClostridium difficileinfections in Japan
Authors: Takahashi Masahiko , Mori Nobuaki , Bito Seiji 
Published: September 2014

ObjectiveTo examine risk factors forClostridium difficileinfection (CDI) morbidity and mortality in Japan.DesignMultimethod investigation including a case–control study and cohort study.Setting47 participating facilities of the National Hospital Organization (NHO).Participants1026 patients with CDI and 878 patients in the control group over the age of 18 years admitted to the subject NHO facilities from November 2010 to October 2011.Main outcome measuresIn a case–control study, we identify risk factors for CDI development. Next, in a cohort study, we identify risk factors for all-cause mortality within 30 days following CDI onset.ResultsA total of 1026 cases of CDI meeting the definitions of this investigation were identified, encompassing 878 patients at 42 of the 47 subject facilities. In the case–control study, we identified, compared with no antibiotics use, use of first-generation and second-generation cephem antibiotics (OR 1.44; 95% CI 1.10 to 1.87), use of third-generation and fourth-generation cephem antibiotics (OR 1.86; 95% CI 1.48 to 2.33) and use of carbapenem antibiotics (OR 1.87; 95% CI 1.44 to 2.42) the risk factors for CDI development. However, use of penicillin was not identified as a risk factor. In the cohort study, sufficient data for analysis was available for 924 CDI cases; 102 of them (11.0%) resulted in death within 30 days of CDI onset. Compared with no anti-CDI drug use, use of vancomycin was associated with reduced risk of mortality (OR 0.43; 95% CI 0.25 to 0.75) whereas metronidazole was not.ConclusionsThe findings mirror those of previous studies from Europe and North America, identifying the administration of broad-spectrum antibiotics as a risk factor for CDI development. The use of vancomycin is associated with a decreased risk of mortality.
Variation in the recording of common health conditions in routine hospital data: study using linked survey and administrative data in New South Wales, Australia
Authors: Lujic Sanja , Watson Diane E , Randall Deborah A , Simpson Judy M , Jorm Louisa R 
Published: September 2014

ObjectivesTo investigate the nature and potential implications of under-reporting of morbidity information in administrative hospital data.Setting and participantsRetrospective analysis of linked self-report and administrative hospital data for 32 832 participants in the large-scale cohort study (45 and Up Study), who joined the study from 2006 to 2009 and who were admitted to 313 hospitals in New South Wales, Australia, for at least an overnight stay, up to a year prior to study entry.Outcome measuresAgreement between self-report and recording of six morbidities in administrative hospital data, and between-hospital variation and predictors of positive agreement between the two data sources.ResultsAgreement between data sources was good for diabetes (κ=0.79); moderate for smoking (κ=0.59); fair for heart disease, stroke and hypertension (κ=0.40, κ=0.30 and κ =0.24, respectively); and poor for obesity (κ=0.09), indicating that a large number of individuals with self-reported morbidities did not have a corresponding diagnosis coded in their hospital records. Significant between-hospital variation was found (ranging from 8% of unexplained variation for diabetes to 22% for heart disease), with higher agreement in public and large hospitals, and hospitals with greater depth of coding.ConclusionsThe recording of six common health conditions in administrative hospital data is highly variable, and for some conditions, very poor. To support more valid performance comparisons, it is important to stratify or control for factors that predict the completeness of recording, including hospital depth of coding and hospital type (public/private), and to increase efforts to standardise recording across hospitals. Studies using these conditions for risk adjustment should also be cautious of their use in smaller hospitals.
Assessing the effectiveness of 3 months day and night home closed-loop insulin delivery in adults with suboptimally controlled type 1 diabetes: a randomised crossover study protocol
Authors: Leelarathna Lalantha , Dellweg Sibylle , Mader Julia K , Barnard Katharine , Benesch Carsten , Ellmerer Martin , Heinemann Lutz , Kojzar Harald , Thabit Hood , Wilinska Malgorzata E , Wysocki Tim , Pieber Thomas R , Arnolds Sabine , Evans Mark L , Hovorka Roman 
Published: September 2014

IntroductionDespite therapeutic advances, many people with type 1 diabetes are still unable to achieve optimal glycaemic control, limited by the occurrence of hypoglycaemia. The objective of the present study is to determine the effectiveness of day and night home closed-loop over the medium term compared with sensor-augmented pump therapy in adults with type 1 diabetes and suboptimal glycaemic control.Methods and analysisThe study will adopt an open label, three-centre, multinational, randomised, two-period crossover study design comparing automated closed-loop glucose control with sensor augmented insulin pump therapy. The study will aim for 30 completed participants. Eligible participants will be adults (≥18 years) with type 1 diabetes treated with insulin pump therapy and suboptimal glycaemic control (glycated haemoglobin (HbA1c) ≥7.5% (58 mmol/mmol) and ≤10% (86 mmol/mmol)). Following a 4-week optimisation period, participants will undergo a 3-month use of automated closed-loop insulin delivery and sensor-augmented pump therapy, with a 4–6 week washout period in between. The order of the interventions will be random. All analysis will be conducted on an intention to treat basis. The primary outcome is the time spent in the target glucose range from 3.9 to 10.0 mmol/L based on continuous glucose monitoring levels during the 3 months free living phase. Secondary outcomes include HbA1c changes; mean glucose and time spent above and below target glucose levels. Further, participants will be invited at baseline, midpoint and study end to participate in semistructured interviews and complete questionnaires to explore usability and acceptance of the technology, impact on quality of life and fear of hypoglycaemia.Ethics and disseminationEthical approval has been obtained at all sites. Before screening, all participants will be provided with oral and written information about the trial. The study will be disseminated by peer-review publications and conference presentations.Trial registration numberNCT01961622 (ClinicalTrials.gov).
Little nippers
Authors: Roger Paul 
Published: September 2014

THIS series gives readers the opportunity to consider and contribute to discussion of some of the ethical dilemmas that can arise in veterinary practice. Each month, a case scenario is presented, followed by discussion of some of the issues involved.In addition, a possible way forward is suggested; however, there is rarely a cut‐and‐dried answer in such cases, and readers may wish to suggest an alternative approach. This month's dilemma, ‘Little nippers’, was submitted and is discussed by Paul Roger. Readers with comments to contribute are invited to send them as soon as possible, so that they can be considered for publication in the next issue. Discussion of the dilemma ‘Follow‐up fiasco’, which was published in the July/August issue of In Practice, appears on page 431.The series is being coordinated by Siobhan Mullan, of the University of Bristol. It is hoped it will provide a framework that will help practices find solutions when facing similar dilemmas.
Reduced cerebrovascular reserve is associated with an increased risk of postoperative ischemic lesions during carotid artery stenting
Authors: Koyanagi Masaomi , Yoshida Kazumichi , Kurosaki Yoshitaka , Sadamasa Nobutake , Narumi Osamu , Sato Tsukasa , Chin Masaki , Handa Akira , Yamagata Sen , Miyamoto Susumu 
Published: September 2014

BackgroundReduced cerebrovascular reserve (CVR) is associated with increased risk of ischemic events in carotid steno-occlusive diseases.ObjectiveTo determine whether pretreatment CVR can predict postoperative ischemic lesions after carotid artery stenting (CAS) by retrospective analysis.MethodsWe retrospectively reviewed the medical records of 46 patients (42 men; mean age 74.2±8.3 years) who underwent CAS and preprocedural cerebral blood flow measurement by quantitative single-photon emission CT. Ischemic lesions were evaluated by diffusion-weighted image (DWI) within 72 h after the intervention. We also evaluated plaque characteristics using black-blood MR plaque imaging.ResultsNew ipsilateral DWI-positive lesions were found in 11 cases (23.9%). Patients were classified into two groups based on the presence or absence of new DWI-positive lesions, and no significant differences in characteristics were found between the DWI-positive and DWI-negative groups, except for age and CVR of the ipsilateral middle cerebral artery (MCA) territory. The DWI-positive group was significantly older than the DWI-negative group (79.7±4.1 vs 72.5±8.6 years; p=0.0085) and had lower average regional CVR (1.4±18.2% vs 22.4±25.8%; p=0.016). MR plaque imaging showed no significant difference in relative overall plaque MR signal intensity between the two groups (1.53±0.37 vs 1.34±0.26; p=0.113). In multivariate logistic regression analysis, lower CVR of the ipsilateral MCA territory (<11%) was the only independent risk factor for new ischemic lesions following CAS (OR=6.99; 95% CI 1.17 to 41.80; p=0.033).ConclusionsImpaired pretreatment CVR was associated with increased incidence of new infarction after CAS.
Diagnostic angiography skill acquisition with a secondary curve catheter: phase 2 of a curriculum-based endovascular simulation program
Authors: Spiotta Alejandro M , Kellogg Ryan T , Vargas Jan , Chaudry M Imran , Turk Aquilla S , Turner Raymond D 
Published: September 2014

BackgroundWe have previously reported the efficacy of a simulator-based training paradigm for residents in neurosurgery with little or no prior experience in diagnostic cerebral angiography with straightfoward arch anatomy. This study investigates the utility of a simulation-based training curriculum for the acquisition of skills employing a secondary curve catheter to navigate more complex arch anatomy.MethodsResidents at the Medical University of South Carolina (MUSC) with moderate exposure to diagnostic angiography enrolled into a standardized Institutional Review Board-approved training protocol using SimSuite Compass and Simbionix simulators. The task involved (in order) forming the Simmons catheter in the left subclavian artery and then selecting the brachiocephalic, left common carotid and left vertebral arteries.ResultsAll participants improved their total time to complete the task over the course from the first to last trial. Each milestone within the overall task also demonstrated an improvement across trials for each participant. Following the hands-on experience, participants’ rating of their knowledge of arch anatomy and vessel selection technique improved to that between competence and high competence (values of 3.3±0.49 (p<0.005) and 3.1±0.38 (p<0.01), respectively). Comfort with use of the Simmons catheter improved to a value of 2.9±0.38 (p<0.001), between an experienced learner and competence. Participants rated the usefulness of the training environment as very high (4.1±0.90 out of maximum 5).ConclusionsResidents became more proficient at vessel selection in a type II and bovine arch over a relatively compressed time period, with both objective and subjective data demonstrating acquisition of skill sets and increased confidence.
Imaging and management of greater trochanteric pain syndrome
Authors: Chowdhury Rajat , Naaseri Sahar , Lee Justin , Rajeswaran Gajan 
Published: September 2014

Abstract
Greater trochanteric pain syndrome (GTPS) is a commonly diagnosed regional pain syndrome with a wide spectrum of aetiologies, reflecting the anatomy of the structures outside the hip joint capsule. There are five muscle tendons that insert on to the greater trochanter and three bursae in the region of the greater trochanter. The term GTPS includes tendinopathies, tendinous tears, bursal inflammation and effusion. There are a range of treatments and therapies depending on the specific diagnosis and severity of the condition. Many patients with GTPS can be successfully managed conservatively with weight loss and non-steroidal anti-inflammatory drugs. Patients suffering from more chronic pain can receive varying degrees of symptomatic relief with lateral hip corticosteroid and local anaesthetic injections. More severe refractory cases of GTPS can be treated with surgical intervention. It is therefore important to make the correct diagnosis to ensure that appropriate management can be implemented. The clinical features of GTPS however are often non-specific because common conditions such as lumbar radicular pain and hip joint osteoarthritis can present with an almost identical form of lateral hip pain. The various diagnostic imaging modalities have particular strengths and weaknesses with ultrasound being the best first-line investigation due to its availability, low cost, dynamic nature and ability to guide treatments such as steroid injections. MRI can be very helpful in the further investigation of patients in whom there is diagnostic uncertainty as to the cause of lateral hip pain and in whom specialist orthopaedic referral is being considered.
Oxidation processes and their effects on the magnetic remanence of Early Cretaceous subaerial basalts from Sierra Chica de Córdoba, Argentina
Authors: Geuna S. E. , Lagorio S. L. , Vizán H. 
Published: September 2014

Abstract

We carried out magnetic analyses on a sequence of Cretaceous alkaline–transitional subaerial basalts of Córdoba Province, Argentina, which have high-Ti magnetite as the main opaque phase. Three different groups are identified based on the degree of high-temperature oxidation during the lava extrusion, combined with superimposed maghemitization and hematization. In the first group, titanomagnetites are optically homogeneous or exhibit coarse intergrowths with ilmenite. The magnetic susceptibility and its variation with temperature and magnetic field point to Ti-poorer compositions than those indicated by electron microprobe, which is interpreted as due to low-temperature oxidation with subsolvus microexsolution. The second group of basalts suffered moderate high-temperature oxidation, with crowded exsolved ilmenite laths within a Ti-poor magnetite
ss
host, followed by maghemitization and hematite replacement. The third group shows a strongly advanced degree of low-temperature alteration, with the virtual disappearance of magnetite. Based on magnetic properties and field tests applied to the magnetic remanence, we interpret that maghemitization and hematization must have been responsible for the acquisition of a stable magnetic remanence, in the presence of hydrothermal fluids coeval with volcanism. The most advanced degree of alteration, typical of highly porous amygdaloidal lava flows and volcanic breccias, occurred later, probably due to weathering.