bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcription of the Herpes Simplex Virus 1 Genome during Productive and Quiescent Infection of Neuronal and Nonneuronal Cells
Authors: Harkness Justine M. , Kader Muhamuda , DeLuca Neal A. 
Published: April 2014

ABSTRACT

Herpes simplex virus 1 (HSV-1) can undergo a productive infection in nonneuronal and neuronal cells such that the genes of the virus are transcribed in an ordered cascade. HSV-1 can also establish a more quiescent or latent infection in peripheral neurons, where gene expression is substantially reduced relative to that in productive infection. HSV mutants defective in multiple immediate early (IE) gene functions are highly defective for later gene expression and model some aspects of latency
in vivo
. We compared the expression of wild-type (wt) virus and IE gene mutants in nonneuronal cells (MRC5) and adult murine trigeminal ganglion (TG) neurons using the Illumina platform for cDNA sequencing (RNA-seq). RNA-seq analysis of wild-type virus revealed that expression of the genome mostly followed the previously established kinetics, validating the method, while highlighting variations in gene expression within individual kinetic classes. The accumulation of immediate early transcripts differed between MRC5 cells and neurons, with a greater abundance in neurons. Analysis of a mutant defective in all five IE genes (d109) showed dysregulated genome-wide low-level transcription that was more highly attenuated in MRC5 cells than in TG neurons. Furthermore, a subset of genes in d109 was more abundantly expressed over time in neurons. While the majority of the viral genome became relatively quiescent, the latency-associated transcript was specifically upregulated. Unexpectedly, other genes within repeat regions of the genome, as well as the unique genes just adjacent the repeat regions, also remained relatively active in neurons. The relative permissiveness of TG neurons to viral gene expression near the joint region is likely significant during the establishment and reactivation of latency.

IMPORTANCE
During productive infection, the genes of HSV-1 are transcribed in an ordered cascade. HSV can also establish a more quiescent or latent infection in peripheral neurons. HSV mutants defective in multiple immediate early (IE) genes establish a quiescent infection that models aspects of latency
in vivo
. We simultaneously quantified the expression of all the HSV genes in nonneuronal and neuronal cells by RNA-seq analysis. The results for productive infection shed further light on the nature of genes and promoters of different kinetic classes. In quiescent infection, there was greater transcription across the genome in neurons than in nonneuronal cells. In particular, the transcription of the latency-associated transcript (LAT), IE genes, and genes in the unique regions adjacent to the repeats persisted in neurons. The relative activity of this region of the genome in the absence of viral activators suggests a more dynamic state for quiescent genomes persisting in neurons.
Shaky drawing: what is the rate of decline during prospective follow-up of essential tremor?
Authors: Louis Elan D , Michalec Monica , Gillman Art 
Published: April 2014

ObjectiveFew studies have attempted to estimate the rate of decline over time in essential tremor (ET). The study objectives were to: (1) measure change, deriving a single summary measure for the entire group, and relate it to a commonly used clinical rating scale (ie, yearly change in points on that scale); (2) to assess change as a function of baseline clinical characteristics and (3) to answer the basic clinical question—is change perceptible/obvious during the follow-up of ET cases?SettingProspective collection of longitudinal data on ET cases enrolled in a study of the environmental epidemiology of ET at Columbia University Medical Center (2000–2008).Participants116 unselected ET cases.InterventionsEach case underwent the same evaluation at baseline and during one follow-up visit (mean follow-up interval (range)=5.8 (1.4–12.4) years).Primary and secondary outcome measuresWe assessed tremor during a commonly affected daily activity—drawing (ie, spirography), quantifying tremor using a simple, standardised 10-point rating scale developed by Bain and Findley.ResultsThe Bain and Findley spiral score increased at an average rate of 0.12±0.23 points per year (maximum=1 point/year). In cases who had been followed for ≥5 years, the change was obvious—a blinded neurologist was able to correctly order their spirals (baseline vs follow-up) in three-fourth of cases. The rate of change was higher in cases with versus without familial ET (p=0.01).ConclusionsTremor in ET is slowly progressive; yet in the majority of cases, a clear difference in handwritten spirals was visible with a follow-up interval of five or more years. There may be differences between familial and non-familial ET in the rate of progression. These clinical data are intended to aid in the prognostic discussions that treating physicians have with their patients with ET.
Intervention Now To Eliminate Repeat Unintended Pregnancy in Teenagers (INTERUPT): a systematic review of intervention effectiveness and cost-effectiveness, qualitative and realist synthesis of implementation factors and user engagement
Authors: Whitaker Rh , Hendry M , Booth A , Carter B , Charles J , Craine N , Edwards R T , Lyons M , Noyes J , Pasterfield D , Rycroft-Malone J , Williams N 
Published: April 2014

BackgroundThe UK has the highest rate of teenage pregnancies in Western Europe, a fifth are repeat pregnancies. Unintended conceptions can result in emotional, psychological and educational harm to teenage girls, often with enduring implications for their life chances. Babies of teenage mothers have increased mortality in their first year and increased risk of poverty, educational underachievement and unemployment later in life, with associated societal costs.Methods and analysisWe will conduct a streamed, mixed-methods systematic review to find and evaluate interventions designed to reduce repeat unintended teen pregnancies.Our aims are to identify Who is at greater risk of repeat unintended pregnancies? Which interventions are effective, cost-effective, how they work, in what setting and for whom? What are the barriers and facilitators to intervention uptake? Traditional electronic database searches will be augmented by targeted searches for evidence ‘clusters’ and guided by an advisory group of experts and stakeholders. To address the topic's inherent complexities, we will use a highly structured, innovative and iterative approach combining methodological techniques tailored to each stream of evidence. Quantitative data will be synthesised with reference to Cochrane guidelines for public health interventions. Qualitative evidence addressing facilitators and barriers to the uptake of interventions, experience and acceptability of interventions will be synthesised thematically. We will apply the principles of realist synthesis to uncover theories and mechanisms underpinning interventions. We will conduct an integration and overarching narrative of findings authenticated by client group feedback.Ethics and disseminationWe will publish the complete review in ‘Health Technology Assessment’ and sections in specialist peer-reviewed journals. We will present at national and international conferences in the fields of public health, reproductive medicine and review methodology. Findings will be fed back to service users and practitioners via workshops run by the partner collaborators.Trail registration numberPROSPERO CRD42012003168.Cochrane registration numberi=fertility/0068.
Tailoring platelet inhibition according to multiple electrode aggregometry decreases the rate of thrombotic complications after intracranial flow-diverting stent implantation
Authors: Oran Ismail , Cinar Celal , Bozkaya Halil , Korkmaz Mehmet 
Published: April 2014

Background and purposePretreatment with dual antiaggregant drugs is accepted as a standard step in intracranial stent implantation. The aim of this study was to determine whether tailored antiaggregant medication based on platelet reactivity testing with multiple electrode aggregometry (Multiplate) yields superior outcomes after intracranial flow-diverting stent (FDS) implantation compared with standard clopidogrel treatment.MethodsWe retrospectively analyzed the following data from 100 consecutive patients: endovascular procedure characteristics, antiaggregant medications, procedural variables, and perioperative complications after FDS implantation for intracranial aneurysm. Patients were divided into two groups: uniform treatment with clopidogrel (untailored, early phase) and tailored treatment based on the results of aggregometry (late phase). Statistical comparisons included the Fisher exact test to compare categorical variables between the standard and aggregometry groups and the Mann–Whitney U test to compare ADP test values within the aggregometry group between groups receiving tailored or untailored treatment.ResultsIn the aggregometry group (68 patients, 71 procedures) there were 17 (25%) clopidogrel-resistant patients, according to a cut-off value of 468 area under the aggregation curve; 12 underwent FDS implantation under tailored antiaggregant medication. In the standard treatment group (32 patients, 33 procedures) there were 3 (9.1%) spontaneous thrombotic events and 1 (3.3%) technical hemorrhagic complication. In the aggregometry group there were 2 (2.8%) spontaneous hemorrhagic events and 1 (1.4%) technical ischemic complication. In the aggregometry group, thrombotic complications and morbidity were lower than in the standard (no test) group (p<0.03).ConclusionsTailoring platelet reactivity according to multiple electrode aggregometry decreases the rate of thrombotic complications after intracranial FDS implantation.
Modifying flow in the ACA–ACoA complex: endovascular treatment option for wide-neck internal carotid artery bifurcation aneurysms
Authors: Nossek Erez , Chalif David J , Levine Mitchell , Setton Avi 
Published: April 2014

BackgroundTreatment of selected wide-neck internal carotid artery (ICA) bifurcation aneurysms remains challenging for clip reconstruction and for endovascular options.ObjectiveTo describe a new endovascular treatment technique for wide-neck ICA bifurcation (ICAb) aneurysms.MethodsWe have employed a treatment approach that uses both complete proximal occlusion and reversal of flow in the ipsilateral A1 segment, using different endovascular modalities such as coils, stent-assisted coiling, or flow diverters (FDs) plus coiling concomitantly. This endovascular technique may overcome the challenges of current treatments and high recanalization rates for coiled ICAb aneurysms.ResultsWe treated four patients in whom we redirected the pre-existing flow in the supraclinoid ICA into the ipsilateral A1 and M1 segments, to a new unilateral, linear flow from the supraclinoid ICA solely into the ipsilateral M1 segment. This resulted in the establishment of flow from the contralateral A1 segment into the ipsilateral A1 segment, allowing supply of only demanding perforating arteries on this specific (ipsilateral) segment. This technique was not associated with any new neurological deficits or radiographic ischemia. The four patients reviewed were all treated using coils. One was treated with a standard stent. The other two were treated with a FD.ConclusionsWe found that the proposed technique of flow modification can allow for hemodynamic conversion of ICAb to ‘side-wall’ aneurysm. In patients with good collateral flow through the anterior communicating complex, this treatment paradigm is safe and effective.
Serum Immunoglobulin E and Risk of Pancreatic Cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial
Authors: Olson Sara H. , Hsu Meier , Wiemels Joseph L. , Bracci Paige M. , Zhou Mi , Patoka Joseph , Reisacher William R. , Wang Julie , Kurtz Robert C. , Silverman Debra T. , Stolzenberg-Solomon Rachael Z. 
Published: April 2014

Abstract
Epidemiologic studies have consistently found that self-reported allergies are associated with reduced risk of pancreatic cancer. Our aim was to prospectively assess the relationship between serum immunoglobulin E (IgE), a marker of allergy, and risk. This nested case–control study within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) included subjects enrolled in 1994 to 2001 and followed through 2010. There were 283 cases of pancreatic cancer and 544 controls matched on age, gender, race, and calendar date of blood draw. Using the ImmunoCAP system, we measured total IgE (normal, borderline, elevated), IgE to respiratory allergens, and IgE to food allergens (negative or positive) in serum collected at baseline. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression. We assessed interactions with age, gender, smoking, body mass index, and time between randomization and case diagnosis. Overall, there was no association between the IgE measures and risk. We found a statistically significant interaction by baseline age: in those aged ≥65 years, elevated risks were observed for borderline total IgE (OR, 1.43; 95% CI, 0.88–2.32) and elevated total IgE (OR, 1.98; 95% CI, 1.16–3.37) and positive IgE to food allergens (OR, 2.83; 95% CI, 1.29–6.20); among participants &lt;65 years, ORs were &lt;1. Other interactions were not statistically significant. The reduced risk of pancreatic cancer associated with self-reported allergies is not reflected in serum IgE. Cancer Epidemiol Biomarkers Prev; 23(7); 1414–20. ©2014 AACR.
Autophagy Inhibition Augments the Anticancer Effects of Epirubicin Treatment in Anthracycline-Sensitive and -Resistant Triple-Negative Breast Cancer
Authors: Chittaranjan Suganthi , Bortnik Svetlana , Dragowska Wieslawa H. , Xu Jing , Abeysundara Namal , Leung Amy , Go Nancy E. , DeVorkin Lindsay , Weppler Sherry A. , Gelmon Karen , Yapp Donald T. , Bally Marcel B. , Gorski Sharon M. 
Published: April 2014

Abstract
Purpose: Triple-negative breast cancers (TNBC) are defined by a lack of expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (ERBB2/HER2). Although initially responsive to chemotherapy, most recurrent TNBCs develop resistance, resulting in disease progression. Autophagy is a lysosome-mediated degradation and recycling process that can function as an adaptive survival response during chemotherapy and contribute to chemoresistance. Our goal was to determine whether autophagy inhibition improves treatment efficacy in TNBC cells in tumors either sensitive or refractory to anthracyclines.
Experimental Design: We used in vitro and in vivo models of TNBC using cell lines sensitive to epirubicin and other anthracyclines, as well as derivative lines, resistant to the same drugs. We assessed basal autophagy levels and the effects of chemotherapy on autophagy in parental and resistant cells. Applying various approaches to inhibit autophagy alone and in combination with chemotherapy, we assessed the effects on cell viability in vitro and tumor growth rates in vivo.
Results: We demonstrated that epirubicin induced autophagic flux in TNBC cells. Epirubicin-resistant lines exhibited at least 1.5-fold increased basal autophagy levels and, when treated with autophagy inhibitors, showed a significant loss in viability, indicating dependence of resistant cells on autophagy for survival. Combination of epirubicin with the autophagy inhibitor hydroxychloroquine resulted in a significant reduction in tumor growth compared with monotherapy with epirubicin.
Conclusion: Autophagy inhibition enhances therapeutic response in both anthracycline-sensitive and -resistant TNBC and may be an effective new treatment strategy for this disease. Clin Cancer Res; 20(12); 3159–73. ©2014 AACR.
Immunotherapy for Hepatoma Using a Dual-Function Vector with Both Immunostimulatory and Pim-3–Silencing Effects
Authors: Guo Qie , Lan Peixiang , Yu Xin , Han Qiuju , Zhang Jian , Tian Zhigang , Zhang Cai 
Published: April 2014

Abstract
Tumorigenesis is an immortalization process in which the growth of normal cells is uncontrolled and programmed cell death is suppressed. Molecular biologic and immunologic studies have revealed that the aberrant expression of some proto-oncogenes boosts proliferation and inhibits apoptosis, which is vital for tumor development. The hypofunction of the host immune system also drives the development and metastasis of malignant tumors. Pim-3, a member of the Pim family, is aberrantly expressed in several cancers. Data suggest that Pim-3 inhibits apoptosis by phosphorylating the proapoptotic BH3-only protein Bad. Here, we constructed a dual-function small hairpin RNA (shRNA) vector containing an shRNA targeting Pim-3 and a TLR7-stimulating ssRNA. Stimulation with this bi-functional vector in vitro promoted significant apoptosis of Hepa1-6 cells by regulating the expression of apoptosis-related proteins and induced secretion of type I IFNs. Most importantly, this bi-functional vector more effectively inhibited subcutaneous Hepa1-6 cell growth than did single shRNA and ssRNA treatment in vivo. Natural killer (NK), CD4+ T, and CD8+ T cells and macrophages were required for effective tumor suppression, and CD4+ T cells were shown to play a helper role in the activation of NK cells, possibly by regulating the secretion of Th1 or Th2 cytokines. This ssRNA–shRNA bi-functional vector may represent a promising approach for tumor therapy. Mol Cancer Ther; 13(6); 1503–13. ©2014 AACR.
N
ε
-(Carboxymethyl)lysine-Receptor for Advanced Glycation End Product Axis Is a Key Modulator of Obesity-Induced Dysregulation of Adipokine Expression and Insulin Resistance
Authors: Gaens Katrien H.J. , Goossens Gijs H. , Niessen Petra M. , van Greevenbroek Marleen M. , van der Kallen Carla J.H. , Niessen Hans W. , Rensen Sander S. , Buurman Wim A. , Greve Jan Willem M. , Blaak Ellen E. , van Zandvoort Marc A. , Bierhaus Angelika , Stehouwer Coen D.A. , Schalkwijk Casper G. 
Published: April 2014

Objective—

Dysregulation of inflammatory adipokines by the adipose tissue plays an important role in obesity-associated insulin resistance. Pathways leading to this dysregulation remain largely unknown. We hypothesized that the receptor for advanced glycation end products (RAGE) and the ligand N
ε
-(carboxymethyl)lysine (CML) are increased in adipose tissue and, moreover, that activation of the CML–RAGE axis plays an important role in obesity-associated inflammation and insulin resistance.

Approach and Results—

In this study, we observed a strong CML accumulation and increased expression of RAGE in adipose tissue in obesity. We confirmed in cultured human preadipocytes that adipogenesis is associated with increased levels of CML and RAGE. Moreover, CML induced a dysregulation of inflammatory adipokines in adipocytes via a RAGE-dependent pathway. To test the role of RAGE in obesity-associated inflammation further, we constructed an obese mouse model that is deficient for RAGE (ie, RAGE
–/–
/Leptr
Db–/–
mice). RAGE
–/–
/Leptr
Db–/–
mice displayed an improved inflammatory profile and glucose homeostasis when compared with RAGE
+/+
/Leptr
Db–/–
mice. In addition, CML was trapped in adipose tissue in RAGE
+/+
/Leptr
Db–/–
mice but not in RAGE
–/–
/Leptr
Db–/–
. RAGE-mediated trapping in adipose tissue provides a mechanism underlying CML accumulation in adipose tissue and explaining decreased CML plasma levels in obese subjects. Decreased CML plasma levels in obese individuals were strongly associated with insulin resistance.

Conclusions—
RAGE-mediated CML accumulation in adipose tissue and the activation of the CML–RAGE axis are important mechanisms involved in the dysregulation of adipokines in obesity, thereby contributing to the development of obesity-associated insulin resistance.
Fibrin-Targeted Magnetic Resonance Imaging Allows In Vivo Quantification of Thrombus Fibrin Content and Identifies Thrombi Amenable for Thrombolysis
Authors: Andia Marcelo E. , Saha Prakash , Jenkins Julia , Modarai Bijan , Wiethoff Andrea J. , Phinikaridou Alkystis , Grover Steven P. , Patel Ashish S. , Schaeffter Tobias , Smith Alberto , Botnar Rene M. 
Published: April 2014

Objective—
Deep venous thrombosis is a major health problem. Thrombolytic therapies are effective in recanalizing the veins and preventing post-thrombotic complications, but there is no consensus on selection criteria. The aim of this study was to investigate a fibrin-specific MRI contrast agent (EP-2104R) for the accurate quantification of thrombus’ fibrin content in vivo and for the identification of thrombus suitable for thrombolysis.

Approach and Results—

Venous thrombosis was induced in the inferior vena cava of 8- to 10-week-old male BALB/C mice and MRI performed 2, 4, 7, 10, 14, and 21 days later. Eighteen mice were scanned at each time point pre and 2 hours post injection of EP-2104R (8.0 μmol/kg) with 12 mice at each time point used to correlate fibrin contrast uptake with thrombus’ histological stage and fibrin content. Six mice at each time point were immediately subjected to intravascular thrombolytic therapy (10 mg/kg of tissue-type plasminogen activator). Mice were imaged to assess response to lytic therapy 24 hours after thrombolytic treatment. Two mice at each time point were scanned post injection of 0.2 mmol/kg of Gd-DTPA (gadolinium with diethylenetriaminepentacetate, Magnevist, Schering AG, Berlin, Germany) for control purpose. Contrast uptake was correlated positively with the fibrin content of the thrombus measured by Western blotting (
R
2
=0.889;
P
<0.001). Thrombus relaxation rate (
R
1
) post contrast and the change in visualized thrombus size on late gadolinium enhancement inversion recovery MRI pre–EP-2104R and post–EP-2104R injection were the best predictors for successful thrombolysis (area under the curve, 0.989 [95% confidence interval, 0.97–1.00] and 0.994 [95% confidence interval, 0.98–1.00] respectively).

Conclusions—
MRI with a fibrin-specific contrast agent accurately estimates thrombus fibrin content in vivo and identifies thrombi that are amenable for thrombolysis.