bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel Mechanism of MDA-7/IL-24 Cancer-Specific Apoptosis through SARI Induction
Authors: Dash Rupesh , Bhoopathi Praveen , Das Swadesh K. , Sarkar Siddik , Emdad Luni , Dasgupta Santanu , Sarkar Devanand , Fisher Paul B. 
Published: November 2013

Abstract
Subtraction hybridization combined with induction of cancer cell terminal differentiation in human melanoma cells identified melanoma differentiation–associated gene-7/interleukin-24 (mda-7/IL-24) and SARI (suppressor of AP-1, induced by IFN) that display potent antitumor activity. These genes are not constitutively expressed in cancer cells and forced expression of mda-7/IL-24 (Ad.mda-7) or SARI (Ad.SARI) promotes cancer-specific cell death. Ectopic expression of mda-7/IL-24 induces SARI mRNA and protein in a panel of different cancer cells, leading to cell death, without harming corresponding normal cells. Simultaneous inhibition of K-ras downstream extracellular signal-regulated kinase 1/2 signaling in pancreatic cancer cells reverses the translational block of MDA-7/IL-24 and induces SARI expression and cell death. Using SARI-antisense-based approaches, we demonstrate that SARI expression is necessary for mda-7/IL-24 antitumor effects. Secreted MDA-7/IL-24 protein induces antitumor “bystander” effects by promoting its own expression. Recombinant MDA-7/IL-24 (His-MDA-7) induces SARI expression, supporting the involvement of SARI in the MDA-7/IL-24-driven autocrine loop, culminating in antitumor effects. Moreover, His-MDA-7, after binding to its cognate receptors (IL-20R1/IL-20R2 or IL-22R/IL-20R2), induces intracellular signaling by phosphorylation of p38 MAPK, leading to transcription of a family of growth arrest and DNA damage inducible (GADD) genes, culminating in apoptosis. Inhibition of p38 MAPK fails to induce SARI following Ad.mda-7 infection. These findings reveal the significance of the mda-7/IL-24-SARI axis in cancer-specific killing and provide a potential strategy for treating both local and metastatic disease. Cancer Res; 74(2); 563–74. ©2013 AACR.
MM-141, an IGF-IR– and ErbB3-Directed Bispecific Antibody, Overcomes Network Adaptations That Limit Activity of IGF-IR Inhibitors
Authors: Fitzgerald Jonathan B. , Johnson Bryan W. , Baum Jason , Adams Sharlene , Iadevaia Sergio , Tang Jian , Rimkunas Victoria , Xu Lihui , Kohli Neeraj , Rennard Rachel , Razlog Maja , Jiao Yang , Harms Brian D. , Olivier Kenneth J. , Schoeberl Birgit , Nielsen Ulrik B. , Lugovskoy Alexey A. 
Published: November 2013

Abstract
Although inhibition of the insulin-like growth factor (IGF) signaling pathway was expected to eliminate a key resistance mechanism for EGF receptor (EGFR)-driven cancers, the effectiveness of IGF-I receptor (IGF-IR) inhibitors in clinical trials has been limited. A multiplicity of survival mechanisms are available to cancer cells. Both IGF-IR and the ErbB3 receptor activate the PI3K/AKT/mTOR axis, but ErbB3 has only recently been pursued as a therapeutic target. We show that coactivation of the ErbB3 pathway is prevalent in a majority of cell lines responsive to IGF ligands and antagonizes IGF-IR–mediated growth inhibition. Blockade of the redundant IGF-IR and ErbB3 survival pathways and downstream resistance mechanisms was achieved with MM-141, a tetravalent bispecific antibody antagonist of IGF-IR and ErbB3. MM-141 potency was superior to monospecific and combination antibody therapies and was insensitive to variation in the ratio of IGF-IR and ErbB3 receptors. MM-141 enhanced the biologic impact of receptor inhibition in vivo as a monotherapy and in combination with the mTOR inhibitor everolimus, gemcitabine, or docetaxel, through blockade of IGF-IR and ErbB3 signaling and prevention of PI3K/AKT/mTOR network adaptation. Mol Cancer Ther; 13(2); 410–25. ©2013 AACR.
Selective Inhibition of Pancreatic Ductal Adenocarcinoma Cell Growth by the Mitotic MPS1 Kinase Inhibitor NMS-P715
Authors: Slee Roger B. , Grimes Brenda R. , Bansal Ruchi , Gore Jesse , Blackburn Corinne , Brown Lyndsey , Gasaway Rachel , Jeong Jaesik , Victorino Jose , March Keith L. , Colombo Riccardo , Herbert Brittney-Shea , Korc Murray 
Published: November 2013

Abstract
Most solid tumors, including pancreatic ductal adenocarcinoma (PDAC), exhibit structural and numerical chromosome instability (CIN). Although often implicated as a driver of tumor progression and drug resistance, CIN also reduces cell fitness and poses a vulnerability that can be exploited therapeutically. The spindle assembly checkpoint (SAC) ensures correct chromosome-microtubule attachment, thereby minimizing chromosome segregation errors. Many tumors exhibit upregulation of SAC components such as MPS1, which may help contain CIN within survivable limits. Prior studies showed that MPS1 inhibition with the small molecule NMS-P715 limits tumor growth in xenograft models. In cancer cell lines, NMS-P715 causes cell death associated with impaired SAC function and increased chromosome missegregation. Although normal cells appeared more resistant, effects on stem cells, which are the dose-limiting toxicity of most chemotherapeutics, were not examined. Elevated expression of 70 genes (CIN70), including MPS1, provides a surrogate measure of CIN and predicts poor patient survival in multiple tumor types. Our new findings show that the degree of CIN70 upregulation varies considerably among PDAC tumors, with higher CIN70 gene expression predictive of poor outcome. We identified a 25 gene subset (PDAC CIN25) whose overexpression was most strongly correlated with poor survival and included MPS1. In vitro, growth of human and murine PDAC cells is inhibited by NMS-P715 treatment, whereas adipose-derived human mesenchymal stem cells are relatively resistant and maintain chromosome stability upon exposure to NMS-P715. These studies suggest that NMS-P715 could have a favorable therapeutic index and warrant further investigation of MPS1 inhibition as a new PDAC treatment strategy. Mol Cancer Ther; 13(2); 307–15. ©2013 AACR.
Prevalence, Factors Associated With, and Prognostic Effects of Preoperative Anemia on Short- and Long-Term Mortality in Patients Undergoing Transcatheter Aortic Valve Implantation
Authors: Nuis Rutger-Jan , Sinning Jan-Malte , Rodés-Cabau Josep , Gotzmann Michael , van Garsse Leen , Kefer Joelle , Bosmans Johan , Yong Gerald , Dager Antonio E. , Revilla-Orodea Ana , Urena Marina , Nickenig Georg , Werner Nikos , Maessen Jos , Astarci Parla , Perez Sergio , Benitez Luis M. , Amat-Santos Ignacio J. , López Javier , Dumont Eric , van Mieghem Nicolas , van Gelder Teun , van Domburg Ron T. , de Jaegere Peter P. 
Published: November 2013

Background—
There is scant information on the prevalence and factors associated with preoperative anemia in patients undergoing transcatheter aortic valve implantation (TAVI) and whether it is associated with mortality. We sought to determine the prevalence and factors associated with preoperative anemia in addition to the prognostic effects of the various levels of preoperative hemoglobin level on mortality in patients undergoing TAVI.

Methods and Results—

Ten-center observational study encompassing 1696 patients with aortic stenosis who underwent TAVI was conducted. Anemia was defined by the World Health Organization criteria (hemoglobin <12.0 g/dL in women and <13.0 g/dL in men). The prevalence of preoperative anemia was 57%. Patient-related factors associated with preoperative anemia were (descending order of odds ratio [95% confidence interval]) as follows: anemia-related medication (4.90 [3.08–7.80]), history of heart failure (1.77 [1.43–2.20]), male sex (1.69 [1.32–2.16]), mitral regurgitation grade ≥III (1.61 [1.15–2.25]), history of malignancy (1.44 [1.03–2.09]), and peripheral vascular disease (1.33 [1.04–1.70]). The creatinine clearance was inversely associated with preoperative anemia (odds ratio, 0.92 [0.87–0.97]). In multivariable analyses, preoperative anemia was not associated with 30-day mortality (1.72 [0.96–3.12];
P
=0.073) but showed the strongest association with 1-year mortality with a hazard ratio (95% confidence interval) of 2.78 (1.60–4.82) in patients with hemoglobin <10 g/dL. Patients with anemia received ≥1 blood transfusion 2× more often, but the indication of transfusion was unrelated to overt bleeding in 60%. Blood transfusion was associated with mortality at 30 days (odds ratio, 1.25 [95% confidence interval, 1.08–3.67]) and during follow-up (hazard ratio, 1.09 [95% confidence interval, 1.03–1.14]).

Conclusions—
Preoperative anemia is prevalent in >50% of patients undergoing TAVI. Various baseline factors were related to anemia, which in turn was associated with 1-year mortality. Patients with anemia received more transfusions but mostly for indications unrelated to overt bleeding, whereas transfusion was independently associated with both early and 1-year mortality. These findings indicate that optimization of baseline factors related to preoperative anemia, in addition to more strict criteria of the use of blood products, may improve outcome after TAVI.
Impact of Worsening Renal Dysfunction on the Comparative Efficacy of Bivalirudin and Platelet Glycoprotein IIb/IIIa Inhibitors
Authors: Perdoncin Emily , Zhang Min , Riba Arthur , LaLonde Thomas A. , Grines Cindy L. , Gurm Hitinder S. 
Published: November 2013

Background—
Use of bivalirudin has been associated with a reduction in the incidence of bleeding in patients undergoing percutaneous coronary intervention. Patients with chronic kidney disease, a known predictor of post–percutaneous coronary intervention bleeding, are under-represented in clinical trials.

Methods and Results—

We evaluated the outcome of 64 052 patients who underwent percutaneous coronary intervention from 2007 to 2009 at 33 hospitals in Michigan and were treated with bivalirudin (28 378) or with heparin and glycoprotein IIb/IIIa inhibitors (35 674). Propensity-matched analysis was adjusted for the nonrandomized use of the 2 strategies. Patients treated with bivalirudin were older, had a lower glomerular filtration rate, and had more comorbidities. Use of bivalirudin was associated with fewer transfusions (2.8% versus 4.2%;
P
<0.0001), gastrointestinal bleeds (0.5% versus 1.3%;
P
<0.0001), and vascular complications (1.0% versus 2.5%;
P
<0.0001), with no difference in survival. Bleeding complications were more common with worsening renal function, but use of bivalirudin was associated with less bleeding across the continuum of renal dysfunction.

Conclusions—
The risk of bleeding after percutaneous coronary intervention increases with worsening chronic kidney disease. Bivalirudin was associated with a dramatically reduced risk of bleeding across all categories of renal dysfunction. Our study findings suggest that bivalirudin monotherapy is an acceptable, if not the more appropriate alternative, to heparin and glycoprotein IIb/IIIa inhibitors in patients with chronic kidney disease.
Multicenter Accuracy and Interobserver Agreement of Spot Sign Identification in Acute Intracerebral Hemorrhage
Authors: Huynh Thien J. , Flaherty Matthew L. , Gladstone David J. , Broderick Joseph P. , Demchuk Andrew M. , Dowlatshahi Dar , Meretoja Atte , Davis Stephen M. , Mitchell Peter J. , Tomlinson George A. , Chenkin Jordan , Chia Tze L. , Symons Sean P. , Aviv Richard I. 
Published: November 2013

Background and Purpose—
Rapid, accurate, and reliable identification of the computed tomography angiography spot sign is required to identify patients with intracerebral hemorrhage for trials of acute hemostatic therapy. We sought to assess the accuracy and interobserver agreement for spot sign identification.

Methods—
A total of 131 neurology, emergency medicine, and neuroradiology staff and fellows underwent imaging certification for spot sign identification before enrolling patients in 3 trials targeting spot-positive intracerebral hemorrhage for hemostatic intervention (STOP-IT, SPOTLIGHT, STOP-AUST). Ten intracerebral hemorrhage cases (spot-positive/negative ratio, 1:1) were presented for evaluation of spot sign presence, number, and mimics. True spot positivity was determined by consensus of 2 experienced neuroradiologists. Diagnostic performance, agreement, and differences by training level were analyzed.

Results—

Mean accuracy, sensitivity, and specificity for spot sign identification were 87%, 78%, and 96%, respectively. Overall sensitivity was lower than specificity (
P
<0.001) because of true spot signs incorrectly perceived as spot mimics. Interobserver agreement for spot sign presence was moderate (
k
=0.60). When true spots were correctly identified, 81% correctly identified the presence of single or multiple spots. Median time needed to evaluate the presence of a spot sign was 1.9 minutes (interquartile range, 1.2–3.1 minutes). Diagnostic performance, interobserver agreement, and time needed for spot sign evaluation were similar among staff physicians and fellows.

Conclusions—
Accuracy for spot identification is high with opportunity for improvement in spot interpretation sensitivity and interobserver agreement particularly through greater reliance on computed tomography angiography source data and awareness of limitations of multiplanar images. Further prospective study is needed.
Understanding Stroke Survivorship
Authors: Skolarus Lesli E. , Burke James F. , Brown Devin L. , Freedman Vicki A. 
Published: November 2013

Background and Purpose—
Limitations in essential daily activities are common among older adults after stroke, but little is known about restrictions in their ability to participate in valued social activities. We sought to broaden our understanding of disability after stroke by characterizing poststroke participation restrictions and investigating the extent to which they are accounted for by differences in physical and cognitive capacity, aphasia/dysarthria, depressive, and anxiety symptoms.

Methods—

Data from the 2011 National Health and Aging Trends Study (NHATS) were used to identify 892 self-reported stroke survivors aged ≥65 years. One-to-one propensity matching was performed on demographics and comorbidities to create a matched sample. Participation restrictions were defined as reductions/absence in social activities valued by respondents because of their health or functioning. Physical and cognitive capacity, depressive and anxiety symptoms were measured by validated scales and aphasia/dysarthria by a single question. Comparisons using survey-weighted χ
2
tests and logistic regression were made.

Results—

Stroke survivors had more participation restrictions (32.8% versus 23.5%; odds ratio, 1.59; 95% confidence interval, 1.28–1.95;
P
<0.01) than controls. Differences between stroke survivors and controls in any participation restriction and several components (attending religious service, clubs/classes, and going out for enjoyment) were eliminated after adjusting for physical capacity. Depressive and anxiety symptoms and aphasia/dysarthria were independent predictors of participation restrictions.

Conclusions—
Stroke survivors have more participation restrictions than can be accounted for by sociodemographic profiles and comorbidity burden. Future work aimed at improving physical capacity, reducing depressive and anxiety symptoms, and improving aphasia/dysarthria has potential to enhance participation.
Pediatric Intracerebral Hemorrhage Score
Authors: Beslow Lauren A. , Ichord Rebecca N. , Gindville Melissa C. , Kleinman Jonathan T. , Engelmann Kyle , Bastian Rachel A. , Licht Daniel J. , Smith Sabrina E. , Hillis Argye E. , Jordan Lori C. 
Published: November 2013

Background and Purpose—
The intracerebral hemorrhage (ICH) score is the most commonly used clinical grading scale for outcome prediction after adult ICH. We created a similar scale in children to inform clinical care and assist in clinical research.

Methods—
Children, full-term newborns to 18 years, with spontaneous ICH were prospectively enrolled from 2007 to 2012 at 3 centers. The pediatric ICH score was created by identifying factors associated with poor outcome. The score’s ability to detect moderate disability or worse and severe disability or death was examined with sensitivity, specificity, and area under the receiver operating characteristic curve.

Results—
The pediatric ICH score components include ICH volume >2% to 3.99% of total brain volume (TBV): 1 point; ICH volume ≥4% TBV: 2 points; acute hydrocephalus: 1 point; herniation: 1 point; and infratentorial location: 1 point. The score ranges from 0 to 5. At 3-month follow-up of 60 children, 10 were severely disabled or dead, 30 had moderate disability, and 20 had good recovery. A pediatric ICH score ≥1 predicted moderate disability or worse with a sensitivity of 75% (95% confidence interval [CI], 59% to 87%) and a specificity of 70% (95% CI, 46% to 88%). A pediatric ICH score ≥2 predicted severe disability or death with a sensitivity and specificity of 90% (95% CI, 55% to 99%) and 68% (95% CI, 53% to 80%), respectively. The area under the receiver operating characteristic curve for classifying outcome as severe disability or death was 0.88 (95% CI, 0.78–0.97).

Conclusions—
The pediatric ICH score is a simple clinical grading scale that may ultimately be used for risk stratification, clinical care, and research.
Seeing without Knowing: Neural Signatures of Perceptual Inference in the Absence of Report
Authors: Vandenbroucke Annelinde R. E. , Fahrenfort Johannes J. , Sligte Ilja G. , Lamme Victor A. F. 
Published: November 2013

Abstract
Every day, we experience a rich and complex visual world. Our brain constantly translates meaningless fragmented input into coherent objects and scenes. However, our attentional capabilities are limited, and we can only report the few items that we happen to attend to. So what happens to items that are not cognitively accessed? Do these remain fragmentary and meaningless? Or are they processed up to a level where perceptual inferences take place about image composition? To investigate this, we recorded brain activity using fMRI while participants viewed images containing a Kanizsa figure, an illusion in which an object is perceived by means of perceptual inference. Participants were presented with the Kanizsa figure and three matched nonillusory control figures while they were engaged in an attentionally demanding distractor task. After the task, one group of participants was unable to identify the Kanizsa figure in a forced-choice decision task; hence, they were “inattentionally blind.” A second group had no trouble identifying the Kanizsa figure. Interestingly, the neural signature that was unique to the processing of the Kanizsa figure was present in both groups. Moreover, within-subject multivoxel pattern analysis showed that the neural signature of unreported Kanizsa figures could be used to classify reported Kanizsa figures and that this cross-report classification worked better for the Kanizsa condition than for the control conditions. Together, these results suggest that stimuli that are not cognitively accessed are processed up to levels of perceptual interpretation.
Neural Correlates of State- and Strength-based Perception
Authors: Aly Mariam , Ranganath Charan , Yonelinas Andrew P. 
Published: November 2013

Abstract
Perceptual judgments can be based on two kinds of information: state-based perception of specific, detailed visual information, or strength-based perception of global or relational information. State-based perception is discrete in the sense that it either occurs or fails, whereas strength-based perception is continuously graded from weak to strong. The functional characteristics of these types of perception have been examined in some detail, but whether state- and strength-based perception are supported by different brain regions has been largely unexplored. A consideration of empirical work and recent theoretical proposals suggests that parietal and occipito-temporal regions may be differentially associated with state- and strength-based signals, respectively. We tested this parietal/occipito-temporal state/strength hypothesis using fMRI and a visual perception task that allows separation of state- and strength-based perception. Participants made same/different judgments on pairs of faces and scenes using a 6-point confidence scale where “6” responses indicated a state of perceiving specific details that had changed, and “1” to “5” responses indicated judgments based on varying strength of relational match/mismatch. Regions in the lateral and medial posterior parietal cortex (supramarginal gyrus, posterior cingulate cortex, and precuneus) were sensitive to state-based perception and were not modulated by varying levels of strength-based perception. In contrast, bilateral fusiform gyrus activation was increased for strength-based “different” responses compared with misses and did not show state-based effects. Finally, the lateral occipital complex showed increased activation for state-based responses and additionally showed graded activation across levels of strength-based perception. These results offer support for a state/strength distinction between parietal and temporal regions, with the lateral occipital complex at the intersection of state- and strength-based processing.
Automatic and Probabilistic Foehn Diagnosis with a Statistical Mixture Model
Authors: Plavcan David , Mayr Georg J. , Zeileis Achim 
Published: November 2013

AbstractDiagnosing foehn winds from weather station data downwind of topographic obstacles requires distinguishing them from other downslope winds, particularly nocturnal ones driven by radiative cooling. An automatic classification scheme to obtain reproducible results that include information about the (un)certainty of the diagnosis is presented. A statistical mixture model separates foehn and no-foehn winds in a measured time series of wind. In addition to wind speed and direction, it accommodates other physically meaningful classifiers such as the (potential) temperature difference to an upwind station (e.g., near the crest) or relative humidity. The algorithm was tested for Wipp Valley in the central Alps against human expert classification and a previous objective method (Drechsel and Mayr 2008), which the new method outperforms. Climatologically, using only wind information gives nearly identical foehn frequencies as when using additional covariables. A data record length of at least one year is required for satisfactory results. The suitability of mixture models for objective classification of foehn at other locations will have to be tested in further studies.