bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prediction of Stage, Grade, and Survival in Bladder Cancer Using Genome-wide Expression Data: A Validation Study
Authors: Lauss Martin , Ringnér Markus , Höglund Mattias 
Published: August 2010

Abstract
Purpose: To evaluate performances of published gene signatures for the assessment of urothelial carcinoma.
Experimental Design: We evaluated 28 published gene signatures designed for diagnostic and prognostic purposes of urothelial cancer. The investigated signatures include eight signatures for stage, five for grade, four for progression, and six for survival. We used two algorithms for classification, nearest centroid classification and support vector machine, and Cox regression to evaluate signature performance in four independent data sets.
Results: The overlap of genes among the signatures was low, ranging from 11% among stage signatures to 0.6% among survival signatures. The published signatures predicted muscle-invasive and high-grade tumors with accuracies in the range of 70% to 90%. The performance for a given signature varied considerably with the validation data set used, and interestingly, some of the best performing signatures were not designed for the tested classification problem. In addition, several nonbladder-derived gene signatures performed equally well. Large randomly selected gene signatures performed better than the published signatures, and by systematically increasing signature size, we show that signatures with &gt;150 genes are needed to obtain robust performance in independent validation data sets. None of the published survival signatures performed better than random assignments when applied to independent validation data.
Conclusion: We conclude that gene expression signatures with &gt;150 genes predict muscle-invasive growth and high-grade tumors with robust accuracies. Special considerations have to be taken when designing gene signatures for outcome in bladder cancer. Clin Cancer Res; 16(17); 4421–33. ©2010 AACR.
Food and Oral Antineoplastics: More Than Meets the Eye
Authors: Jain Rajul K. , Brar Satjit S. , Lesko Lawrence J. 
Published: August 2010

Abstract
Food can alter the bioavailability of orally administered drugs. Description of food effects in product labels and information about administration in relation to food are influenced by a variety of factors. Because food effects can change drug efficacy and toxicity, it is important that physicians and patients be aware of them. Clin Cancer Res; 16(17); 4305–7. ©2010 AACR.
Activating Stress-Activated Protein Kinase–Mediated Cell Death and Inhibiting Epidermal Growth Factor Receptor Signaling: A Promising Therapeutic Strategy for Prostate Cancer
Authors: Kumar Raj , Srinivasan Sowmyalakshmi , Pahari Pallab , Rohr Jürgen , Damodaran Chendil 
Published: August 2010

AbstractEpidermal growth factor receptor (EGFR) activation is an important event that regulates mitogenic signaling, such as the Raf, mitogen-activated protein kinase (MAPK), and extracellular signal–regulated kinase 1/2 cascades. EGFR activation has been implicated in the transition of prostate cancer from androgen dependence to independence. Therefore, inhibition of EGFR may effectively suppress prostate cancer growth and progression. The goal of this study was to determine whether the natural compound psoralidin alters EGFR-mediated signaling resulting in the inhibition of prostate cancer growth. Results suggest that inhibition of EGFR alone (by serum deprivation) fails to induce stress-mediated protein kinases (SAPK), namely, Jun NH2-terminal kinase/c-Jun signaling, in androgen-independent prostate cancer (AIPC) cells. Treatment with psoralidin, however, inhibited both constitutive and EGF-induced EGFR activation and simultaneously triggered SAPK signaling, resulting in the induction of apoptosis in AIPC cells. In addition, psoralidin downregulated EGFR-regulated MAPK signaling and inhibited cell proliferation in AIPC cells. Oral administration of psoralidin effectively suppressed PC-3 xenograft tumors in nude mice. Compared with control tumors, inhibition of pEGFR expression and an increase in the phosphorylation, activation, and nuclear translocation of c-Jun were observed in psoralidin-treated tumor sections. Our studies suggest that psoralidin may be a potent therapeutic agent that modulates EGFR-mediated key epigenetic events in AIPC. Mol Cancer Ther; 9(9); 2488–96. ©2010 AACR.
Substitution of Adenovirus Serotype 3 Hexon onto a Serotype 5 Oncolytic Adenovirus Reduces Factor X Binding, Decreases Liver Tropism, and Improves Antitumor Efficacy
Authors: Short Joshua J. , Rivera Angel A. , Wu Hongju , Walter Mark R. , Yamamoto Masato , Mathis J. Michael , Curiel David T. 
Published: August 2010

Abstract
Following intravascular delivery, an important route of administration for many clinical applications, the liver is the predominant site of adenovirus serotype 5 (Ad5) sequestration, thereby posing a risk of toxicity. In this regard, it has recently been shown that the Ad5 capsid binds to the blood coagulation factor X (FX) via the Ad5 hexon protein. This interaction mediates the majority of Ad5 liver transduction. Patient FX levels can be diminished by the administration of warfarin, a vitamin K inhibitor in the liver that decreases FX production; however, warfarin is a potent anticoagulant and can have a number of undesired side effects. Therefore, genetic modification of the virus to ablate FX binding is the preferred approach. Modifications of the hexon protein, specifically within the hypervariable 5 (HVR5) and 7 (HVR7) regions, have produced Ad5 vectors that show minimal liver sequestration. Our laboratory has pioneered adenovirus hexon modifications, including insertion of peptide ligands into the hypervariable regions and substitution of the adenovirus hexon with hexon proteins from alternate serotypes. Substitution of the adenovirus serotype 3 (Ad3) hexon protein onto the Ad5 capsid has been further characterized with regard to its interaction with FX and incorporated into an infectivity-enhanced conditionally replicative adenovirus (CRAd). In vitro evaluation of these hexon-modified vectors showed decreased binding to FX and decreased cell transduction via FX-mediated pathways. Furthermore, in vivo biodistribution studies in mice exhibited a decrease in liver sequestration. With the use of xenograft tumor models, the antitumor efficacy of the hexon-modified CRAds was enhanced over nonmodified controls. Mol Cancer Ther; 9(9); 2536–44. ©2010 AACR.
The Novel Tryptamine Derivative JNJ-26854165 Induces Wild-Type p53- and E2F1-Mediated Apoptosis in Acute Myeloid and Lymphoid Leukemias
Authors: Kojima Kensuke , Burks Jared K. , Arts Janine , Andreeff Michael 
Published: August 2010

Abstract
The development of small-molecule activators of p53 is currently focused on malignancies containing a wild-type p53 genotype, which is present in most leukemias. JNJ-26854165 is one such p53-activating agent, but its mechanism of action remains to be elucidated. Here, we report the effects of JNJ-26854165 in acute leukemias. JNJ-26854165 treatment induced p53-mediated apoptosis in acute leukemia cells with wild-type p53, in which p53 rapidly drives transcription-independent apoptosis followed by activation of a transcription-dependent pathway. JNJ-26854165 accelerated the proteasome-mediated degradation of p21 and antagonized the transcriptional induction of p21 by p53. Interestingly, JNJ-26854165 induced S-phase delay and upregulated E2F1 expression in p53 mutant cells, resulting in apoptosis preferentially of S-phase cells. E2F1 knockdown blocked apoptosis induced by JNJ-26854165 in p53 mutant cells. Apoptotic activity of JNJ-26854165 against primary acute leukemia cells was maintained in leukemia/stroma cocultures, unlike doxorubicin, which has reduced cytrotoxicity in coculture systems. JNJ-26854165 synergizes with 1-β-arabinofuranosylcytosine or doxorubicin to induce p53-mediated apoptosis. Our data suggest that JNJ-26854165 may provide a novel therapeutic approach for the treatment of acute leukemias. The presence of p53-independent apoptotic activity in addition to p53-mediated apoptosis induction, if operational in vivo, may prevent the selection of p53 mutant subclones during therapy. Mol Cancer Ther; 9(9); 2545–57. ©2010 AACR.
Survival After Cardiac Transplantation in Patients With Hypertrophic Cardiomyopathy
Authors: Maron Martin S. , Kalsmith Benjamin M. , Udelson James E. , Li Wenjun , DeNofrio David 
Published: August 2010

Background—
Heart transplant is a treatment option for selected patients with hypertrophic cardiomyopathy (HCM). However, the prevalence, clinical profile, and outcome of this subgroup of HCM patients are uncertain. Therefore, we sought to determine the occurrence, clinical characteristics, and prognosis of HCM patients who underwent cardiac transplantation in the United States during a 15-year period.

Methods and Results—

Demographic, clinical, and survival outcomes of 26 706 adult (age ≥18 years), heart-only transplant recipients between January 1990 and December 2004 were acquired from the United Network of Organ Sharing Registry. Pretransplant diagnoses were classified as follows: HCM (n=303, 1%) and non-HCM (26 403, 99%), comprising 3 patient subgroups: (1) ischemic cardiomyopathy (n=14 308, 54%), (2) dilated cardiomyopathy (n=11 760, 44%), and (3) restrictive cardiomyopathy (n=335, 1%). Study follow-up began at the time of heart transplant and was 76±44 months (mean±SD) among survivors. The 1-, 5-, and 10-year overall transplant survival for HCM patients was 85%, 75%, and 61%, respectively, with a trend toward greater survival compared with that of non-HCM transplant patients (82%, 70%, and 49%, respectively; log-rank test,
P
=0.05). However, propensity-matched, covariate-adjusted, Cox regression model analysis showed better survival over time (
P
<0.01) among the HCM patients. When HCM posttransplant survival was compared with that in each of the non-HCM patient subgroups, HCM patients had more favorable survival than did those transplanted for ischemic cardiomyopathy (
P
=0.02). In contrast, HCM posttransplant survival did not differ from that of patients transplanted for restrictive (
P
=0.08) or dilated (
P
=0.25) cardiomyopathy.

Conclusions—
HCM patients compose a small subset (1%) of the overall population of patients who undergo heart transplantation in the United States. Nonetheless, survival after transplant among HCM patients is comparable to that of patients transplanted for non-HCM cardiovascular diseases, with possible enhanced survival over time.
Polymer Injection Therapy to Reverse Remodel the Papillary Muscles
Authors: Solis Jorge , Levine Robert A. , Johnson Benjamin , Guerrero J. Luis , Handschumacher Mark D. , Sullivan Suzanne , Lam Kaitlyn , Berlin Jason , Braithwaite Gavin J.C. , Muratoglu Orhun K. , Vlahakes Gus J. , Hung Judy 
Published: August 2010

Background—
Ischemic mitral regurgitation (MR) results from displacement of the papillary muscles caused by ischemic ventricular distortion. Progressive left ventricular (LV) remodeling has challenged therapy. Our hypothesis is that repositioning of the papillary muscles can be achieved by injection of polyvinyl-alcohol (PVA) hydrogel polymer into the myocardium in chronic MR despite advanced LV remodeling.

Methods and Results—

Ten sheep underwent ligation of the circumflex branches to produce chronic ischemic MR over 8 weeks. PVA was injected into the myocardium underlying the infarcted papillary muscle. Two-dimensional and 3D echocardiograms and hemodynamic data were obtained before infarct (baseline), before PVA (chronic MR), and after PVA. PVA injection significantly decreased MR from moderate to severe to trace (MR vena contracta, 5.8±1.2 to1.8±1.3 mm; chronic MR to post-PVA stage;
P
=0.0003). This was associated with a decrease in infarcted papillary muscle–to–mitral annulus tethering distance (30.3±5.7 to 25.9±4.6 mm,
P
=0.02), tenting volume (1.8±0.7 to 1.4±0.5 mL,
P
=0.01), and leaflet closure area (8.8±1.3 cm
2
to 7.6±1.3 cm
2
,
P
=0.004) from chronic MR to post-PVA stages. PVA was not associated with significant decreases in LV ejection fraction (41±3% versus 40±3%,
P
=NS), end-systolic elastance, τ (82±36 ms to 72±26,
P
=NS), or LV stiffness coefficient (0.05±0.04 to 0.03±0.01).

Conclusions—
PVA hydrogel injections improve coaptation and reduce remodeling in chronic MR without impairing LV systolic and diastolic function. This new approach offers a potential alternative for relieving tethering and ischemic MR by correcting papillary muscle position.
Relationship Between Arterial and Fibrous Cap Remodeling
Authors: Yamada Ryotaro , Okura Hiroyuki , Kume Teruyoshi , Saito Ken , Miyamoto Yoshinori , Imai Koichiro , Tsuchiya Tetsuo , Maehama Tomoko , Okahashi Noriko , Obase Kikuko , Hayashida Akihiro , Neishi Yoji , Kawamoto Takahiro , Yoshida Kiyoshi 
Published: August 2010

Background—
Positive arterial remodeling and thin fibrous cap are characteristics of rupture-prone or vulnerable plaque. The natural course of the fibrous cap thickness and the relationship between serial arterial remodeling and changes in fibrous cap thickness are unknown. Therefore, the purpose of this study was to evaluate the relationship between changes in fibrous cap thickness and arterial remodeling by using optical coherence tomography (OCT) and intravascular ultrasound (IVUS) during 6-month follow-up.

Methods and Results—

Both IVUS and OCT examinations were performed on 108 vessels from 36 patients with ischemic heart disease who underwent percutaneous coronary intervention. Fifty-eight fibroatheromas were selected from 82 nonsignificant, nonculprit lesions (angiographic diameter stenosis, 25% to 75%; plaque burden, >40% by IVUS). Fibroatheroma was defined by OCT as lipid-rich plaque in >1 quadrant that has lipid. Thickness of the fibrous cap was measured by OCT. IVUS and OCT examinations were repeated at 6-month follow-up. Serial changes and relationships between IVUS indices and fibrous cap thickness were investigated. Overall, fibrous cap thickness (98.1±38.9 to 96.9±44.5 μm) as well as IVUS indices did not change significantly within 6 months. The percent changes in fibrous cap thickness correlated negatively and significantly (
r
=−0.54;
P
<0.0001; generalized estimating equation adjusted,
r
=−0.42;
P
=0.001) with the percent changes in external elastic membrane cross-sectional area.

Conclusions—
Arterial remodeling is related to changes in fibrous cap thickness. Positive arterial remodeling is not only an adaptive process, but also related to thinning of the fibrous cap.
Rosuvastatin for Primary Prevention Among Individuals With Elevated High-Sensitivity C-Reactive Protein and 5% to 10% and 10% to 20% 10-Year Risk
Authors: Ridker Paul M , MacFadyen Jean G. , Nordestgaard Børge G. , Koenig Wolfgang , Kastelein John J.P. , Genest Jacques , Glynn Robert J. 
Published: August 2010

Background—
Recent primary prevention guidelines issued in Canada endorse the use of statin therapy among individuals at “intermediate risk” who have elevated levels of high-sensitivity C-reactive protein (hsCRP). However, trial data directly addressing whether this recommendation defines a patient population in which statin therapy is effective have not previously been published.

Methods and Results—

In the Justification for Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial, which demonstrated a 44% reduction in first vascular events when rosuvastatin 20 mg was compared with placebo among 17 802 primary prevention patients with LDL cholesterol <130 mg/dL and hsCRP ≥2 mg/L, 6091 participants (2525 women, 3566 men) had baseline estimated 10-year Framingham risks of 5% to 10% and 7340 participants (1404 women, 5936 men) had baseline estimated Framingham risk of 11% to 20%. In these 2 “intermediate risk” subgroups, relative risk reductions consistent with the overall trial treatment effect were observed (hazard ratio, 0.55; 95% confidence interval, 0.36 to 0.84; 5-year number needed to treat=40,
P
=0.005 for those with 5% to 10% risk; hazard ratio, 0.51; 95% confidence interval, 0.39 to 0.68, 5-year number needed to treat=18,
P
<0.0001 for those with 11% to 20% risk). Use of the Reynolds Risk Score to stratify the study population gave similar results but reclassified large numbers of individuals into lower- or higher-risk groups. The majority of women with elevated hsCRP who benefited from rosuvastatin were at 5% to 10% 10-year risk at study entry using either global risk scoring system.

Conclusions—
Consistent with recent evidence-based Canadian Cardiovascular Society guidelines for primary prevention, the JUPITER trial demonstrates that rosuvastatin 20 mg significantly reduces major cardiovascular events among men and women with elevated hsCRP and “intermediate risk” defined either as 5% to 10% or 10% to 20% 10-year risk.

Clinical Trial Registration—

URL:
http://clinicaltrials.gov
. Unique identifier: NCT00239681.
National Patterns of Risk-Standardized Mortality and Readmission for Acute Myocardial Infarction and Heart Failure
Authors: Bernheim Susannah M. , Grady Jacqueline N. , Lin Zhenqiu , Wang Yun , Wang Yongfei , Savage Shantal V. , Bhat Kanchana R. , Ross Joseph S. , Desai Mayur M. , Merrill Angela R. , Han Lein F. , Rapp Michael T. , Drye Elizabeth E. , Normand Sharon-Lise T. , Krumholz Harlan M. 
Published: August 2010

Background—
Patient outcomes provide a critical perspective on quality of care. The Centers for Medicare and Medicaid Services (CMS) is publicly reporting hospital 30-day risk-standardized mortality rates (RSMRs) and risk-standardized readmission rates (RSRRs) for patients hospitalized with acute myocardial infarction (AMI) and heart failure (HF). We provide a national perspective on hospital performance for the 2010 release of these measures.

Methods and Results—
The hospital RSMRs and RSRRs are calculated from Medicare claims data for fee-for-service Medicare beneficiaries, 65 years or older, hospitalized with AMI or HF between July 1, 2006, and June 30, 2009. The rates are calculated using hierarchical logistic modeling to account for patient clustering, and are risk-adjusted for age, sex, and patient comorbidities. The median RSMR for AMI was 16.0% and for HF was 10.8%. Both measures had a wide range of hospital performance with an absolute 5.2% difference between hospitals in the 5th versus 95th percentile for AMI and 5.0% for HF. The median RSRR for AMI was 19.9% and for HF was 24.5% (3.9% range for 5th to 95th percentile for AMI, 6.7% for HF). Distinct regional patterns were evident for both measures and both conditions.

Conclusions—
High RSRRs persist for AMI and HF and clinically meaningful variation exists for RSMRs and RSRRs for both conditions. Our results suggest continued opportunities for improvement in patient outcomes for HF and AMI.
Biomechanical Considerations in the Competitive Swimmer’s Shoulder
Authors: Heinlein Scott A. , Cosgarea Andrew J. 
Published: August 2010

Context: Competitive swimming has become an increasingly popular sport in the United States. In 2007, more than 250 000 competitive swimmers were registered with USA Swimming, the national governing body. The average competitive swimmer swims approximately 60 000 to 80 000 m per week. With a typical count of 8 to 10 strokes per 25-m lap, each shoulder performs 30 000 rotations each week. This places tremendous stress on the shoulder girdle musculature and glenohumeral joint, and it is why shoulder pain is the most frequent musculoskeletal complaint among competitive swimmers. Evidence Acquisition: Articles were obtained through a variety of medical search sources, including Medline, Google Scholar, and review articles from 1980 through January 2010. Results: The most common cause of shoulder pain in swimmers is supraspinatus tendinopathy. Glenohumeral instability and labral tears have also been reported, but a paucity of information remains regarding prevalence and treatment in swimmers. Conclusion: Because of the great number of stroke repetitions and force generated through the upper extremity, the shoulder is uniquely vulnerable to injury in the competitive swimmer. Comprehensive evaluation should include the entire kinetic chain, including trunk strength and core stability.
Defect of plasmacytoid dendritic cells in warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome patients
Authors: Tassone Laura , Moratto Daniele , Vermi William , De Francesco Maria , Notarangelo Lucia D. , Porta Fulvio , Lougaris Vassilios , Facchetti Fabio , Plebani Alessandro , Badolato Raffaele 
Published: August 2010

Abstract
Warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome is a genetic disease that is caused by heterozygous mutations of the CXCR4 gene. These mutations confer an increased leukocyte response to the CXCR4-ligand CXCL12, resulting in abnormal homeostasis of many leukocyte types, including neutrophils and lymphocytes. Analysis of the myeloid and plasmacytoid dendritic cell blood counts in WHIM patients revealed a striking defect in the number of plasmacytoid dendritic cells as well as a partial reduction of the number of myeloid dendritic cells, compared with healthy subjects. Moreover, the production of interferon-α by mononuclear cells in response to herpes simplex infection, or after stimulation with the Toll-like receptor 9 ligand CpG, was undetectable in WHIM patients. Because plasmacytoid dendritic cells play a key role in the defense against viruses and their generation and motility are in part dependent on CXCR4, we hypothesized that the susceptibility of WHIM patients to warts is related to the abnormal homeostasis of plasmacytoid dendritic cells.
HMGA1 down-regulation is crucial for chromatin composition and a gene expression profile permitting myogenic differentiation
Authors: Brocher Jan , Vogel Benjamin , Hock Robert 
Published: August 2010

Abstract

Background
High mobility group A (HMGA) proteins regulate gene transcription through architectural modulation of chromatin and the formation of multi-protein complexes on promoter/enhancer regions. Differential expression of HMGA variants has been found to be important for distinct differentiation processes and deregulated expression was linked to several disorders. Here we used mouse C2C12 myoblasts and C2C12 cells stably over-expressing HMGA1a-eGFP to study the impact of deregulated HMGA1 expression levels on cellular differentiation.

Results
We found that induction of the myogenic or osteogenic program of C2C12 cells caused an immediate down-regulation of HMGA1. In contrast to wild type C2C12 cells, an engineered cell line with stable over-expression of HMGA1a-eGFP failed to differentiate into myotubes. Immunolocalization studies demonstrated that sustained HMGA1a-eGFP expression prevented myotube formation and chromatin reorganization that normally accompanies differentiation. Western Blot analyses showed that elevated HMGA1a-eGFP levels affected chromatin composition through either down-regulation of histone H1 or premature expression of MeCP2. RT-PCR analyses further revealed that sustained HMGA1a expression also affected myogenic gene expression and caused either down-regulation of genes such as MyoD, myogenin, Igf1, Igf2, Igfbp1-3 or up-regulation of the transcriptional repressor Msx1. Interestingly, siRNA experiments demonstrated that knock-down of HMGA1a was required and sufficient to reactivate the myogenic program in induced HMGA1a over-expressing cells.

Conclusions
Our data demonstrate that HMGA1 down-regulation after induction is required to initiate the myogenic program in C2C12 cells. Sustained HMGA1a expression after induction prevents expression of key myogenic factors. This may be due to specific gene regulation and/or global effects on chromatin. Our data further corroborate that altered HMGA1 levels influence the expression of other chromatin proteins. Thus, HMGA1 is able to establish a specific chromatin composition. This work contributes to the understanding of how differential HMGA1 expression is involved in chromatin organization during cellular differentiation processes and it may help to comprehend effects of HMGA1 over-expression occurring in malign or benign tumours.