bluuebunny/crossref_metadata_2025_split huggingface dataset:
Polo-like Kinase Plk2 Is an Epigenetic Determinant of Chemosensitivity and Clinical Outcomes in Ovarian Cancer
Authors: Syed Nelofer , Coley Helen M. , Sehouli Jalid , Koensgen Dominique , Mustea Alexander , Szlosarek Peter , McNeish Iain , Blagden Sarah P. , Schmid Peter , Lovell David P. , Hatzimichael Eleftheria , Crook Tim 
Published: March 2011

Abstract
Resistance to platinum- and taxane-based chemotherapy remains a major clinical impediment to effective management of epithelial ovarian cancer (EOC). To gain insights into resistance mechanisms, we compared gene and confirmed expression patterns of novel EOC cell lines selected for paclitaxel and carboplatin resistance. Here, we report that resistance can be conferred by downregulation of the Polo-like kinase Plk2. Mechanistic investigations revealed that downregulation occurred at the level of transcription via associated DNA methylation of the CpG island in the Plk2 gene promoter in cell lines, primary tumors, and patient sera. Inhibitory RNA (RNAi)-mediated knockdown and ectopic overexpression established a critical functional role for Plk2 in determining apoptotic sensitivity to paclitaxel and carboplatin. In drug-resistant human EOC cell lines, Plk2 promoter methylation varied with the degree of drug resistance and transcriptional silencing of the promoter. RNAi-dependent knockdown of Plk2 abrogated G2-M cell-cycle blockade by paclitaxel, conferring resistance to both paclitaxel and platinum. Conversely, ectopic expression of Plk2 restored sensitivity to G2-M cell-cycle blockade and cytotoxicity triggered by paclitaxel. In clinical cases, DNA methylation of the Plk2 CpG island in tumor tissue was associated with a higher risk of relapse in patients treated postoperatively with carboplatin and paclitaxel (P = 0.003). This trend was also reflected in the analysis of matched serum samples. Taken together, our results implicate Plk2 as a clinically important determinant of chemosensitivity, in support of the candidacy of Plk2 as a theranostic marker to inform EOC management. Cancer Res; 71(9); 3317–27. ©2011 AACR.
Cep63 Recruits Cdk1 to the Centrosome: Implications for Regulation of Mitotic Entry, Centrosome Amplification, and Genome Maintenance
Authors: Löffler Harald , Fechter Anne , Matuszewska Marc , Saffrich Rainer , Mistrik Martin , Marhold Joachim , Hornung Christin , Westermann Frank , Bartek Jiri , Krämer Alwin 
Published: March 2011

Abstract
Centrosomes are central regulators of mitosis that are often amplified in cancer cells. Centrosomes function both as organizers of the mitotic spindle and as reaction centers to trigger activation of Cdk1 and G2/M transition in the cell cycle, but their functional organization remains incomplete. Recent proteomic studies have identified novel components of the human centrosome including Cep63, a protein of unknown function that Xenopus studies have implicated in mitotic spindle assembly and spindle inactivation after DNA damage. Here, we report that human Cep63 binds to and recruits Cdk1 to centrosomes, and thereby regulates mitotic entry. RNAi-mediated Cep63 depletion in U2OS cancer cells induced polyploidization through mitotic skipping. Elicitation of this phenotype was associated with downregulation of centrosomal Cdk1, mimicking the phenotype induced by direct depletion of Cdk1. In contrast, Cep63 overexpression induced de novo centrosome amplification during cell-cycle interphase. Induction of this phenotype was suppressible by cell treatment with the Cdk inhibitor roscovitine. In a survey of 244 neuroblastoma cases, Cep63 mRNA overexpression was associated with MYCN oncogene amplification and poor prognosis. In cultured cells, Cep63 overexpression was associated with an enhancement in replication-induced DNA breakage. Together, our findings define human Cep63 as a centrosomal recruitment factor for Cdk1 that is essential for mitotic entry, providing a physical link between the centrosome and the cell-cycle machinery. Cancer Res; 71(6); 2129–39. ©2011 AACR.
Overcoming Temozolomide Resistance in Glioblastoma via Dual Inhibition of NAD+ Biosynthesis and Base Excision Repair
Authors: Goellner Eva M. , Grimme Bradford , Brown Ashley R. , Lin Ying-Chih , Wang Xiao-Hong , Sugrue Kelsey F. , Mitchell Leah , Trivedi Ram N. , Tang Jiang-bo , Sobol Robert W. 
Published: March 2011

Abstract
Glioblastoma multiforme (GBM) is a devastating brain tumor with poor prognosis and low median survival time. Standard treatment includes radiation and chemotherapy with the DNA alkylating agent temozolomide (TMZ). However, a large percentage of tumors are resistant to the cytotoxic effects of the TMZ-induced DNA lesion O6-methylguanine due to elevated expression of the repair protein O6-methylguanine-DNA methyltransferase (MGMT) or a defect in the mismatch repair (MMR) pathway. Although a majority of the TMZ-induced lesions (N7-methylguanine and N3-methyladenine) are base excision repair (BER) substrates, these DNA lesions are also readily repaired. However, blocking BER can enhance response to TMZ and therefore the BER pathway has emerged as an attractive target for reversing TMZ resistance. Our lab has recently reported that inhibition of BER leads to the accumulation of repair intermediates that induce energy depletion–mediated cell death via hyperactivation of poly(ADP-ribose) polymerase. On the basis of our observation that TMZ-induced cell death via BER inhibition is dependent on the availability of nicotinamide adenine dinucleotide (NAD+), we have hypothesized that combined BER and NAD+ biosynthesis inhibition will increase TMZ efficacy in glioblastoma cell lines greater than BER inhibition alone. Importantly, we find that the combination of BER and NAD+ biosynthesis inhibition significantly sensitizes glioma cells with elevated expression of MGMT and those deficient in MMR, two genotypes normally associated with TMZ resistance. Dual targeting of these two interacting pathways (DNA repair and NAD+ biosynthesis) may prove to be an effective treatment combination for patients with resistant and recurrent GBM. Cancer Res; 71(6); 2308–17. ©2011 AACR.
CARMA3 is Crucial for EGFR-Induced Activation of NF-κB and Tumor Progression
Authors: Jiang Tang , Grabiner Brian , Zhu Yifan , Jiang Changying , Li Hongxiu , You Yun , Lang Jingyu , Hung Mien-Chie , Lin Xin 
Published: March 2011

AbstractEGF activates NF-κB, and constitutively activated NF-κB contributes to EGFR mutation-associated tumorigenesis, but it remains unclear precisely how EGFR signaling leads to NF-κB activation. Here we report that CARMA3, a caspase recruitment domain (CARD)-containing scaffold molecule, is required for EGF-induced NF-κB activation. CARMA3 deficiency impaired the activation of the IKK complex following EGF stimulation, resulting in a defect of EGF-induced IκBα phosphorylation and NF-κB activation. We found that CARMA3 and Bcl10 contributed to several characteristics of EGFR-associated malignancy, including proliferation, survival, migration, and invasion. Most importantly, CARMA3 contributed to tumor growth in vivo. Our findings elucidate a crucial link between EGFR-proximal signaling components and the downstream IKK complex, and they suggest a new therapeutic target for treatment of EGFR-driven cancers. Cancer Res; 71(6); 2183–92. ©2011 AACR.
Sildenafil Reverses ABCB1- and ABCG2-Mediated Chemotherapeutic Drug Resistance
Authors: Shi Zhi , Tiwari Amit K. , Shukla Suneet , Robey Robert W. , Singh Satyakam , Kim In-Wha , Bates Susan E. , Peng Xingxiang , Abraham Ioana , Ambudkar Suresh V. , Talele Tanaji T. , Fu Li-Wu , Chen Zhe-Sheng 
Published: March 2011

Abstract
Sildenafil is a potent and selective inhibitor of the type 5 cGMP (cyclic guanosine 3′,5′-monophosphate)-specific phosphodiesterase that is used clinically to treat erectile dysfunction and pulmonary arterial hypertension. Here, we report that sildenafil has differential effects on cell surface ABC transporters such as ABCB1, ABCC1, and ABCG2 that modulate intracompartmental and intracellular concentrations of chemotherapeutic drugs. In ABCB1-overexpressing cells, nontoxic doses of sildenafil inhibited resistance and increased the effective intracellular concentration of ABCB1 substrate drugs such as paclitaxel. Similarly, in ABCG2-overexpressing cells, sildenafil inhibited resistance to ABCG2 substrate anticancer drugs, for example, increasing the effective intracellular concentration of mitoxantrone or the fluorescent compound BODIPY-prazosin. Sildenafil also moderately inhibited the transport of E217βG and methotrexate by the ABCG2 transporter. Mechanistic investigations revealed that sildenafil stimulated ABCB1 ATPase activity and inhibited photolabeling of ABCB1 with [125I]-iodoarylazidoprazosin (IAAP), whereas it only slightly stimulated ABCG2 ATPase activity and inhibited photolabeling of ABCG2 with [125I]-IAAP. In contrast, sildenafil did not alter the sensitivity of parental, ABCB1-, or ABCG2-overexpressing cells to non-ABCB1 and non-ABCG2 substrate drugs, nor did sildenafil affect the function of another ABC drug transporter, ABCC1. Homology modeling predicted the binding conformation of sildenafil within the large cavity of the transmembrane region of ABCB1. Overall, we found that sildenafil inhibits the transporter function of ABCB1 and ABCG2, with a stronger effect on ABCB1. Our findings suggest a possible strategy to enhance the distribution and potentially the activity of anticancer drugs by jointly using a clinically approved drug with known side effects and drug–drug interactions. Cancer Res; 71(8); 3029–41. ©2011 AACR.
Genetic Ablation of PKC Epsilon Inhibits Prostate Cancer Development and Metastasis in Transgenic Mouse Model of Prostate Adenocarcinoma
Authors: Hafeez Bilal Bin , Zhong Weixiong , Weichert Jamey , Dreckschmidt Nancy E. , Jamal Mohammad Sarwar , Verma Ajit K. 
Published: March 2011

Abstract
Protein kinase C epsilon (PKCϵ), a novel PKC isoform, is overexpressed in prostate cancer (PCa) and correlates with disease aggressiveness. However, the functional contribution of PKCϵ to development or progression of PCa remained to be determined. Here we present the first in vivo genetic evidence that PKCϵ is essential for both the development and metastasis of PCa in the transgenic mouse model of prostate adenocarcinoma (TRAMP). Heterozygous or homozygous genetic deletions of PKCϵ in FVB/N TRAMP inhibited PCa development and metastasis as analyzed by positron emission tomography/computed tomography, tumor weight determinations, and histopathology. We also examined biomarkers associated with tumor progression in this model, including markers of survival, proliferation, angiogenesis, inflammation, and metastatic progression. To find clues about the genes regulated by PKCϵ and linked to the Stat3 signaling pathway, we carried out focused PCR arrays of JAK/STAT signaling in excised PCa tissues from PKCϵ wild-type and nullizygous TRAMP mice. Notably, PKCϵ loss was associated with significant downregulation of proliferative and metastatic genes C/EBPβ (CCAAT/enhancer binding protein β), CRP (C-reactive protein), CMK, EGFR (epidermal growth factor receptor), CD64, Jun B, and gp130. Taken together, our findings offer the first genetic evidence of the role of PKCϵ in PCa development and metastasis. PKCϵ may be potential target for prevention and/or treatment of PCa. Cancer Res; 71(6); 2318–27. ©2011 AACR.
Secondary Prevention Risk Interventions Via Telemedicine and Tailored Patient Education (SPRITE)
Authors: Shah Bimal R. , Adams Martha , Peterson Eric D. , Powers Benjamin , Oddone Eugene Z. , Royal Kira , McCant Felicia , Grambow Steven C. , Lindquist Jennifer , Bosworth Hayden B. 
Published: March 2011

Background—
Secondary prevention by risk factor modification improves patient outcomes, yet it is often not achieved in clinical practice. Reasons for failure stem from challenges of prioritizing risk factor reduction and engaging patients in changing their behaviors. We hypothesize that a novel telemedicine intervention with tailored patient education could improve cardiovascular risk factors.

Methods—
To evaluate this intervention, we propose enrolling 450 patients with a recent myocardial infarction and hypertension into a 3-arm randomized, controlled trial. The first arm (n=150) will receive home blood pressure (BP) monitors plus a nurse-delivered, telephone-based tailored patient education intervention and will be enrolled into HealthVault, a Microsoft electronic health record platform. The second arm (n=150) will also receive BP monitors plus a tailored patient education intervention and be enrolled in HeartVault. However, the patient education intervention will be delivered by a Web-based program and will cover topics identical to those in the nurse-delivered intervention. Both arms will be compared with a control group receiving standard care (n=150). All participants will have an in-person assessment at baseline and at completion of the study, including standardized measurements of BP, LDL cholesterol, and glycosylated hemoglobin (in diabetic subjects). The study design will allow assessment of a telephone-based, nurse-administered disease management program versus standard care. The main outcome of interest is the reduction in systolic BP in each intervention group compared with the control group at 12 months. Secondary outcomes assessed will include reductions in LDL cholesterol, body weight, and glycosylated hemoglobin, as well as adherence to evidence-based therapies and improvement in health behaviors.

Conclusion—
If successful in optimizing BP control, managing other coronary heart disease risk factors, and demonstrating a lower cost, the Web-based disease management tool has the potential to enhance coronary artery disease management, quality of care, and ultimately, patient outcomes.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00901277.
An Administrative Claims Measure Suitable for Profiling Hospital Performance Based on 30-Day All-Cause Readmission Rates Among Patients With Acute Myocardial Infarction
Authors: Krumholz Harlan M. , Lin Zhenqiu , Drye Elizabeth E. , Desai Mayur M. , Han Lein F. , Rapp Michael T. , Mattera Jennifer A. , Normand Sharon-Lise T. 
Published: March 2011

Background—
National attention has increasingly focused on readmission as a target for quality improvement. We present the development and validation of a model approved by the National Quality Forum and used by the Centers for Medicare & Medicaid Services for hospital-level public reporting of risk-standardized readmission rates for patients discharged from the hospital after an acute myocardial infarction.

Methods and Results—
We developed a hierarchical logistic regression model to calculate hospital risk-standardized 30-day all-cause readmission rates for patients hospitalized with acute myocardial infarction. The model was derived using Medicare claims data for a 2006 cohort and validated using claims and medical record data. The unadjusted readmission rate was 18.9%. The final model included 31 variables and had discrimination ranging from 8% observed 30-day readmission rate in the lowest predictive decile to 32% in the highest decile and a C statistic of 0.63. The 25th and 75th percentiles of the risk-standardized readmission rates across 3890 hospitals were 18.6% and 19.1%, with fifth and 95th percentiles of 18.0% and 19.9%, respectively. The odds of all-cause readmission for a hospital 1 SD above average were 1.35 times that of a hospital 1 SD below average. Hospital-level adjusted readmission rates developed using the claims model were similar to rates produced for the same cohort using a medical record model (correlation, 0.98; median difference, 0.02 percentage points).

Conclusions—
This claims-based model of hospital risk-standardized readmission rates for patients with acute myocardial infarction produces estimates that are excellent surrogates for those produced from a medical record model.
Human Cardiac Stem Cell Differentiation Is Regulated by a Mircrine Mechanism
Authors: Hosoda Toru , Zheng Hanqiao , Cabral-da-Silva Mauricio , Sanada Fumihiro , Ide-Iwata Noriko , Ogórek Barbara , Ferreira-Martins João , Arranto Christian , D'Amario Domenico , del Monte Federica , Urbanek Konrad , D'Alessandro David A. , Michler Robert E. , Anversa Piero , Rota Marcello , Kajstura Jan , Leri Annarosa 
Published: March 2011

RETRACTION
This article has been retracted:

Circulation
. 2019;139:e1. DOI: 10.1161/CIR.0000000000000644
Successful strategies for educating hard-to-reach populations: Lessons learned from Massachusetts’ train-the-trainer project using the Helping You Take Care of Yourself curriculum
Authors: Besculides Melanie , Trebino Lisa , Nelson Heather 
Published: March 2011

Objective: To assess the effectiveness of providing education on breast, cervical and cardiovascular health to hard-to-reach women throughout Massachusetts using an innovative derivation of the ‘train-the-trainer’ approach. Innovation included use of contracts with community-based organizations (CBOs) that required data collection in return for payment. Design: Quantitative and qualitative evaluation. Setting: Hard-to-reach women throughout Massachusetts. Methods: Contracted with CBOs to conduct educational sessions on breast, cervical, and cardiovascular health using a standardized curriculum. Collected and analyzed quantitative data from 2,526 women educated by CBOs to assess the programme’s reach and effectiveness. Interviewed staff involved in programme implementation and conducted focus groups with women educated to identify programme successes and areas for improvement. Results: Thirty-three unique CBOs conducted 264 educational sessions, educating 2,526 women in one or more units (breast, cervical, or cardiovascular health) of the Helping You Take Care of Yourself curriculum. Quantitative data were obtained to assess programme effectiveness and the curriculum successfully increased knowledge for all health units. Qualitative evaluation identified several factors that contributed to the success of the programme, including: establishing relationships with CBOs that had existing ties in target communities; executing memoranda of understanding that required data collection for payment; developing curriculum toolkits and intensive staff training; and delivering education in small group settings. Conclusion: The innovative structure of implementation of a ‘train-the-trainer’ approach allowed for expanded reach of the health education curriculum, educating more than 2,000 hard-to-reach women. The strategies employed can be applied to other health education programmes.
Post-stroke fatigue: a treatment protocol that is being evaluated
Authors: Zedlitz AMEE , Fasotti L , Geurts ACH 
Published: March 2011

This series of articles for rehabilitation in practice aims to cover a knowledge element of the rehabilitation medicine curriculum. Nevertheless they are intended to be of interest to a multidisciplinary audience. The competency addressed in this article is the neuropsychologist. AbstractPurpose: Post-stroke fatigue is a common and debilitating complaint, which has only recently received attention in clinical rehabilitation. Until now, no evidence-based treatments have been available for the condition. Therefore, a new treatment was designed to reduce post-stroke fatigue complaints: Cognitive and Graded Activity Training (COGRAT). Rationale: Following the premise that post-stroke fatigue is primarily caused by brain damage, the treatment aims to prevent fatigue and to manage existing fatigue symptoms. The purpose of the added graded activity programme is to reduce fatigue by changing cognitions and enhancing physical fitness. Theory into practice: COGRAT consists of a cognitive treatment and graded activity programme in small groups over 12 weeks. In the cognitive treatment, patients receive education on post-stroke fatigue and register their activities and fatigue to gain insight into their daily agenda and fatigability. Patients are then taught several compensation strategies. Cognitive behavioural therapy is used to diminish anxiety, facilitate behavioural change and manage fatigue symptoms. The graded activity programme consists of walking on a treadmill, strength training and home work assignments. Maximum heart rate and strength are increased from 40% at the beginning of the training to a maximum of 70%. Considerations for future improvements: COGRAT is currently being evaluated in outpatients with severe post-stroke fatigue in a multicentre randomized controlled trial. Preliminary data suggest both positive short- and long-term effects. Adaptations for other neurological patient groups suffering from fatigue are suggested.
Exercise training leads to a reduction of elevated myostatin levels in patients with chronic heart failure
Authors: Lenk Karsten , Erbs Sandra , Höllriegel Robert , Beck Ephraim , Linke Axel , Gielen Stephan , Winkler Sven Möbius , Sandri Marcus , Hambrecht Rainer , Schuler Gerhard , Adams Volker 
Published: March 2011

Background: In chronic heart failure (CHF), cardiac cachexia is often associated with the terminal stage of this disease. In animal studies it has been demonstrated that myostatin, a key regulator of skeletal muscle mass, is elevated in advanced stages of this syndrome. Design: The aim of the present study was to investigate the expression of myostatin in patients with late stage CHF (NYHA IIIb) in comparison to healthy subjects. Furthermore the effects of physical exercise on myostatin were analyzed. Methods: Twenty-four patients were either randomized to a sedentary control group (CHF-S) or exercise training (CHF-E). At baseline and after 12 weeks mRNA and myostatin protein in the peripheral skeletal muscle as well as myostatin serum concentration were measured. Furthermore 12 age-matched healthy men were compared to all patients at baseline (HC). Results: CHF patients showed a two-fold increase of myostatin mRNA ( p = 0.05) and a 1.7-fold ( p = 0.01) augmentation of protein content in skeletal muscle compared to healthy subjects. In late-stage CHF, exercise training led to a 36% reduction of the mRNA and a 23% decrease of the myostatin protein compared to baseline. The serum concentration of myostatin revealed no significant alteration between the groups. Conclusion: In the skeletal muscle, myostatin increases significantly in the course of CHF. The observed effects of a significant reduction of myostatin in skeletal muscle after 12 weeks of exercise training demonstrate the reversibility of molecular changes that might be able to halt the devastating process of muscle wasting in chronic heart failure.
Lentiviral vector common integration sites in preclinical models and a clinical trial reflect a benign integration bias and not oncogenic selection
Authors: Biffi Alessandra , Bartolomae Cynthia C. , Cesana Daniela , Cartier Natalie , Aubourg Patrik , Ranzani Marco , Cesani Martina , Benedicenti Fabrizio , Plati Tiziana , Rubagotti Enrico , Merella Stefania , Capotondo Alessia , Sgualdino Jacopo , Zanetti Gianluigi , von Kalle Christof , Schmidt Manfred , Naldini Luigi , Montini Eugenio 
Published: March 2011

AbstractA recent clinical trial for adrenoleukodystrophy (ALD) showed the efficacy and safety of lentiviral vector (LV) gene transfer in hematopoietic stem progenitor cells. However, several common insertion sites (CIS) were found in patients' cells, suggesting that LV integrations conferred a selective advantage. We performed high-throughput LV integration site analysis on human hematopoietic stem progenitor cells engrafted in immunodeficient mice and found the same CISs reported in patients with ALD. Strikingly, most CISs in our experimental model and in patients with ALD cluster in megabase-wide chromosomal regions of high LV integration density. Conversely, cancer-triggering integrations at CISs found in tumor cells from γretroviral vector–based clinical trials and oncogene-tagging screenings in mice always target a single gene and are contained in narrow genomic intervals. These findings imply that LV CISs are produced by an integration bias toward specific genomic regions rather than by oncogenic selection.