bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long-term Follow-up of MRC Myeloma IX Trial: Survival Outcomes with Bisphosphonate and Thalidomide Treatment
Authors: Morgan Gareth J. , Davies Faith E. , Gregory Walter M. , Bell Susan E. , Szubert Alexander J. , Cook Gordon , Drayson Mark T. , Owen Roger G. , Ross Fiona M. , Jackson Graham H. , Child J. Anthony 
Published: August 2013

Abstract
Purpose: Medical Research Council (MRC) Myeloma IX was a phase III trial evaluating bisphosphonate and thalidomide-based therapy for newly diagnosed multiple myeloma. Results were reported previously after a median follow-up of 3.7 years (current controlled trials number: ISRCTN68454111). Survival outcomes were reanalyzed after an extended follow-up (median, 5.9 years).
Experimental Design: At first randomization, patients (N = 1,970) were assigned to bisphosphonate (clodronic acid or zoledronic acid) and induction therapies [cyclophosphamide–vincristine–doxorubicin–dexamethasone (CVAD) or cyclophosphamide–thalidomide–dexamethasone (CTD) followed by high-dose therapy plus autologous stem cell transplantation for younger/fitter patients (intensive pathway), and melphalan–prednisone (MP) or attenuated CTD (CTDa) for older/less fit patients (nonintensive pathway)]. At second randomization, patients were assigned to thalidomide maintenance therapy or no maintenance. Interphase FISH (iFISH) was used to analyze cytogenics.
Results: Zoledronic acid significantly improved progression-free survival (PFS; HR, 0.89; P = 0.02) and overall survival (OS; HR, 0.86; P = 0.01) compared with clodronic acid. In the intensive pathway, CTD showed noninferior PFS and OS compared with CVAD, with a trend toward improved OS in patients with favorable cytogenics (P = 0.068). In the nonintensive pathway, CTDa significantly improved PFS (HR, 0.81; P = 0.007) compared with MP and there was an emergent survival benefit after 18 to 24 months. Thalidomide maintenance improved PFS (HR, 1.44; P &lt; 0.0001) but not OS (HR, 0.96; P = 0.70), and was associated with shorter OS in patients with adverse cytogenics (P = 0.01).
Conclusions: Long-term follow-up is essential to identify clinically meaningful treatment effects in myeloma subgroups based on cytogenetics. Clin Cancer Res; 19(21); 6030–8. ©2013 AACR.
Steroidogenic Enzyme AKR1C3 Is a Novel Androgen Receptor-Selective Coactivator that Promotes Prostate Cancer Growth
Authors: Yepuru Muralimohan , Wu Zhongzhi , Kulkarni Anand , Yin Feng , Barrett Christina M. , Kim Juhyun , Steiner Mitchell S. , Miller Duane D. , Dalton James T. , Narayanan Ramesh 
Published: August 2013

Abstract
Purpose: Castration-resistant prostate cancer (CRPC) may occur by several mechanisms including the upregulation of androgen receptor (AR), coactivators, and steroidogenic enzymes, including aldo keto reductase 1C3 (AKR1C3). AKR1C3 converts weaker 17-keto androgenic precursors to more potent 17-hydroxy androgens and is consistently the major upregulated gene in CRPC. The studies in the manuscript were undertaken to examine the role of AKR1C3 in AR function and CRPC.
Experimental Design: LNCaP cells stably transfected with AKR1C3 and VCaP cells endogenously expressing AKR1C3 were used to understand the effect of AKR1C3 on prostate cancer cell and tumor growth in nude mice. Chromatin immunoprecipitation, confocal microscopy, and co-immunoprecipitation studies were used to understand the recruitment of AKR1C3, intracellular localization of AKR1C3 and its interaction with AR in cells, tumor xenograft, and in Gleason sum 7 CRPC tissues. Cells were transiently transfected for AR transactivation. Novel small-molecule AKR1C3-selective inhibitors were synthesized and characterized in androgen-dependent prostate cancer and CRPC models.
Results: We identified unique AR-selective coactivator- and prostate cancer growth-promoting roles for AKR1C3. AKR1C3 overexpression promotes the growth of both androgen-dependent prostate cancer and CRPC xenografts, with concomitant reactivation of androgen signaling. AKR1C3 interacted with AR in prostate cancer cells, xenografts, and in human CRPC samples and was recruited to the promoter of an androgen-responsive gene. The coactivator and growth-promoting functions of AKR1C3 were inhibited by an AKR1C3-selective competitive inhibitor.
Conclusions: AKR1C3 is a novel AR-selective enzymatic coactivator and may represent the first of more than 200 known nuclear hormone receptor coactivators that can be pharmacologically targeted. Clin Cancer Res; 19(20); 5613–25. ©2013 AACR.
Alpha-Smooth Muscle Actin (ACTA2) Is Required for Metastatic Potential of Human Lung Adenocarcinoma
Authors: Lee Hye Won , Park Young Mi , Lee Se Jeong , Cho Hyun Jung , Kim Duk-Hwan , Lee Jung-Il , Kang Myung-Soo , Seol Ho Jun , Shim Young Mog , Nam Do-Hyun , Kim Hyeon Ho , Joo Kyeung Min 
Published: August 2013

Abstract
Purpose: Metastatic relapse of primary lung cancer leads to therapeutic resistance and unfavorable clinical prognosis; therefore, identification of key molecules associated with metastatic conversion has significant clinical implications. We previously identified a link between early brain metastasis of lung adenocarcinoma and amplification of the α-smooth muscle actin (ACTA2) gene. The aim of present study was to investigate the prognostic and functional significance of ACTA2 expression in cancer cells for the metastatic potential of lung adenocarcinomas.
Experimental Design: ACTA2 expression was analyzed in tumor cells from 263 patients with primary lung adenocarcinomas by immunohistochemistry, and was correlated with clinicopathologic parameters. The expression of ACTA2 in human lung adenocarcinoma cells was modulated with short hairpin RNAs (shRNA) and siRNAs specifically targeting ACTA2.
Results: The patients with lung adenocarcinomas with high ACTA2 expression in tumor cells showed significantly enhanced distant metastasis and unfavorable prognosis. ACTA2 downregulation remarkably impaired in vitro migration, invasion, clonogenicity, and transendothelial penetration of lung adenocarcinoma cells without affecting proliferation. Consistent with the in vitro results, depletion of ACTA2 in human lung adenocarcinoma PC14PE6 cells significantly reduced their metastatic potential without altering their tumorigenic potential. Expression of c-MET and FAK in lung adenocarcinoma cells was also reduced by ACTA2-targeting siRNAs and shRNAs, and was accompanied by a loss of mesenchymal characteristics.
Conclusions: These findings indicate that ACTA2 regulates c-MET and FAK expression in lung adenocarcinoma cells, which positively and selectively influence metastatic potential. Therefore, ACTA2 could be a promising prognostic biomarker and/or therapeutic target for metastatic lung adenocarcinoma. Clin Cancer Res; 19(21); 5879–89. ©2013 AACR.
UNC569, a Novel Small-Molecule Mer Inhibitor with Efficacy against Acute Lymphoblastic Leukemia In Vitro and In Vivo
Authors: Christoph Sandra , DeRyckere Deborah , Schlegel Jennifer , Frazer J. Kimble , Batchelor Lance A. , Trakhimets Alesia Y. , Sather Susan , Hunter Debra M. , Cummings Christopher T. , Liu Jing , Yang Chao , Kireev Dmitri , Simpson Catherine , Norris-Drouin Jacqueline , Hull-Ryde Emily A. , Janzen William P. , Johnson Gary L. , Wang Xiaodong , Frye Stephen V. , Earp H. Shelton , Graham Douglas K. 
Published: August 2013

Abstract
Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Although survival rates have improved, patients with certain biologic subtypes still have suboptimal outcomes. Current chemotherapeutic regimens are associated with short- and long-term toxicities and novel, less toxic therapeutic strategies are needed. Mer receptor tyrosine kinase is ectopically expressed in ALL patient samples and cell lines. Inhibition of Mer expression reduces prosurvival signaling, increases chemosensitivity, and delays development of leukemia in vivo, suggesting that Mer tyrosine kinase inhibitors are excellent candidates for targeted therapies. Brain and spinal tumors are the second most common malignancies in childhood. Multiple chemotherapy approaches and radiotherapies have been attempted, yet overall survival remains dismal. Mer is also abnormally expressed in atypical teratoid/rhabdoid tumors (AT/RT), providing a rationale for targeting Mer as a therapeutic strategy. We have previously described UNC569, the first small-molecule Mer inhibitor. This article describes the biochemical and biologic effects of UNC569 in ALL and AT/RT. UNC569 inhibited Mer activation and downstream signaling through ERK1/2 and AKT, determined by Western blot analysis. Treatment with UNC569 reduced proliferation/survival in liquid culture, decreased colony formation in methylcellulose/soft agar, and increased sensitivity to cytotoxic chemotherapies. MYC transgenic zebrafish with T-ALL were treated with UNC569 (4 μmol/L for two weeks). Fluorescence was quantified as indicator of the distribution of lymphoblasts, which express Mer and enhanced GFP. UNC569 induced more than 50% reduction in tumor burden compared with vehicle- and mock-treated fish. These data support further development of Mer inhibitors as effective therapies in ALL and AT/RT. Mol Cancer Ther; 12(11); 2367–77. ©2013 AACR.
Significance of Inducible Very Fast Ventricular Tachycardia (Cycle Length 200–230 ms) After Early Reperfusion for ST-Segment–Elevation Myocardial Infarction
Authors: Zaman Sarah , Kumar Saurabh , Sullivan Janice , Narayan Arun , Thiagalingam Aravinda , Ross David L. , Kovoor Pramesh 
Published: August 2013

Background—
Electrophysiological study (EPS) after myocardial infarction may have a role in identifying patients at risk of sudden cardiac death. It has been shown previously that inducible very fast ventricular tachycardia (VT; cycle length [CL], 200–230 ms) is predictive of arrhythmia recurrence; however, its significance early after reperfusion in ST-segment–elevation myocardial infarction is unknown.

Methods and Results—

Consecutive patients with ST-segment–elevation myocardial infarction treated with primary percutaneous coronary intervention with a left ventricular ejection fraction ≤40% underwent early EPS with an implantable-cardioverter defibrillator implanted for inducible VT, but not for a negative EPS. The end point was the cumulative incidence of death or first arrhythmic event (defined as resuscitated cardiac arrest or spontaneous ventricular tachyarrhythmia). A total of 1721 patients with ST-segment–elevation myocardial infarction underwent early left ventricular ejection fraction assessment (median, 4 days after myocardial infarction) with a left ventricular ejection fraction ≤40% in 24%. EPS was performed in 290 eligible patients with no arrhythmia or ventricular fibrillation/flutter (CL<200 ms) induced in 203 patients (EPS negative, group 1), monomorphic VT induced in 87 patients, consisting of very fast VT in 67% (group 2; n=58), and standard VT (CL>230 ms) in 33% (group 3; n=29). Kaplan–Meier 4-year cumulative incidence of death or arrhythmia was 8.2±2.3%, 33.1±7.1%, and 37.0±10.2% in groups 1, 2, and 3, respectively (
P
<0.001).

Conclusions—
The majority of inducible VT in patients who have been reperfused early after ST-segment–elevation myocardial infarction is very fast VT (CL, 200–230 ms). This very fast VT incurs at least a similar risk of arrhythmia or death as inducible standard VT (CL>230 ms) and a significantly higher risk than patients with a negative EPS.
Arrhythmia Phenotype During Fetal Life Suggests Long-QT Syndrome Genotype
Authors: Cuneo Bettina F. , Etheridge Susan P. , Horigome Hitoshi , Sallee Denver , Moon-Grady Anita , Weng Hsin-Yi , Ackerman Michael J. , Benson D. Woodrow 
Published: August 2013

Background—
Fetal arrhythmias characteristic of long QT syndrome (LQTS) include torsades de pointes (TdP) and/or 2° atrioventricular block, but sinus bradycardia, defined as fetal heart rate <3% for gestational age, is most common. We hypothesized that prenatal rhythm phenotype might predict LQTS genotype and facilitate improved risk stratification and management.

Method and Results—

Records of subjects exhibiting fetal LQTS arrhythmias were reviewed. Fetal echocardiograms, neonatal ECG, and genetic testing were evaluated. We studied 43 subjects exhibiting fetal LQTS arrhythmias: TdP±2° atrioventricular block (group 1, n=7), isolated 2° atrioventricular block (group 2, n=4), and sinus bradycardia (group 3, n=32). Mutations in known LQTS genes were found in 95% of subjects tested. SCN5A mutations occurred in 71% of group 1, whereas 91% of subjects with KCNQ1 mutations were in group 3. Small numbers of subjects with KCNH2 mutations (n=4) were scattered in all 3 groups. Age at presentation did not differ among groups, and most subjects (n=42) were live-born with gestational ages of 37.5±2.8 weeks (mean±SD). However, those with TdP were typically delivered earlier. Prenatal treatment in group 1 terminated (n=2) or improved (n=4) TdP. The neonatal heart rate–corrected QT interval (mean±SE) of group 1 (664.7±24.9) was longer than neonatal heart rate–corrected QT interval in both group 2 (491.2±27.6;
P
=0.004) and group 3 (483.1±13.7;
P
<0.001). Despite medical and pacemaker therapy, postnatal cardiac arrest (n=4) or sudden death (n=1) was common among subjects with fetal/neonatal TdP.

Conclusions—
Rhythm phenotypes of fetal LQTS have genotype-suggestive features that, along with heart rate–corrected QT interval duration, may risk stratify perinatal management.
Outcome After Implantation of a Cardioverter-Defibrillator in Patients With Brugada Syndrome
Authors: Sacher Frédéric , Probst Vincent , Maury Philippe , Babuty Dominique , Mansourati Jacques , Komatsu Yuki , Marquie Christelle , Rosa Antonio , Diallo Abou , Cassagneau Romain , Loizeau Claire , Martins Raphael , Field Michael E. , Derval Nicolas , Miyazaki Shinsuke , Denis Arnaud , Nogami Akihiko , Ritter Philippe , Gourraud Jean-Baptiste , Ploux Sylvain , Rollin Anne , Zemmoura Adlane , Lamaison Dominique , Bordachar Pierre , Pierre Bertrand , Jaïs Pierre , Pasquié Jean-Luc , Hocini Mélèze , Legal François , Defaye Pascal , Boveda Serge , Iesaka Yoshito , Mabo Philippe , Haïssaguerre Michel 
Published: August 2013

Background—
Implantable cardioverter-defibrillator indications in Brugada syndrome remain controversial, especially in asymptomatic patients. Previous outcome data are limited by relatively small numbers of patients or short follow-up durations. We report the outcome of patients with Brugada syndrome implanted with an implantable cardioverter-defibrillator in a large multicenter registry.

Methods and Results—
A total of 378 patients (310 male; age, 46±13 years) with a type 1 Brugada ECG pattern implanted with an implantable cardioverter-defibrillator (31 for aborted sudden cardiac arrest, 181 for syncope, and 166 asymptomatic) were included. Fifteen patients (4%) were lost to follow-up. During a mean follow-up of 77±42 months, 7 patients (2%) died (1 as a result of an inappropriate shock), and 46 patients (12%) had appropriate device therapy (5±5 shocks per patient). Appropriate device therapy rates at 10 years were 48% for patients whose implantable cardioverter-defibrillator indication was aborted sudden cardiac arrest, 19% for those whose indication was syncope, and 12% for the patients who were asymptomatic at implantation. At 10 years, rates of inappropriate shock and lead failure were 37% and 29%, respectively. Inappropriate shock occurred in 91 patients (24%; 4±4 shocks per patient) because of lead failure (n=38), supraventricular tachycardia (n=20), T-wave oversensing (n=14), or sinus tachycardia (n=12). Importantly, introduction of remote monitoring, programming a high single ventricular fibrillation zone (>210–220 bpm), and a long detection time were associated with a reduced risk of inappropriate shock.

Conclusions—
Appropriate therapies are more prevalent in symptomatic Brugada syndrome patients but are not insignificant in asymptomatic patients (1%/y). Optimal implantable cardioverter-defibrillator programming and follow-up dramatically reduce inappropriate shock. However, lead failure remains a major problem in this population.
Purification of Cardiomyocytes From Differentiating Pluripotent Stem Cells Using Molecular Beacons That Target Cardiomyocyte-Specific mRNA
Authors: Ban Kiwon , Wile Brian , Kim Sangsung , Park Hun-Jun , Byun Jaemin , Cho Kyu-Won , Saafir Talib , Song Ming-Ke , Yu Shan Ping , Wagner Mary , Bao Gang , Yoon Young-Sup 
Published: August 2013

Background—
Although methods for generating cardiomyocytes from pluripotent stem cells have been reported, current methods produce heterogeneous mixtures of cardiomyocytes and noncardiomyocyte cells. Here, we report an entirely novel system in which pluripotent stem cell–derived cardiomyocytes are purified by cardiomyocyte-specific molecular beacons (MBs). MBs are nanoscale probes that emit a fluorescence signal when hybridized to target mRNAs.

Method and Results—
Five MBs targeting mRNAs of either cardiac troponin T or myosin heavy chain 6/7 were generated. Among 5 MBs, an MB that targeted myosin heavy chain 6/7 mRNA (MHC1-MB) identified up to 99% of HL-1 cardiomyocytes, a mouse cardiomyocyte cell line, but <3% of 4 noncardiomyocyte cell types in flow cytometry analysis, which indicates that MHC1-MB is specific for identifying cardiomyocytes. We delivered MHC1-MB into cardiomyogenically differentiated pluripotent stem cells through nucleofection. The detection rate of cardiomyocytes was similar to the percentages of cardiac troponin T– or cardiac troponin I–positive cardiomyocytes, which supports the specificity of MBs. Finally, MHC1-MB–positive cells were sorted by fluorescence-activated cell sorter from mouse and human pluripotent stem cell differentiating cultures, and ≈97% cells expressed cardiac troponin T or cardiac troponin I as determined by flow cytometry. These MB-based sorted cells maintained their cardiomyocyte characteristics, which was verified by spontaneous beating, electrophysiological studies, and expression of cardiac proteins. When transplanted in a myocardial infarction model, MB-based purified cardiomyocytes improved cardiac function and demonstrated significant engraftment for 4 weeks without forming tumors.

Conclusions—
We developed a novel cardiomyocyte selection system that allows production of highly purified cardiomyocytes. These purified cardiomyocytes and this system can be valuable for cell therapy and drug discovery.
Falls prevention education for older adults during and after hospitalization: A systematic review and meta-analysis
Authors: Lee Den-Ching A , Pritchard Elizabeth , McDermott Fiona , Haines Terry P 
Published: August 2013

Objectives: To assess the effectiveness of patient education in reducing falls, promoting behavioural change and the uptake of prevention activities in older adults during and after hospitalization. Design: Systematic review and meta-analysis. Methods: A systematic search of five health science databases was performed up to November 2012. Studies that investigated patient education as a single intervention or in a multifactorial falls prevention programme in the hospital and/or post-discharge community settings, were eligible for inclusion. Standard meta-analysis methods were used to assess the effectiveness of patient education compared to usual care. Tests for heterogeneity, subgroup meta-analyses and a priori subgroup meta-analyses were performed for primary outcomes where appropriate. Primary outcomes were incidence of falls, falls-related injury and healthcare use due to falls. Secondary outcomes were mechanisms of behavioural change in falls prevention. Qualitative data were analysed by narrative review. Results: Falls prevention programmes that contained patient education were effective in reducing fall rates amongst hospital inpatients and post-discharge populations (risk ratio [RR] 0.77, 95% confidence interval [CI] 0.69 to 0.87), and in reducing the proportion of patients who became fallers in hospital (RR 0.78, 95% CI 0.7 to 0.87). Patient education generally increased knowledge about falls and awareness of prevention strategies. The uptake of strategies may be dependent on the activities being targeted. Conclusion: Falls prevention education should be recommended for older adults while in hospital and following discharge. Falls education programmes should consider the use of intensive face-to-face patient education with multimedia materials in preference to provision of written information alone or brief amounts of interpersonal contact.
Factors Associated With the Failure of Surgical Treatment for Femoroacetabular Impingement
Authors: Saadat Ehsan , Martin Scott D. , Thornhill Thomas S. , Brownlee Sarah A. , Losina Elena , Katz Jeffrey N. 
Published: August 2013

Background: With the recent increased recognition of femoroacetabular impingement (FAI) as a cause of hip pain and early osteoarthritis, surgical treatment has proliferated. There is a growing body of literature on outcomes of surgical intervention for FAI, but factors associated with inferior surgical outcomes have not been reviewed systematically. Purpose: To review the available literature and identify factors associated with the failure of open or arthroscopic surgery for FAI. Study Design: Systematic review. Methods: Using the PubMed database, we searched for relevant English-language articles published from January 1966 through August 2012. Inclusion criteria were a primary focus on the surgical treatment of FAI, measurement of functional or pain outcomes, identification of treatment failures, and statistical analysis of factors leading to failure. Exclusion criteria were review articles, technique-only articles, and studies of nonoperative management. Two definitions of failure were considered: (1) a lack of statistically significant improvement in validated measures of pain, function, or satisfaction postoperatively; and (2) revision surgery or conversion to hip arthroplasty because of persistent symptoms. The consistency of association between preoperative variables and clinical outcomes was reported across all studies. Results: Thirteen studies were included. Three were retrospective; there were no randomized controlled trials. Many studies had important methodological limitations. Preoperative cartilage damage or osteoarthritis had the strongest and most consistent relationship with conversion to hip arthroplasty and with a lack of improvement in pain or function. Greater age at the index operation, worse preoperative modified Harris Hip Score, and longer duration of symptoms preoperatively (>1.5 years) were associated with conversion to hip arthroplasty. Conclusion: Older age, presence of arthritic changes, longer duration of symptoms, and worse preoperative pain and functional scores are associated with poor outcomes of surgery for FAI. Incorporation of these data into discussions with patients may facilitate informed, shared decision making about the surgical treatment of FAI.