bluuebunny/crossref_metadata_2025_split huggingface dataset:
A randomised controlled trial comparing surgical intervention rates between two protocols for the management of asymptomatic adnexal tumours in postmenopausal women
Authors: Nunes Natalie , Foo Xulin , Widschwendter Martin , Jurkovic Davor 
Published: December 2012

IntroductionDetection of asymptomatic adnexal tumours in postmenopausal women has increased due to wider use of diagnostic ultrasound and imaging quality improvements. Reliable methods to differentiate between benign and malignant tumours are required to avoid delays in treating ovarian cancer and to prevent unnecessary interventions for benign lesions. In the UK, the Royal College of Obstetricians and Gynaecologists has issued guidance for the management of adnexal cysts in postmenopausal women, which is considered standard in routine clinical practice. The protocol utilises the Risk of Malignancy Index to assess the risk of adnexal lesion being malignant. This protocol has a relatively high intervention rate in order to avoid a delay in a cancer diagnosis. The Simple Rules Protocol designed by International Ovarian Tumour Analysis Group reports a low false-positive rate in the diagnosis of ovarian cancer without a loss of sensitivity and therefore has the potential to reduce unnecessary interventions in asymptomatic postmenopausal women with benign cysts.Methods and analysis140 postmenopausal women aged 40–80, with incidentally detected adnexal tumours on ultrasound scan will be recruited to this study. They will be randomly allocated, to be assessed and managed according to either of the two protocols under investigation. In both arms of the study the tumours will be classified into three groups: high, intermediate or low risk of malignancy. Women with high risk of malignancy will be referred for management in a tertiary cancer centre, women with low-risk tumours will be managed expectantly, while those with intermediate risk findings have surgery in their local hospital units. Analysis will be on an intention-to-treat basis.Ethics and disseminationResearch ethical approval was granted by the North London Research Ethical Committee 2 (10/H0724/48). Trial results will be published according to the CONSORT statement.Trial registration numberRegistration athttp://www.controlled-trials.com/ISRCTN89034131/. ISRCTN89034131
Epigenetic Repression of miR-31 Disrupts Androgen Receptor Homeostasis and Contributes to Prostate Cancer Progression
Authors: Lin Pei-Chun , Chiu Ya-Lin , Banerjee Samprit , Park Kyung , Mosquera Juan Miguel , Giannopoulou Eugenia , Alves Pedro , Tewari Ashutosh K. , Gerstein Mark B. , Beltran Himisha , Melnick Ari M. , Elemento Olivier , Demichelis Francesca , Rubin Mark A. 
Published: December 2012

AbstractAndrogen receptor signaling plays a critical role in prostate cancer pathogenesis. Yet, the regulation of androgen receptor signaling remains elusive. Even with stringent androgen deprivation therapy, androgen receptor signaling persists. Here, our data suggest that there is a complex interaction between the expression of the tumor suppressor miRNA, miR-31, and androgen receptor signaling. We examined primary and metastatic prostate cancer and found that miR-31 expression was reduced as a result of promoter hypermethylation, and importantly, the levels of miR-31 expression were inversely correlated with the aggressiveness of the disease. As the expression of androgen receptor and miR-31 was inversely correlated in the cell lines, our study further suggested that miR-31 and androgen receptor could mutually repress each other. Upregulation of miR-31 effectively suppressed androgen receptor expression through multiple mechanisms and inhibited prostate cancer growth in vivo. Notably, we found that miR-31 targeted androgen receptor directly at a site located in the coding region, which was commonly mutated in prostate cancer. In addition, miR-31 suppressed cell-cycle regulators including E2F1, E2F2, EXO1, FOXM1, and MCM2. Together, our findings suggest a novel androgen receptor regulatory mechanism mediated through miR-31 expression. The downregulation of miR-31 may disrupt cellular homeostasis and contribute to the evolution and progression of prostate cancer. We provide implications for epigenetic treatment and support clinical development of detecting miR-31 promoter methylation as a novel biomarker. Cancer Res; 73(3); 1232–44. ©2012 AACR.
A Potent Combination of the Novel PI3K Inhibitor, GDC-0941, with Imatinib in Gastrointestinal Stromal Tumor Xenografts: Long-Lasting Responses after Treatment Withdrawal
Authors: Floris Giuseppe , Wozniak Agnieszka , Sciot Raf , Li Haifu , Friedman Lori , Van Looy Thomas , Wellens Jasmien , Vermaelen Peter , Deroose Christophe M. , Fletcher Jonathan A. , Debiec-Rychter Maria , Schöffski Patrick 
Published: December 2012

Abstract
Purpose: Oncogenic signaling in gastrointestinal stromal tumors (GIST) is sustained via PI3K/AKT pathway. We used a panel of six GIST xenograft models to assess efficacy of GDC-0941 as single agent or in combination with imatinib (IMA).
Experimental Design: Nude mice (n = 136) were grafted bilaterally with human GIST carrying diverse KIT mutations. Mice were orally dosed over four weeks, grouped as follows: (A) control; (B) GDC-0941; (C) imatinib, and (D) GDC+IMA treatments. Xenografts regrowth after treatment discontinuation was assessed in groups C and D for an additional four weeks. Tumor response was assessed by volume measurements, micro-PET imaging, histopathology, and immunoblotting. Moreover, genomic alterations in PTEN/PI3K/AKT pathway were evaluated.
Results: In all models, GDC-0941 caused tumor growth stabilization, inhibiting tumor cell proliferation, but did not induce apoptosis. Under GDC+IMA, profound tumor regression, superior to either treatment alone, was observed. This effect was associated with the best histologic response, a nearly complete proliferation arrest and increased apoptosis. Tumor regrowth assays confirmed superior activity of GDC+IMA over imatinib; in three of six models, tumor volume remained reduced and stable even after treatment discontinuation. A positive correlation between response to GDC+IMA and PTEN loss, both on gene and protein levels, was found.
Conclusion: GDC+IMA has significant antitumor efficacy in GIST xenografts, inducing more substantial tumor regression, apoptosis, and durable effects than imatinib. Notably, after treatment withdrawal, tumor regression was sustained in tumors exposed to GDC+IMA, which was not observed under imatinib. Assessment of PTEN status may represent a useful predictive biomarker for patient selection. Clin Cancer Res; 19(3); 620–30. ©2012 AACR.
Knockdown of PAK4 or PAK1 Inhibits the Proliferation of Mutant KRAS Colon Cancer Cells Independently of RAF/MEK/ERK and PI3K/AKT Signaling
Authors: Tabusa Hana , Brooks Teresa , Massey Andrew J. 
Published: December 2012

Abstract
The p21-activated kinase (PAK) serine/threonine kinases are important effectors of the small GTPases Rac and Cdc42, and play significant roles in controlling cell growth, motility, and transformation. Knockdown of PAK4 or PAK1 inhibited the proliferation of mutant KRAS or BRAF colon cancer cells in vitro. Dependence on PAK4 or PAK1 protein for colon cancer cell proliferation was independent of PAK4 or PAK1 protein expression levels. Mutant KRAS HCT116 colorectal cells were the most sensitive to PAK4 or PAK1 knockdown resulting in the potent inhibition of anchorage-dependent and -independent proliferation as well as the formation and proliferation of HCT116 colon cancer spheroids. This inhibition of proliferation did not correlate with inhibition of RAF/MEK/ERK or PI3K/AKT signaling. In HCT116 cells, knockdown of PAK4 or PAK1 caused changes to the actin cytoskeleton resulting in reduced basal spread and cell elongation and increased cell rounding. These cytoskeletal rearrangements seemed to be independent of LIMK/cofilin/paxillin phosphorylation. PAK4 or PAK1 knockdown initially induced growth arrest in HCT116 cells followed by cell death at later time points. Inhibition of the antiapoptotic proteins Bcl-2 and Bcl-XL with the pharmacologic inhibitor ABT-737 increased effector caspase activation and apoptosis, and reduced cell survival with PAK4 or PAK1 knockdown. These results support a role for the PAKs in the proliferation of mutant KRAS-driven colorectal carcinoma cells via pathways not involving RAF/MEK/ERK and PI3K/AKT signaling. Mol Cancer Res; 11(2); 109–21. ©2012 AACR.
miRNA-145 Targets v-ets Erythroblastosis Virus E26 Oncogene Homolog 1 to Suppress the Invasion, Metastasis, and Angiogenesis of Gastric Cancer Cells
Authors: Zheng Liduan , Pu Jiarui , Qi Teng , Qi Meng , Li Dan , Xiang Xuan , Huang Kai , Tong Qiangsong 
Published: December 2012

Abstract
Recent evidence shows that v-ets erythroblastosis virus E26 oncogene homolog 1 (Ets1) is implicated in tumor development and progression. However, the clinical potentials and underlying mechanisms of Ets1 in gastric cancer progression and metastasis remain largely unknown. In this study, Ets1 immunostaining was identified in 56 of 84 (66.7%) gastric cancer tissues, which was correlated with tumor invasion and metastasis. In gastric cancer specimens and cell lines, miRNA-145 (miR-145) was downregulated and inversely correlated with Ets1 expression. Bioinformatics analysis and luciferase reporter assay revealed that miR-145 directly targeted the 3′-untranslated region (3′-UTR) of Ets1 mRNA. Overexpression or knockdown of miR-145 responsively altered both the mRNA and protein levels of Ets1 and its downstream genes, matrix metalloproteinase (MMP-1)-1 and -9, in gastric cancer cell lines SGC-7901 and MKN-45. Ectopic expression of miR-145 suppressed the invasion, metastasis, and angiogenesis of SGC-7901 and MKN-45 cells in vitro and in vivo. In addition, the effects of miR-145 on Ets1 expression, migration, invasion, and angiogenesis were rescued by restoration of Ets1 expression in these cells. Furthermore, anti-miR-145 inhibitor promoted the migration, invasion, and angiogenesis, whereas siRNA-mediated Ets1 knockdown phenocopied the effects of miR-145 overexpression in gastric cancer cells. These results show that miR-145 suppresses Ets1 expression via the binding site in the 3′-UTR, thus inhibiting the invasion, metastasis, and angiogenesis of gastric cancer cells. Mol Cancer Res; 11(2); 182–93. ©2012 AACR.
Noncovalent Wild-type–Sparing Inhibitors of EGFR T790M
Authors: Lee Ho-June , Schaefer Gabriele , Heffron Timothy P. , Shao Lily , Ye Xiaofen , Sideris Steve , Malek Shiva , Chan Emily , Merchant Mark , La Hank , Ubhayakar Savita , Yauch Robert L. , Pirazzoli Valentina , Politi Katerina , Settleman Jeff 
Published: December 2012

Abstract
Approximately half of EGFR-mutant non–small cell lung cancer (NSCLC) patients treated with small-molecule EGFR kinase inhibitors develop drug resistance associated with the EGF receptor (EGFR) T790M “gatekeeper” substitution, prompting efforts to develop covalent EGFR inhibitors, which can effectively suppress EGFR T790M in preclinical models. However, these inhibitors have yet to prove clinically efficacious, and their toxicity in skin, reflecting activity against wild-type EGFR, may limit dosing required to effectively suppress EGFR T790M in vivo. While profiling sensitivity to various kinase inhibitors across a large cancer cell line panel, we identified indolocarbazole compounds, including a clinically well-tolerated FLT3 inhibitor, as potent and reversible inhibitors of EGFR T790M that spare wild-type EGFR. These findings show the use of broad cancer cell profiling of kinase inhibitor efficacy to identify unanticipated novel applications, and they identify indolocarbazole compounds as potentially effective EGFR inhibitors in the context of T790M-mediated drug resistance in NSCLC.
Significance: EGFR-mutant lung cancer patients who respond to currently used EGFR kinase inhibitors invariably develop drug resistance, which is associated with the EGFR T790M resistance mutation in about half these cases. We unexpectedly identified a class of reversible potent inhibitors of EGFR T790M that do not inhibit wild-type EGFR, revealing a promising therapeutic strategy to overcome T790M-associated drug-resistant lung cancers. Cancer Discov; 3(2); 168–81. ©2012 AACR.
See related commentary by Brewer and Pao, p. 138
This article is highlighted in the In This Issue feature, p. 125
Automated Quantitative 3-Dimensional Modeling of the Aortic Valve and Root by 3-Dimensional Transesophageal Echocardiography in Normals, Aortic Regurgitation, and Aortic Stenosis
Authors: Calleja Anna , Thavendiranathan Paaladinesh , Ionasec Razvan Ioan , Houle Helene , Liu Shizhen , Voigt Ingmar , Sai Sudhakar Chittoor , Crestanello Juan , Ryan Thomas , Vannan Mani A. 
Published: December 2012

Background—
We tested the ability of a novel automated 3-dimensional (3D) algorithm to model and quantify the aortic root from 3D transesophageal echocardiography (TEE) and computed tomographic (CT) data.

Methods and Results—

We compared the quantitative parameters obtained by automated modeling from 3D TEE (n=20) and CT data (n=20) to those made by 2D TEE and targeted 2D from 3D TEE and CT in patients without valve disease (normals). We also compared the automated 3D TEE measurements in severe aortic stenosis (n=14), dilated root without aortic regurgitation (n=15), and dilated root with aortic regurgitation (n=20). The automated 3D TEE sagittal annular diameter was significantly greater than the 2D TEE measurements (
P
=0.004). This was also true for the 3D TEE and CT coronal annular diameters (
P
<0.01). The average 3D TEE and CT annular diameter was greater than both their respective 2D and 3D sagittal diameters (
P
<0.001). There was no significant difference in 2D and 3D measurements of the sinotubular junction and sinus of valsalva diameters (
P
>0.05) in normals, but these were significantly different (
P
<0.05) in abnormals. The 3 automated intercommissural distance and leaflet length and height did not show significant differences in the normals (
P
>0.05), but all 3 were significantly different compared with the abnormal group (
P
<0.05). The automated 3D annulus commissure coronary ostia distances in normals showed significant difference between 3D TEE and CT (
P
<0.05); also, these parameters by automated 3D TEE were significantly different in abnormal (
P
<0.05). Finally, the automated 3D measurements showed excellent reproducibility for all parameters.

Conclusions—
Automated quantitative 3D modeling of the aortic root from 3D TEE or CT data is technically feasible and provides unique data that may aid surgical and transcatheter interventions.
Sex Differences in Aortic Valve Calcification Measured by Multidetector Computed Tomography in Aortic Stenosis
Authors: Aggarwal Shivani R. , Clavel Marie-Annick , Messika-Zeitoun David , Cueff Caroline , Malouf Joseph , Araoz Philip A. , Mankad Rekha , Michelena Hector , Vahanian Alec , Enriquez-Sarano Maurice 
Published: December 2012

Background—
Aortic valve calcification (AVC) is the intrinsic mechanism of valvular obstruction leading to aortic stenosis (AS) and is measurable by multidetector computed tomography. The link between sex and AS is controversial and that with AVC is unknown.

Methods and Results—

We prospectively performed multidetector computed tomography in 665 patients with AS (aortic valve area, 1.05±0.35 cm
2
; mean gradient, 39±19 mm Hg) to measure AVC and to assess the impact of sex on the AVC–AS severity link in men and women. AS severity was comparable between women and men (peak aortic jet velocity: 4.05±0.99 versus 3.93±0.91 m/s,
P
=0.11; aortic valve area index: 0.55±0.20 versus 0.56±0.18 cm
2
/m
2
;
P
=0.46). Conversely, AVC load was lower in women versus men (1703±1321 versus 2694±1628 arbitrary units;
P
<0.0001) even after adjustment for their smaller body surface area or aortic annular area (both
P
<0.0001). Thus, odds of high-AVC load were much greater in men than in women (odds ratio, 5.07;
P
<0.0001). Although AVC showed good associations with hemodynamic AS severity in men and women (all
r
>0.67;
P
<0.0001), for any level of AS severity measured by peak aortic jet velocity or aortic valve area index, AVC load, absolute or indexed, was higher in men versus women (all
P
≤0.01).

Conclusions—
In this large AS population, women incurred similar AS severity than men for lower AVC loads, even after indexing for their smaller body size. Hence, the relationship between valvular calcification process and AS severity differs in women and men, warranting further pathophysiological inquiry. For AS severity diagnostic purposes, interpretation of AVC load should be different in men and in women.
Achievement of Guideline-Concordant Care and In-Hospital Outcomes in Patients With Coronary Artery Disease in Teaching and Nonteaching Hospitals
Authors: Tam Lori M. , Fonarow Gregg C. , Bhatt Deepak L. , Grau-Sepulveda Maria V. , Hernandez Adrian F. , Peterson Eric D. , Schwamm Lee H. , Giugliano Robert P. 
Published: December 2012

Background—
Secondary prevention therapies improve longitudinal outcomes in patients with coronary artery disease. Previous studies showed that teaching hospitals (THs) more consistently use evidence-based secondary prevention therapies than non-THs (NTHs). It is unclear whether these differences persist after initiation of a national quality improvement system.

Methods and Results—

We analyzed 270902 patients across 361 hospitals in the Get With The Guidelines–Coronary Artery Disease program from June 2000 to September 2009. The primary outcome was guideline-concordant care, defined as compliance with all Get With The Guidelines–Coronary Artery Disease quality measures: (1) aspirin within 24 hours, (2) aspirin at discharge, (3) angiotensin-converting enzyme inhibitor/angiotensin receptor blockers for systolic dysfunction, (4) β-blockers at discharge, (5) lipid therapy if low-density lipoprotein >100 mg/dL, and (6) smoking cessation. We used multivariate modeling to compare the relationship between TH and NTH status on quality measures, in-hospital mortality, and length of stay. Guideline-concordant care was higher at THs (78.4% versus 73.3%; P<0.01). The adjusted odds ratio between 2000 and 2009 for guideline-concordant care at THs compared with NTHs was 2.78 (confidence interval, 1.28–6.06;
P
=0.01). Guideline-concordant care increased from 2000 to 2009 at THs (n=176; 65.3%→88.3%; adjusted odds ratio for year increase, 1.24 [confidence interval, 1.16–1.30; P<0.01]) and NTHs (n=185; 61.0%→93.9%; adjusted odds ratio for year increase, 1.35 [confidence interval, 1.26–1.45];
P
<0.01). THs had shorter length of stay (adjusted odds ratio, 0.74 for length of stay >4 days; confidence interval, 0.58–0.94) from 2000 to 2009. Lower in-hospital mortality was observed at THs (3.7% versus 4.4% at NTHs;
P
<0.01), but this was not significant after adjustment.

Conclusions—
Adherence to guideline-recommended therapies increased over time with participation in the Get With The Guidelines–Coronary Artery Disease program, regardless of the teaching status. Guideline-concordant care over the full decade was higher in THs; however, NTHs demonstrated greater incremental improvement over time.
Integrated Regional Networks for ST-Segment–Elevation Myocardial Infarction Care in Developing Countries
Authors: Solla Davi Jorge Fontoura , de Mattos Paiva Filho Ivan , Delisle Jacques Edouard , Braga Alecianne Azevedo , de Moura João Batista , de Moraes Xavier , Filgueiras Nivaldo Menezes , Carvalho Marcela Embiruçu , Martins Mariana Steque , Neto Orlando Manganotti , Filho Paulo Roberto , de Souza Roriz Pollianna 
Published: December 2012

Background—
Regionalized integrated networks for ST-segment–elevation myocardial infarction (STEMI) care have been proposed as a step forward in overcoming real-world obstacles, but data are lacking on its performance in developing countries. We describe an integrated regional STEMI network in Salvador, Bahia, Brazil.

Methods and Results—
The network was created in 2009. It was coordinated by the prehospital emergency medical service and encompassed the public emergency system (prehospital mobile units, community-based emergency units, general hospitals, and cardiology reference centers). The 12-lead ECGs are interpreted via telemedicine. This network operates as follows: The Telemedicine Center sends each ECG suggestive of STEMI to a Regional STEMI Alert Team, which, together with emergency medical services, offers support for thrombolysis or immediate transfer for primary percutaneous coronary intervention. In 14 months, there were 433 suspected victims, of which in 287 (76.5%) the STEMI could be confirmed (age, 62.1±12.5 years; 63.4% men). Most of them were self-transported. The median pain-to-admission time was 180 minutes (interquartile range, 90–473 minutes), and the median admission-to-ECG time was 159.5 minutes (interquartile range, 83.5–340 minutes). The median interval time between the ECG and the telemedicine report was 31 minutes (interquartile range, 21–44 minutes). For those who sought medical attention and had an ECG performed within 12 hours after symptoms onset (n=119), the reperfusion rate was 75.6% (34.4% by thrombolysis and 65.6% by primary percutaneous coronary intervention).

Conclusions—
Regional STEMI networks may be feasible in developing countries. Preliminary results showed this network to be effective, achieving primary reperfusion rtes comparable with those reported internationally despite the obstacles faced.
Blood–Brain Barrier Permeability and Long-Term Clinical and Imaging Outcomes in Cerebral Small Vessel Disease
Authors: Wardlaw Joanna M. , Doubal Fergus N. , Valdes-Hernandez Maria , Wang Xin , Chappell Francesca M. , Shuler Kirsten , Armitage Paul A. , Carpenter Trevor C. , Dennis Martin S. 
Published: December 2012

Background and Purpose—
Increased blood–brain barrier (BBB) permeability occurs in cerebral small vessel disease. It is not known if BBB changes predate progression of small vessel disease.

Methods—
We followed-up patients with nondisabling lacunar or cortical stroke and BBB permeability magnetic resonance imaging after their original stroke. Approximately 3 years later, we assessed functional outcome (Oxford Handicap Score, poor outcome defined as 3–6), recurrent neurological events, and white matter hyperintensity (WMH) progression on magnetic resonance imaging.

Results—

Among 70 patients with mean age of 68 (SD±11) years, median time to clinical follow-up was 39 months (interquartile range, 30–45) and median Oxford Handicap Score was 2 (interquartile range, 1–3); poor functional outcome was associated with higher baseline WMH score (
P
<0.001) and increased basal ganglia BBB permeability (
P
=0.046). Among 48 patients with follow-up magnetic resonance imaging, WMH progression at follow-up was associated with baseline WMH (ANCOVA
P
<0.0001) and age (ANCOVA
P
=0.032).

Conclusions—
Further long-term studies to evaluate the role of BBB dysfunction in progression of small vessel disease are required in studies that are large enough to account for key prognostic influences such as baseline WMH and age.