bluuebunny/crossref_metadata_2025_split huggingface dataset:
RANK Induces Epithelial–Mesenchymal Transition and Stemness in Human Mammary Epithelial Cells and Promotes Tumorigenesis and Metastasis
Authors: Palafox Marta , Ferrer Irene , Pellegrini Pasquale , Vila Sergi , Hernandez-Ortega Sara , Urruticoechea Ander , Climent Fina , Soler Maria Teresa , Muñoz Purificación , Viñals Francesc , Tometsko Mark , Branstetter Dan , Dougall William C. , González-Suárez Eva 
Published: April 2012

Abstract
Paracrine signaling through receptor activator of NF-κB (RANK) pathway mediates the expansion of mammary epithelia that occurs during pregnancy, and activation of RANK pathway promotes mammary tumorigenesis in mice. In this study we extend these previous data to human cells and show that the RANK pathway promotes the development of mammary stem cells and breast cancer. Overexpression of RANK (FL-RANK) in a panel of tumoral and normal human mammary cells induces the expression of breast cancer stem and basal/stem cell markers. High levels of RANK in untransformed MCF10A cells induce changes associated with both stemness and transformation, including mammary gland reconstitution, epithelial–mesenchymal transition (EMT), increased migration, and anchorage-independent growth. In addition, spheroids of RANK overexpressing MCF10A cells display disrupted acinar formation, impair growth arrest and polarization, and luminal filling. RANK overexpression in tumor cells with nonfunctional BRCA1 enhances invasiveness in acinar cultures and increases tumorigenesis and metastasis in immunodeficient mice. High levels of RANK were found in human primary breast adenocarcinomas that lack expression of the hormone receptors, estrogen and progesterone, and in tumors with high pathologic grade and proliferation index; high RANK/RANKL expression was significantly associated with metastatic tumors. Together, our findings show that RANK promotes tumor initiation, progression, and metastasis in human mammary epithelial cells by increasing the population of CD44+CD24− cells, inducing stemness and EMT. These results suggest that RANK expression in primary breast cancer associates with poor prognosis. Cancer Res; 72(11); 2879–88. ©2012 AACR.
Mutations in the Ras–Raf Axis Underlie the Prognostic Value of CD133 in Colorectal Cancer
Authors: Kemper Kristel , Versloot Miranda , Cameron Katherine , Colak Selçuk , de Sousa e Melo Felipe , de Jong Joan H. , Bleackley Joanne , Vermeulen Louis , Versteeg Rogier , Koster Jan , Medema Jan Paul 
Published: April 2012

AbstractPurpose: High expression of cancer stem cell (CSC) marker CD133 has been used as a predictor for prognosis in colorectal cancer (CRC), suggesting that enumeration of CSCs, using CD133, is predictive for disease progression. However, we showed recently that both CD133 mRNA and protein are not downregulated during differentiation of colon CSCs, pointing to an alternative reason for the prognostic value of CD133. We therefore set out to delineate the relation between CD133 expression and prognosis.Experimental Design: A CRC patient series was studied for expression of CD133 and other CSC markers by microarray and quantitative PCR analysis. In addition, several common mutations were analyzed to determine the relation with CD133 expression.Results: CD133 mRNA expression predicted relapse-free survival in our patient series, whereas several other CSC markers could not. Moreover, no correlation was found between expression of other CSC markers and CD133. Interestingly, high CD133 expression was related to mutations in K-Ras and B-Raf, and inhibition of mutant K-Ras or downstream mitogen-activated protein kinase kinase (MEK) signaling decreases CD133 expression. In addition, an activated K-Ras gene expression signature could predict CD133 expression in our patient set as well as data sets of other tumor types.Conclusion: CD133 expression is upregulated in CRC tumors that have a hyperactivated Ras–Raf–MEK–ERK pathway and is therefore related to mutations in K-Ras or B-Raf. As mutations in either gene have been related to poor prognosis, we conclude that CD133 expression is not indicative for CSC numbers but rather related to the mutation or activity status of the Ras–Raf pathway. Clin Cancer Res; 18(11); 3132–41. ©2012 AACR.
MSH3 Protein Expression and Nodal Status in MLH1-Deficient Colorectal Cancers
Authors: Laghi Luigi , Bianchi Paolo , Delconte Gabriele , Celesti Giuseppe , Di Caro Giuseppe , Pedroni Monica , Chiaravalli Anna Maria , Jung Barbara , Capella Carlo , de Leon Maurizio Ponz , Malesci Alberto 
Published: April 2012

Abstract
Purpose: Patients with colorectal cancers (CRC) and high microsatellite instability (MSI) have a better outcome than their chromosome-unstable counterpart. Given the heterogeneity of microsatellite-unstable CRCs, we wanted to see whether any MSI-associated molecular features are specifically associated with prognosis.
Experimental Design: One hundred and nine MSI-high CRCs were typed for primary mismatch repair (MMR) defect and for secondary loss of MMR proteins. Frameshifts at seven target genes, mutations in the RAS pathway, and methylation at MLH1/CDKN2A promoters were also searched. The interplay of molecular findings with clinicopathologic features and patient survival was analyzed.
Results: Of 84 MLH1-deficient CRCs, 31 (36.9%) had MSH3 and 11 (13.1%) had MSH6 loss (P &lt; 0.001), biallelic frameshift mutations at mononucleotide repeats accounting for most (78%) MSH3 losses. As compared with MSH3-retaining cancers, MLH1-deficient tumors with MSH3 loss showed a higher number of mutated target genes (3.94 ± 1.56 vs. 2.79 ± 1.75; P = 0.001), absence of nodal involvement at pathology [N0; OR, 0.11; 95% confidence interval (CI), 0.04–0.43, P &lt; 0.001], and better disease-free survival (P = 0.06). No prognostic value was observed for KRAS status and for MLH1/CDKN2A promoter methylation. The association between MSH3 loss and N0 was confirmed in an independent cohort of 71 MLH1-deficient CRCs (OR, 0.23; 95% CI, 0.06–0.83, P = 0.02).
Conclusions: MLH1-deficient CRCs not expressing MSH3 have a more severe MSI, a lower rate of nodal involvement, and a better postsurgical outcome. Clin Cancer Res; 18(11); 3142–53. ©2012 AACR.
Subclinical Peripheral Neuropathy Is a Common Finding in Colorectal Cancer Patients Prior to Chemotherapy
Authors: Boyette-Davis Jessica A. , Eng Cathy , Wang Xin S. , Cleeland Charles S. , Wendelschafer-Crabb Gwen , Kennedy William R. , Simone Donald A. , Zhang Haijun , Dougherty Patrick M. 
Published: April 2012

Abstract
Purpose: Of the numerous complications associated with cancer and cancer treatment, peripheral neuropathy is a deleterious and persistent patient complaint commonly attributed to chemotherapy. The present study investigated the occurrence of subclinical peripheral neuropathy in patients with colorectal cancer before the initiation of chemotherapy.
Experimental Design: Fifty-two patients underwent extensive quantitative sensory testing (QST) before receiving chemotherapy. Changes in multiple functions of primary afferent fibers were assessed and compared with a group of healthy control subjects. Skin temperature, sensorimotor function, sharpness detection, and thermal detection were measured, as was touch detection, using both conventional (von Frey monofilaments) and novel (Bumps detection test) methodology.
Results: Patients had subclinical deficits, especially in sensorimotor function, detection of thermal stimuli, and touch detection that were present before the initiation of chemotherapy. The measured impairment in touch sensation was especially pronounced when using the Bumps detection test.
Conclusions: The patients with colorectal cancer in this study exhibited deficits in sensory function before undergoing chemotherapy treatment, implicating the disease itself as a contributing factor in chemotherapy-induced peripheral neuropathy. The widespread nature of the observed deficits further indicated that cancer is affecting multiple primary afferent subtypes. Specific to the finding of impaired touch sensation, results from this study highlight the use of newly used methodology, the Bumps detection test, as a sensitive and useful tool in the early detection of peripheral neuropathy. Clin Cancer Res; 18(11); 3180–7. ©2012 AACR.
Bridging the Gap between Preclinical and Clinical Studies Using Pharmacokinetic–Pharmacodynamic Modeling: An Analysis of GDC-0973, a MEK Inhibitor
Authors: Wong Harvey , Vernillet Laurent , Peterson Amy , Ware Joseph A. , Lee Lillian , Martini Jean-Francois , Yu Peiwen , Li Congfen , Rosario Geoffrey Del , Choo Edna F. , Hoeflich Klaus P. , Shi Yongchang , Aftab Blake T. , Aoyama Ron , Lam Sanh Tan , Belvin Marcia , Prescott John 
Published: April 2012

Abstract
Purpose: GDC-0973 is a potent and selective mitogen-activated protein (MAP)/extracellular signal–regulated kinase (ERK) kinase (MEK) inhibitor. Pharmacokinetic–pharmacodynamic (PK–PD) modeling was used to relate GDC-0973 plasma and tumor concentrations, tumor pharmacodynamics and antitumor efficacy to establish pharmacokinetic endpoints and predict active doses in the clinic.
Experimental Design: A PK–PD model was used to characterize GDC-0973 tumor disposition and in vivo potency in WM-266-4 xenograft mice. Simulations were conducted using the PK–PD model along with human pharmacokinetics to identify a target plasma concentration and predict active doses. In vivo potency and antitumor efficacy were characterized in A375 melanoma xenograft mice, and a population-based integrated PK–PD-efficacy model was used to relate tumor pharmacodynamics (%pERK decrease) to antitumor activity.
Results: GDC-0973 showed a sustained tumor pharmacodynamic response due to longer residence in tumor than in plasma. Following single doses of GDC-0973, estimated in vivo IC50 values of %pERK decrease based on tumor concentrations in xenograft mice were 0.78 (WM-266-4) and 0.52 μmol/L (A375). Following multiple doses of GDC-0973, the estimated in vivo IC50 value in WM-266-4 increased (3.89 μmol/L). Human simulations predicted a minimum target plasma concentration of 83 nmol/L and an active dose range of 28 to 112 mg. The steep relationship between tumor pharmacodynamics (%pERK decrease) and antitumor efficacy suggests a pathway modulation threshold beyond which antitumor efficacy switches on.
Conclusions: Clinical observations of %pERK decrease and antitumor activity were consistent with model predictions. This article illustrates how PK–PD modeling can improve the translation of preclinical data to humans by providing a means to integrate preclinical and early clinical data. Clin Cancer Res; 18(11); 3090–9. ©2012 AACR.
Identification and Characterization of MEL-3, a Novel AR Antagonist That Suppresses Prostate Cancer Cell Growth
Authors: Helsen Christine , Marchand Arnaud , Chaltin Patrick , Munck Sebastian , Voet Arnout , Verstuyf Annemieke , Claessens Frank 
Published: April 2012

Abstract
Antiandrogens are an important component of prostate cancer therapy as the androgen receptor (AR) is the key regulator of prostate cancer growth and survival. Current AR antagonists, such as bicalutamide and hydroxyflutamide, have a low affinity for the AR and as a result block AR signaling insufficiently. Moreover, many patients develop a resistance for bicalutamide or hydroxyflutamide during therapy or show a clinical improvement after withdrawal of the antiandrogen. New and more effective AR antagonists are needed to ensure follow-up of these patients. We therefore developed a screening system to identify novel AR antagonists from a collection of compounds. MEL-3 [8-(propan-2-yl)-5,6-dihydro-4H-pyrazino[3,2,1-jk]carbazole] was selected as potent inhibitor of the AR and was further characterized in vitro. On different prostate cancer cell lines MEL-3 displayed an improved therapeutic profile compared with bicalutamide. Not only cell growth was inhibited but also the expression of androgen-regulated genes: PSA and FKBP5. Prostate cancer is often associated with mutated ARs that respond to a broadened spectrum of ligands including the current antiandrogens used in the clinic, hydroxyflutamide and bicalutamide. The activity of two mutant receptors (AR T877A and AR W741C) was shown to be reduced in presence of MEL-3, providing evidence that MEL-3 can potentially be a follow-up treatment for bicalutamide- and hydroxyflutamide-resistant patients. The mechanism of action of MEL-3 on the molecular level was further explored by comparing the structure–activity relationship of different chemical derivatives of MEL-3 with the in silico docking of MEL-3 derivatives in the binding pocket of the AR. Mol Cancer Ther; 11(6); 1257–68. ©2012 AACR.
Evolutionary Pathways in BRCA1-Associated Breast Tumors
Authors: Martins Filipe C. , De Subhajyoti , Almendro Vanessa , Gönen Mithat , Park So Yeon , Blum Joanne L. , Herlihy William , Ethington Gabrielle , Schnitt Stuart J. , Tung Nadine , Garber Judy E. , Fetten Katharina , Michor Franziska , Polyak Kornelia 
Published: April 2012

Abstract
BRCA1-associated breast tumors display loss of BRCA1 and frequent somatic mutations of PTEN and TP53. Here we describe the analysis of BRCA1, PTEN, and p53 at the single cell level in 55 BRCA1-associated breast tumors and computational methods to predict the relative temporal order of somatic events, on the basis of the frequency of cells with single or combined alterations. Although there is no obligatory order of events, we found that loss of PTEN is the most common first event and is associated with basal-like subtype, whereas in the majority of luminal tumors, mutation of TP53 occurs first and mutant PIK3CA is rarely detected. We also observed intratumor heterogeneity for the loss of wild-type BRCA1 and increased cell proliferation and centrosome amplification in the normal breast epithelium of BRCA1 mutation carriers. Our results have important implications for the design of chemopreventive and therapeutic interventions in this high-risk patient population.
Significance: Defining the temporal order of tumor-driving somatic events is critical for early detection, risk stratification, and the design of chemopreventive therapies. Our combined experimental and computational approach reveal that the loss of wild-type BRCA1 may not be the first event in the majority of BRCA1-associated breast tumors and may not be present in all cancer cells within tumors. Cancer Discov; 2(6); 503–11. ©2012 AACR.
This article is highlighted in the In This Issue feature, p. 473
A Spotlight from Prostate Cancer
Authors: Herschman Harvey R. , Czernin Johannes 
Published: April 2012

Abstract
Serum prostate-specific antigen (PSA) levels are used to monitor the development of prostate cancer, recurrence after surgery, and response to subsequent therapy. However, the clinical implications often are difficult to interpret. Ulmert and colleagues report use of a positron-emitting labeled monoclonal antibody directed to a unique PSA epitope to noninvasively image PSA-positive prostate cancer xenografts and to measure both androgen-stimulated PSA expression and androgen therapy-responsive PSA decreases. Cancer Discov; 2(4); 301–3. ©2012 AACR.
Commentary on Ulmert et al., p. 320.
Impact of Completeness of Revascularization on Long-Term Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus
Authors: Schwartz Leonard , Bertolet Marnie , Feit Frederick , Fuentes Francisco , Sako Edward Y. , Toosi Mehrdad S. , Davidson Charles J. , Ikeno Fumiaki , King Spencer B. 
Published: April 2012

Background—
Patients with diabetes have more extensive coronary disease than those without diabetes, resulting in more challenging percutaneous coronary intervention or surgical (coronary artery bypass graft) revascularization and more residual jeopardized myocardium. The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial provided an opportunity to examine the long-term clinical impact of completeness of revascularization in patients with diabetes.

Methods and Results—

This is a post hoc, nonrandomized analysis of the completeness of revascularization in 751 patients who were randomly assigned to early revascularization, of whom 264 underwent coronary artery bypass graft surgery and 487 underwent percutaneous coronary intervention. The completeness of revascularization was determined by the residual postprocedure myocardial jeopardy index (RMJI). RMJI is a ratio of the number of myocardial territories supplied by a significantly diseased epicardial coronary artery or branch that was not successfully revascularized, divided by the total number of myocardial territories. Mean follow-up for mortality was 5.3 years. Complete revascularization (RMJI=0) was achieved in 37.9% of patients, mildly incomplete revascularization (RMJI >0≤33) in 46.6%, and moderately to severely incomplete revascularization (RMJI >33) in 15.4%. Adjusted event-free survival was higher in patients with more complete revascularization (hazard ratio, 1.14;
P
=0.0018).

Conclusions—
Patients with type 2 diabetes mellitus and less complete revascularization had more long-term cardiovascular events.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00006305.
Transcatheter Aortic Valve Implantation in Patients With Severe Left Ventricular Dysfunction
Authors: Fraccaro Chiara , Al-Lamee Rasha , Tarantini Giuseppe , Maisano Francesco , Napodano Massimo , Montorfano Matteo , Frigo Anna Chiara , Iliceto Sabino , Gerosa Gino , Isabella Giambattista , Colombo Antonio 
Published: April 2012

Background—
Few data exist about transcatheter aortic valve implantation (TAVI) in patients with low ejection fraction. The aim of the study was to analyze safety, feasibility, and efficacy of TAVI in patients with severe left ventricular dysfunction.

Methods and Results—

The study sample (384 patients) was divided into 2 groups: group A (50 patients) with left ventricular ejection fraction (LVEF) ≤35%, and group B (334 patients) with LVEF >35%. Clinical, anatomic, and hemodynamic variables, as well as procedural results and follow-up outcomes, were compared between the groups. Procedural success was reached in 88%, with no significant difference between the groups. The incidence of periprosthetic leak >2+/4 after TAVI was higher in group A. All other complications were similar between the 2 groups. Group A showed a significant and early improvement in LVEF (from 27.7±6.0–35.2±11.1 after TAVI;
P
<0.0001). Thirty-day mortality was 4%; however, this was higher in group A compared with group B (10% versus 3%;
P
=0.010). Predictors of the cumulative late mortality were congestive heart failure, logistic euroSCORE, and moderate-to-severe periprosthetic leakage after TAVI. Estimated survival by Kaplan Meier at 1 year was, respectively, 69% in group A and 87% in group B (log rank <0.0001).

Conclusions—
Transcatheter aortic valve implantation is a safe and effective procedure, even in patients with severe left ventricular dysfunction, leading to a high procedural success rate with an acceptable rate of complications and 30-day mortality. Also in these critically ill patients, TAVI provides clinical amelioration, with early improvement in LVEF.
Impact of Drug-Eluting Stents on Distal Vessels
Authors: Wakabayashi Kohei , Mintz Gary S. , Weissman Neil J. , Stone Gregg W. , Ellis Stephen G. , Grube Eberhard , Ormiston John A. , Turco Mark A. , Pakala Rajbabu , Xue Zhenyi , Desale Sameer , Laynez-Carnicero Ana , Romaguera Rafael , Sardi Gabriel , Pichard Augusto D. , Waksman Ron 
Published: April 2012

Background—
Previous studies have not addressed vessel response >5 mm distal to the stent edge. Therefore, we investigated the impact of paclitaxel-eluting stents (PES) versus bare metal stents (BMS) on distal vessels in the serial intravascular ultrasound substudies of TAXUS IV, V, and VI.

Methods and Results—

TAXUS IV, V, and VI were double-blind, randomized, multicenter, controlled trials comparing PES with BMS. In their intravascular ultrasound substudies, 103 patients (54 BMS, 49 PES) had intravascular ultrasound data ≥10 mm distal to the stent both postprocedure and at 9 months follow-up. Baseline characteristics were similar between the 2 groups. Multilevel modeling was used to account for the variation between patients and within patients among distal segments. Effect of stent type, time, and their interaction was tested using a mixed effect model controlling for distal segments. Postprocedure lumen and vessel were not significantly different between PES versus BMS; however, lumen (
P
=0.006) and vessel (
P
=0.0001) were significantly reduced for BMS at 9-month follow-up but not for PES. Conversely, there was a significant plaque increase from postprocedure to 9-month follow-up for PES (
P
=0.0008) but not for BMS. These vessel responses were statistically consistent among 0- to 5-mm versus 5- to 10-mm versus 10- to 15-mm segments distal to the stent in both groups.

Conclusions—
PES use was associated with plaque increase from baseline to 9-month follow-up >5 mm distal to the stent along with positive remodeling, whereas BMS use was associated with negative remodeling and no plaque increase. These vessel responses were consistent in 5-mm long subsegments: 0 to 5 mm versus 5 to 10 mm versus 10 to 15 mm distal to the stent.

Clinical Trial Registration—

URL:
http://www.clinicaltrial.gov
. Unique identifiers: TAXUS IV—NCT00292474; TAXUS V—NCT00301522; TAXUS VI—NCT00297804.
Magnetic Resonance Imaging With 3-Dimensional Analysis of Left Ventricular Remodeling in Isolated Mitral Regurgitation
Authors: Schiros Chun G. , Dell'Italia Louis J. , Gladden James D. , Clark Donald , Aban Inmaculada , Gupta Himanshu , Lloyd Steven G. , McGiffin David C. , Perry Gilbert , Denney Thomas S. , Ahmed Mustafa I. 
Published: April 2012

Background—
Although surgery is indicated in patients with mitral regurgitation (MR) when left ventricular (LV) end-systolic (LVES) dimension is >40 mm, LV ejection fraction may decrease after mitral valve surgery. We hypothesize that significant LV remodeling before surgery is not reflected by standard echocardiographic parameters measured at the base of the heart.

Methods and Results—

Ninety-four patients (age, 54±11 years; 38% female) with degenerative isolated MR underwent cine magnetic resonance imaging with tissue tagging and 3-dimensional analysis. In 51 control subjects (age, 44±14 years; 53% female), the relation between LVES volume (LVESV) and LVES dimension was quadratic, whereas in 94 MR patients, this relation was cubic, indicating a greater increase in LVESV per LVES dimension among MR patients. Moreover, magnetic resonance imaging LVESV from summated serial short-axis slices was significantly greater than LVESV assessed with the Bullet formula in MR patients, attributed to a more spherical remodeling distal to the tips of the papillary muscles (
P
<0.001). Thirty-five patients underwent mitral valve repair per current guideline recommendations. LV ejection fraction decreased from 61±7% to 54±8% (
P
<0.0001) and maximum shortening decreased significantly below normal at 1 year postoperatively (
P
<0.0001). Despite normalization of LV stroke volume and LV end-diastolic volume/mass ratio, there was a persistent significant increase in distal LVES 3-dimensional radius/wall thickness ratio and LVESV index after surgery.

Conclusions—
Despite apparently preserved LVES dimension, MR patients demonstrate significant spherical mid to apical LVES remodeling that contributes to higher LVESV than predicted by standard geometry-based calculations. Decreased LV strain after surgery suggests that a volumetric analysis of LV remodeling and function may be preferred to evaluate disease progression in isolated MR.