bluuebunny/crossref_metadata_2025 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

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

Purpose: 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

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 < 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 < 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

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

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

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

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

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.
Visualising a region: Phaniswarnath Renu and the archive of the ‘regional–rural’ in the 1950s
Authors: Jha Sadan
Published: April 2012

Anchored in the decade of 1950s, this article focuses on the writings of Phaniswarnath Renu to understand ways in which he represented the rural life of Kosi region. Also known as the old Purnea district of Bihar, this region has been historically visualised as unhealthy and backward. Following Michel Foucault’s notion of heterotopia, the article argues that Renu’s craftsmanship renders the backwardness of this region in a manner that highlights what Edward Soja calls ‘instrumentality of the space’. Unlike the dominant constructs of village life in India, Renu’s villages are neither empty of their geo-cultural specificities nor devoid of placeness. Instead, the landscape of a backward region is densely imbued with particulars that cannot be translocated to any other setting. Renu’s ‘regional–rural’ craftsmanship depended on three mutually connected factors. These include his innovative use of language forms distinguishing him from his predecessors like Premchand; his mobilisation of an enormous amount of information, which I shall call the cultural memory of the region; and third, his technique of storytelling. Together these three produce an archive for the reconstruction of the region at a particular historical juncture. This archive draws our attention to the apathy accrued to the dynamics of space by a large section of litterateurs as well as social scientists otherwise obsessed with the time.
Struggling against Dundee: Bengal jute industry during the nineteenth century
Authors: Ray Indrajit
Published: April 2012

This article seeks to situate Bengal’s jute industry during the nineteenth century in a global perspective. It was a long-established cottage industry in Bengal that entered into the global market before the advent of jute technologies at Dundee, and grew together with the Dundee mills through the mid-nineteenth century. The subsequent emergence of modern mills in Bengal further aggravated the market competition. In view of inadequate deliberations in the existing literature, we intend to investigate four important questions on the contemporary jute industry: ( a) what was the development status of the traditional jute industry in Bengal around the mid-nineteenth century?; ( b) when did it enter into the phase of decline?; ( c) what were the sources of comparative advantages between the Dundee and Calcutta mills?; and ( d) what were the nature and consequences of competition between them? These issues are discussed, and also quantified, wherever possible, on the basis of contemporary data and information. The welfare implications of Bengal jute industry are also evaluated.
PRIO-GRID: A unified spatial data structure
Authors: Tollefsen Andreas Forø , Strand Håvard , Buhaug Halvard
Published: April 2012

Contributions to the quantitative civil war literature increasingly rely on geo-referenced data and disaggregated research designs. While this is a welcome trend, it necessitates geographic information systems (GIS) skills and imposes new challenges for data collection and analysis. So far, solutions to these challenges differ between studies, obstructing direct comparison of findings and hampering replication and extension of earlier work. This article presents a standardized structure for storing, manipulating, and analyzing high-resolution spatial data. PRIO-GRID is a vector grid network with a resolution of 0.5 x 0.5 decimal degrees, covering all terrestrial areas of the world. Gridded data comprise inherently apolitical entities; the grid cells are fixed in time and space, they are insensitive to political boundaries and developments, and they are completely exogenous to likely features of interest, such as civil war outbreak, ethnic settlement patterns, extreme weather events, or the spatial distribution of wealth. Moreover, unlike other disaggregated approaches, gridded data may be scaled up or down in a consistent manner by varying the resolution of the grid. The released dataset comes with cell-specific information on a large selection of political, economic, demographic, environmental, and conflict variables for all years, 1946–2008. A simple descriptive data assessment of population density and economic activity is offered to demonstrate how PRIO-GRID may be applied in quantitative social science research.
Introducing the UCDP Non-State Conflict Dataset
Authors: Sundberg Ralph , Eck Kristine , Kreutz Joakim
Published: April 2012

This article extends the Uppsala Conflict Data Program (UCDP) by presenting new global data on non-state conflict, or armed conflict between two groups, neither of which is the state. The dataset includes conflicts between rebel groups and other organized militias, and thus serves as a complement to existing datasets on armed conflict which have either ignored this kind of violence or aggregated it into civil war. The dataset also includes cases of fighting between supporters of different political parties as well as cases of communal conflict, that is, conflict between two social groups, usually identified along ethnic or religious lines. This thus extends UCDP’s conflict data collection to facilitate the study of topics like rebel fractionalization, paramilitary involvement in conflict violence, and communal or ethnic conflict. In the article, we present a background to the data collection and provide descriptive statistics for the period 1989–2008 and then illustrate how the data can be used with the case of Somalia. These data move beyond state-centric conceptions of collective violence to facilitate research into the causes and consequences of group violence which occurs without state participation.
UN intervention and the duration of international crises
Authors: Beardsley Kyle
Published: April 2012

This article examines the effect of UN actions on the duration of international crises. Four different types of action – assurance, diplomatic engagement, military involvement, and intimidation – and three different outcomes – compromise, victory, and stalemate – are considered. After building on the existing literature to develop expectations of how a third party like the UN shapes crisis trajectories, hypotheses are tested using the International Crisis Behavior (ICB) data and a new events dataset on UN activity. Results from competing-risks models reveal that UN military involvement does well to decrease the risk of one side achieving victory, and diplomatic engagement increases the ability of the belligerents to reach a compromise in the long run. Moreover, diplomatic engagement accompanied by military involvement substantially hastens the pace of stalemate outcomes. Both tactics, however, have some trade-offs. Military involvement can decrease the sense of urgency for compromise; diplomatic engagement can be used for insincere motives and increase the risk of one-sided victory over time. UN actions of assurance and simple intimidation have considerable shortcomings as crisis management vehicles.
Inequality and conflict in federations
Authors: Deiwiks Christa , Cederman Lars-Erik , Gleditsch Kristian Skrede
Published: April 2012

Case study evidence suggests that inequality between regions in federations affects the risk of secessionist conflict. However, the conventional quantitative literature on civil war has found little support for a link between economic inequality and civil war. We argue that this seeming discrepancy in part stems from differences in the conceptualization of inequality and its operationalization, which has focused on individual-level wealth differences. In contrast, we investigate regional-level inequality, which is more readily applicable to understanding possible incentives for internal conflict. We adopt a spatial approach, based on new geo-coded data on administrative units in 31 federal states between 1991 and 2005, economic wealth, and ethnic settlements, and demonstrate strong evidence that regional inequality affects the risk of secessionist conflict. The results indicate that in highly unequal federations, both relatively developed and underdeveloped regions are indeed more likely to be involved in secessionist conflict than regions close to the country average. In addition, we provide evidence that exclusion from central state power as well as ethnic groups’ access to regional institutions are associated with an increased risk for secessionist conflict. The findings on inequality remain robust even when controlling for other confounding factors such as country GDP, population and war history.
Lights, Camera, Music, Interaction! Interactive Persuasion in E-commerce
Authors: Xu Qian , Sundar S. Shyam
Published: April 2012

Heightened interactivity and excitement characterize much of our online browsing, especially when it involves shopping on e-commerce websites. Interactivity is said to affect users’ engagement with the website by expanding their perceptual bandwidth (Sundar, 2007), much like the effect of optimal physiological arousal on cognitive functioning (Kahneman, 1973). We examine the direct and combinatory effects of interactivity and arousal on consumers’ engagement, attitudes, and behavioral intentions in an e-commerce website through a 3 (interactivity: low, medium, high) × 3 (arousal: control, low, high) between-participants experiment ( N = 186). Higher levels of interactivity were found to generate more favorable attitudes and behavioral intentions toward both the website and the product. Interactivity and arousal differed in their effects on various aspects of website engagement. The study also identified several mediators explicating the theoretical mechanism underlying the influence of interactivity on purchase likelihood.
Motivated Selective Attention During Political Ad Processing
Authors: Wang Zheng , Morey Alyssa C. , Srivastava Jatin
Published: April 2012

This study examines the dynamic, real-time interplay between the emotional content of political television ads and individuals’ political attitudes during ad processing based upon the Dynamic Motivational Activation (DMA) theoretical framework. Time-series cross-sectional models were developed to test the effects of three motivational inputs of emotional ads (arousing content, positivity, and negativity) and viewers’ evaluation of the featured candidates on four psychophysiological responses (heart rate, skin conductance level, corrugator electromyography, and zygomatic electromyography). As predicted by the DMA, physiological responses during ad viewing were affected by their own first- and second-order dynamic system feedback effects. These results not only support the predicted dynamic nature of the physiological system but also help disentangle message effects from the moderating and accumulating effects of the physiological system itself. Also as predicted, message motivational inputs interacted with viewers’ political attitudes to determine psychophysiological responses to the ads. Supporters of opposing political candidates showed cardiac-somatic response patterns indicative of disparate attention to the advertised information. Attentional selectivity can be a critical component in determining how information processing influences campaign message reception and effects.
Long-term ECMO treatment in Jehovah’s Witness patient without transfusions
Authors: Lindholm J , Palmér K , Frenckner B
Published: April 2012

A previously healthy 60-year-old male presented with fever, general pain and a C-reactive protein (CRP) of 160 mg/L. He was prescribed doxycycline. In the emergency room three days later, he was intubated and had a saturation of 70% on 100% oxygen. The chest X-ray showed bilateral lobar pneumonia. Streptococcus pneumonia was later verified.

As a Jehovah’s Witness, he had refused blood transfusions, but accepted albumin. Two days after admission, veno-venous extracorporeal membrane oxygenation (V-V ECMO) was started and the patient was then transported on ECMO to Stockholm. After two days, echocardiography showed right cardiac failure and the patient had to be converted to veno-arterial ECMO (VV-A ECMO) by cannulation of the left femoral artery. The haemoglobin decreased from 10.0 to 6.0 g/dL. Iron, folic acid, and erythropoietin were administered to stimulate erythropoesis. Romiplostim, to stimulate the production of platelets, was also started immediately. Blood samples were reduced to a minimum. The ECMO circuit was changed twice, using saline for priming, and the blood in the old circuit was then given back to the patient. The haemoglobin concentration varied between 4.5 and 6.0 g/dL during the ECMO treatment and the platelets between 80 and 140 x109/L.

After 44 days on ECMO, the patient was weaned off ECMO with 50% oxygen and nitric oxide (NO) at 20ppm in the ventilator. Four days after decannulation, he was transferred to a nearby intensive care unit.

Long-term ECMO treatment without transfusion of blood products is possible. Being a Jehovah’s Witness should not automatically be a contraindication for ECMO.
A randomized clinical study of Lu AA21004 in the prevention of relapse in patients with major depressive disorder
Authors: Boulenger Jean-Philippe , Loft Henrik , Florea Ioana
Published: April 2012

The efficacy and tolerability of Lu AA21004 in the prevention of relapse of major depressive disorder (MDD) in patients in remission after acute treatment was evaluated. Patients ( n=639) aged 18–75 years with a primary diagnosis of MDD with a current major depressive episode (MDE) ≥4 weeks’ duration, at least one prior MDE and a MADRS total score ≥26 received 12-week, open-label Lu AA21004 at 5 or 10mg/day. Patients in remission (MADRS ≤10) at both weeks 10 and 12 were assigned to double-blind treatment with either placebo or Lu AA21004 (fixed dose from Week 8).Patients (n=396) were treated, after random assignment to placebo (n=192) or Lu AA21004 (n=204). The primary analysis of time to relapse (full-analysis set, Cox proportional hazard model) showed a statistically significant difference in favour of Lu AA21004 versus placebo with a hazard ratio of 2.01 (95% confidence interval: 1.26–3.21; p=0.0035). The proportion of patients who relapsed was 13% in the Lu AA21004 group ( n=27) and 26% in the placebo group ( n=50). The withdrawal rates due to adverse events were 8% (open-label), and 3% (placebo) and 8% (Lu AA21004) (double-blind). Thus, Lu AA21004 was effective in preventing relapse of MDD and was well tolerated as maintenance treatment.
Predicting the directional change in consumer sentiment
Authors: Yao Juan , Partington Graham , Stevenson Max
Published: April 2012

The Consumer Sentiment Index (CSI) is a widely monitored economic indicator. The index measures consumer expectations, which contain information about potential future changes in consumer spending. Thus, any change in the dynamics of the sentiment index should contain important signals about future consumer behaviour, as well as changes in the real economy and stock returns. In this paper we use Cox’s proportional hazards model to estimate dynamic transition probabilities for a reversal in the CSI. We predict the probability of both positive and negative runs in sentiment surviving in the same state. Lagged changes in consumer sentiment and the frequency of recent reversals of sentiment are found to be significant predictors of a change in state. The model has substantial predictive ability, as measured by both categorical accuracy and a probability scoring rule, the Brier Score (Brier, 1950) out of sample. The predictive accuracy of the model is robust to the impact of the global financial crisis.
The January effect, does options trading matter?
Authors: Truong Cameron
Published: April 2012

This study examines the effect of options trading on the January effect in the period 1996–2009. The options market offers investors an alternative trading venue that circumvents several trading limitations in the equity market and hence enables a higher level of arbitrage activities. In a cross-sectional setting, we find that optioned stocks exhibit significantly lower risk-adjusted returns in January than non-optioned stocks. This effect is not attributed to firm size, illiquidity, or transaction costs. We also find that the January effect is not only smaller but also considerably more short-lived for optioned stocks than for non-optioned stocks. In a firm-specific setting, January risk-adjusted returns are found to be significantly lower in the post-options-listing period than in the pre-options-listing period. These findings support the proposition that options trading enhances information-based trading activities and hence improves the informational efficiency of the equity market.

JEL classifications: G10, G11, G12, G14
The Effect of Platelet-Rich Fibrin Matrix on Rotator Cuff Tendon Healing
Authors: Rodeo Scott A. , Delos Demetris , Williams Riley J. , Adler Ronald S. , Pearle Andrew , Warren Russell F.
Published: April 2012

Background: There is a strong need for methods to improve the biological potential of rotator cuff tendon healing. Platelet-rich fibrin matrix (PRFM) allows delivery of autologous cytokines to healing tissue, and limited evidence suggests a positive effect of platelet-rich plasma on tendon biology.

Purpose: To evaluate the effect of platelet-rich fibrin matrix on rotator cuff tendon healing.

Study Design: Randomized controlled trial; Level of evidence, 2.

Methods: Seventy-nine patients undergoing arthroscopic rotator cuff tendon repair were randomized intraoperatively to either receive PRFM at the tendon-bone interface (n = 40) or standard repair with no PRFM (n = 39). Standardized repair techniques were used for all patients. The postoperative rehabilitation protocol was the same in both groups. The primary outcome was tendon healing evaluated by ultrasound (intact vs defect at repair site) at 6 and 12 weeks. Power Doppler ultrasound was also used to evaluate vascularity in the peribursal, peritendinous, and musculotendinous and insertion site areas of the tendon and bone anchor site. Secondary outcomes included standardized shoulder outcome scales (American Shoulder and Elbow Surgeons [ASES] and L’Insalata) and strength measurements using a handheld dynamometer. Patients and the evaluator were blinded to treatment group. All patients were evaluated at minimum 1-year follow-up. A logistic regression model was used to predict outcome (healed vs defect) based on tear severity, repair type, treatment type (PRFM or control), and platelet count.

Results: Overall, there were no differences in tendon-to-bone healing between the PRFM and control groups. Complete tendon-to-bone healing (intact repair) was found in 24 of 36 (67%) in the PRFM group and 25 of 31 (81%) in the control group ( P = .20). There were no significant differences in healing by ultrasound between 6 and 12 weeks. There were gradual increases in ASES and L’Insalata scores over time in both groups, but there were no differences in scores between the groups. We also found no difference in vascularity in the peribursal, peritendinous, and musculotendinous areas of the tendon between groups. There were no differences in strength between groups. Platelet count had no effect on healing. Logistic regression analysis demonstrated that PRFM was a significant predictor ( P = .037) for a tendon defect at 12 weeks, with an odds ratio of 5.8.

Conclusion: Platelet-rich fibrin matrix applied to the tendon-bone interface at the time of rotator cuff repair had no demonstrable effect on tendon healing, tendon vascularity, manual muscle strength, or clinical rating scales. In fact, the regression analysis suggests that PRFM may have a negative effect on healing. Further study is required to evaluate the role of PRFM in rotator cuff repair.
Characterization of Korean solid recovered fuels (SRFs): an analysis and comparison of SRFs
Authors: Choi Yeon-Seok , Han Soyoung , Choi Hang-Seok , Kim Seock-Joon
Published: April 2012

To date, Korea has used four species of solid recovered fuels (SRFs) which have been certified by the Environmental Ministry of Korea: refuse-derived fuel (RDF), refused plastic fuel (RPF), tyre-derived fuel (TDF), and wood chip fuel (WCF). These fuels have been used in many industrial boilers. In this study, seven regulatory properties associated with each of the four species: particle size, moisture and ash content, lower heating value (LHV), total chlorine, sulfur, and heavy metals content (Pb, As, Cd, Hg, Cr) were analysed. These properties are the main regulation criteria for the usage and transfer of SRFs in Korea. Different properties of each SRF were identified on the basis of data collected over the last 3 years in Korea, and the manufacturing process problem associated with the production of SRFs were considered. It was found that the high moisture content of SRFs (especially WCF) could directly lead to the low LHV of SRFs and that the poor screening and sorting of raw materials could cause defective SRF products with high ash or chlorine contents. The information obtained from this study could contribute to the manufacturing of SRF with good quality.
Commentary: Alternative Cultures in Planning Research—From Extending Scientific Frontiers to Exploring Enduring Questions
Authors: Forsyth Ann
Published: April 2012

As the planning academy has grown and evolved, it has developed different ways of doing planning research. People may (a) work at the scientific frontier, (b) investigate issues of practical relevance, (c) reflect on the implications of practice, or (d) try to answer the enduring questions of planning. These are important differences. Different cultures represent varying ideas about what constitutes an important or significant contribution to the field of planning.
Inulinase production by Geotrichum candidum OC-7 using migratory locusts as a new substrate and optimization process with Taguchi DOE
Authors: Canli Ozden , Tasar Gani Erhan , Taskin Mesut
Published: April 2012

Utilization of migratory locusts ( Locusta migratoria) as a main substrate due to its high protein content for inulinase (2,1-β-d-fructan fructanohydrolase) production by Geotrichum candidum OC-7 was investigated in this study. To optimize fermentation conditions, four influential factors (locust powder (LP) concentration, sucrose concentration, pH and fermentation time) at three levels were investigated using Taguchi orthogonal array (OA) design of experiment (DOE). Inulinase yield obtained from the designed experiments with regard to Taguchi L9 OA was processed with Minitab 15 software at ‘larger is better’ as quality character. The results showed that optimal fermentation conditions determined as LP 30 g/l, sucrose 20 g/l, pH 6.0 and time 48 h. Maximum inulinase activity was recorded as 30.12 U/ml, which was closer to the predicted value (30.56 U/ml). To verify the results, analysis of variance test was employed. LP had the greatest contribution (71.96%) among the other factors. Sucrose had lower contribution (13.96%) than LP. This result demonstrated that LP had a strong effect on inulinase activity and can be used for enzyme production. Taguchi DOE application enhanced enzyme activity to about 3.05-fold versus unoptimized condition and 2.34-fold versus control medium. Consequently, higher inulinase production can be achieved by the utilization of an edible insect material as an alternative substrate and Taguchi DOE presents suitable optimization method for biotechnological process.
Effects of N,N-dimethylformamide on behaviour and regeneration of planarian Dugesia japonica
Authors: Zhang Jianyong , Yuan Zuoqing , Zheng Mingyue , Sun Yuqian , Wang Youjun , Yang Shudong
Published: April 2012

In this study, the toxicity, behavioural and regeneration effects of dimethylformamide (DMF) on planarian Dugesia japonica were investigated. One control and six different concentrations of DMF (10 ppm, 100 ppm, 500 ppm, 1000 ppm, 5000 ppm and 10,000 ppm) were used in triplicate. The results showed that the mortality was directly proportional to the DMF concentration and planarian locomotor velocity (pLMV) was significantly reduced by increasing the exposure time and DMF concentration. pLMV of D. japonica was significantly reduced at a lower concentration of 10 ppm after 7 days of continuous exposure to DMF. The recovery of the motility of planarians pretreated with DMF was found to be time- and dose dependent, all planarians had complete recovery in their motility after 48 h. The appearance of auricles in regenerating animals was easily affected by DMF exposure in comparison with the appearance of eyespot. The present results suggest that the intact adult mobility in the aquatic planarian D. japonica is a more sensitive biomarker than mortality, and the appearance of auricles in regenerating animals is a more sensitive biomarker than eyespot.