bluuebunny/crossref_metadata_2025_split huggingface dataset:
MLK3 Regulates Paxillin Phosphorylation in Chemokine-Mediated Breast Cancer Cell Migration and Invasion to Drive Metastasis
Authors: Chen Jian , Gallo Kathleen A. 
Published: June 2012

Abstract
MLK3 kinase activates multiple mitogen-activated protein kinases and plays a critical role in cancer cell migration and invasion. In the tumor microenvironment, prometastatic factors drive breast cancer invasion and metastasis, but their associated signaling pathways are not well-known. Here, we provide evidence that MLK3 is required for chemokine (CXCL12)-induced invasion of basal breast cancer cells. We found that MLK3 induced robust phosphorylation of the focal adhesion scaffold paxillin on Ser 178 and Tyr 118, which was blocked by silencing or inhibition of MLK3-JNK. Silencing or inhibition of MLK3, inhibition of JNK, or expression of paxillin S178A all led to enhanced Rho activity, indicating that the MLK3–JNK–paxillin axis limits Rho activity to promote focal adhesion turnover and migration. Consistent with this, MLK3 silencing increased focal adhesions and stress fibers in breast cancer cells. MLK3 silencing also decreased the formation of breast cancer lung metastases in vivo, and breast cancer cells derived from mouse lung metastases showed enhanced Ser 178 paxillin phosphorylation. Taken together, our findings suggest that the MLK3–JNK–paxillin signaling axis may represent a potential therapeutic target and/or prognostic marker in breast cancer metastasis. Cancer Res; 72(16); 4130–40. ©2012 AACR.
ERG Rearrangement for Predicting Subsequent Cancer Diagnosis in High-Grade Prostatic Intraepithelial Neoplasia and Lymph Node Metastasis
Authors: Gao Xin , Li Liao-Yuan , Zhou Fang-Jian , Xie Ke-Ji , Shao Chun-Kui , Su Zu-Lan , Sun Qi-Peng , Chen Ming-Kun , Pang Jun , Zhou Xiang-Fu , Qiu Jian-Guang , Wen Xing-Qiao , Yang Ming , Bai Xian-Zhong , Zhang Hao , Ling Li , Chen Zhong 
Published: June 2012

Abstract
Purpose: We aimed to analyze whether ERG rearrangement in biopsies could be used to assess subsequent cancer diagnosis in high-grade prostatic intraepithelial neoplasia (HGPIN) and the risk of lymph node metastasis in early prostate cancer.
Experimental Design: Samples from 523 patients (361 with early prostate cancer and 162 with HGPIN) were collected prospectively. On the basis of the cutoff value established previously, the 162 patients with HGPIN were stratified to two groups: one with an ERG rearrangements rate ≥1.6% (n = 59) and the other with an ERG rearrangements rate &lt;1.6% (n = 103). For the 361 prostate cancer cases undergoing radical prostatectomy, 143 had pelvic lymph node dissection (node-positive, n = 56 and node-negative, n = 87). All ERG rearrangement FISH data were validated with ERG immunohistochemistry.
Results: A total of 56 (of 59, 94.9%) HGPIN cases with an ERG rearrangements rate ≥1.6% and 5 (of 103, 4.9%) HGPIN cases with an ERG rearrangements rate &lt;1.6% were diagnosed with prostate cancer during repeat biopsy follow-ups (P &lt; 0.001). There were significant differences in ERG rearrangement rates between lymph node–positive and -negative prostate cancer (P &lt; 0.001). The optimal cutoff value to predict lymph node metastasis by ERG rearrangement was established, being 2.6% with a sensitivity at 80.4% [95% confidence interval (CI), 67.6–89.8] and a specificity at 85.1% (95% CI, 75.8–91.8). ERG protein expression by immunohistochemistry was highly concordant with ERG rearrangement by FISH.
Conclusions: The presence of ERG rearrangement in HGPIN lesions detected on initial biopsy warrants repeat biopsies and measuring ERG rearrangement could be used for assessing the risk of lymph node metastasis in early prostate cancer. Clin Cancer Res; 18(15); 4163–72. ©2012 AACR.
New Strategies in the Treatment of Mantle Cell Lymphoma
Authors: Deng Changchun , Lee Sangmin , O'Connor Owen A. 
Published: June 2012

AbstractMantle cell lymphoma (MCL) is a rare type of non-Hodgkin lymphoma that traditionally has been thought to possess the poor-risk features of both indolent lymphoma, with its incurability, and aggressive lymphoma, with its ability to proliferate rapidly. Although there is considerable debate as to whether MCL can be cured, a number of retrospective studies are beginning to suggest an improvement in overall survival over the past decade, likely coinciding with the introduction of rituximab, more intensive chemotherapy, and the increasing use of autologous stem cell transplant (ASCT) in first remission. At present, intensive induction chemotherapy regimens consistently produce a response rate of &gt;90%, sometimes even 100% in the first-line setting, and consolidation with ASCT in first remission can improve the complete response rate to 90%. The emergence of a more sophisticated understanding of the underlying pathogenesis, coupled with a host of new agents and targets, has again created new opportunities to improve the care of our patients with MCL. Here, we discuss many of these developments and how they may potentially affect the natural history of this disease. Clin Cancer Res; 18(13); 3499–508. ©2012 AACR.
Galectin-1 Promotes Lung Cancer Progression and Chemoresistance by Upregulating p38 MAPK, ERK, and Cyclooxygenase-2
Authors: Chung Ling-Yen , Tang Shye-Jye , Sun Guang-Huan , Chou Teh-Ying , Yeh Tien-Shun , Yu Sung-Liang , Sun Kuang-Hui 
Published: June 2012

Abstract
Purpose: This study is aimed at investigating the role and novel molecular mechanisms of galectin-1 in lung cancer progression.
Experimental Design: The role of galectin-1 in lung cancer progression was evaluated both in vitro and in vivo by short hairpin RNA (shRNA)-mediated knockdown of galectin-1 in lung adenocarcinoma cell lines. To explore novel molecular mechanisms underlying galectin-1–mediated tumor progression, we analyzed gene expression profiles and signaling pathways using reverse transcription PCR and Western blotting. A tissue microarray containing samples from patients with lung cancer was used to examine the expression of galectin-1 in lung cancer.
Results: We found overexpression of galectin-1 in non–small cell lung cancer (NSCLC) cell lines. Suppression of endogenous galectin-1 in lung adenocarcinoma resulted in reduction of the cell migration, invasion, and anchorage-independent growth in vitro and tumor growth in mice. In particular, COX-2 was downregulated in galectin-1–knockdown cells. The decreased tumor invasion and anchorage-independent growth abilities were rescued after reexpression of COX-2 in galectin-1–knockdown cells. Furthermore, we found that TGF-β1 promoted COX-2 expression through galectin-1 interaction with Ras and subsequent activation of p38 mitogen-activated protein kinase (MAPK), extracellular signal–regulated kinase (ERK), and NF-κB pathway. Galectin-1 knockdown sensitized lung cancer cells to platinum-based chemotherapy (cisplatin). In addition, galectin-1 and COX-2 expression was correlated with the progression of lung adenocarcinoma, and high clinical relevance of both proteins was evidenced (n = 47).
Conclusions: p38 MAPK, ERK, and COX-2 activation are novel mediators for the galectin-1–promoted tumor progression and chemoresistance in lung cancer. Galectin-1 may be an innovative target for combined modality therapy for lung cancer. Clin Cancer Res; 18(15); 4037–47. ©2012 AACR.
EZH2-Regulated DAB2IP Is a Medulloblastoma Tumor Suppressor and a Positive Marker for Survival
Authors: Smits Michiel , van Rijn Sjoerd , Hulleman Esther , Biesmans Dennis , van Vuurden Dannis G. , Kool Marcel , Haberler Christine , Aronica Eleonora , Vandertop W. Peter , Noske David P. , Würdinger Thomas 
Published: June 2012

Abstract
Purpose: Medulloblastoma is the most common malignant brain tumor in children. Despite recent improvements, the molecular mechanisms driving medulloblastoma are not fully understood and further elucidation could provide cues to improve outcome prediction and therapeutic approaches.
Experimental Design: Here, we conducted a meta-analysis of mouse and human medulloblastoma gene expression data sets, to identify potential medulloblastoma tumor suppressor genes.
Results: We identified DAB2IP, a member of the RAS-GTPase–activating protein family (RAS GAP), and showed that DAB2IP expression is repressed in medulloblastoma by EZH2-induced trimethylation. Moreover, we observed that reduced DAB2IP expression correlates significantly with a poor overall survival of patients with medulloblastoma, independent of metastatic stage. Finally, we showed that ectopic DAB2IP expression enhances stress-induced apoptosis in medulloblastoma cells and that reduced expression of DAB2IP in medulloblastoma cells conveys resistance to irradiation-induced cell death.
Conclusion: These results suggest that repression of DAB2IP may at least partly protect medulloblastoma cells from apoptotic cell death. Moreover, DAB2IP may represent a molecular marker to distinguish patients with medulloblastoma at high risk from those with a longer survival prognosis. Clin Cancer Res; 18(15); 4048–58. ©2012 AACR.
A 2-Stage Phase II Design with Direct Assignment Option in Stage II for Initial Marker Validation
Authors: An Ming-Wen , Mandrekar Sumithra J. , Sargent Daniel J. 
Published: June 2012

Abstract
Biomarkers are critical to targeted therapies, as they may identify patients more likely to benefit from a treatment. Several prospective designs for biomarker-directed therapy have been previously proposed, differing primarily in the study population, randomization scheme, or both. Recognizing the need for randomization, yet acknowledging the possibility of promising but inconclusive results after a stage I cohort of randomized patients, we propose a 2-stage phase II design on marker-positive patients that allows for direct assignment in a stage II cohort. In stage I, marker-positive patients are equally randomized to receive experimental treatment or control. Stage II has the option to adopt “direct assignment” whereby all patients receive experimental treatment. Through simulation, we studied the power and type I error rate of our design compared with a balanced randomized two-stage design, and conducted sensitivity analyses to study the effect of timing of stage I analysis, population shift effects, and unbalanced randomization. Our proposed design has minimal loss in power (&lt;1.8%) and increased type I error rate (&lt;2.1%) compared with a balanced randomized design. The maximum increase in type I error rate in the presence of a population shift was between 3.1% and 5%, and the loss in power across possible timings of stage I analysis was less than 1.2%. Our proposed design has desirable statistical properties with potential appeal in practice. The direct assignment option, if adopted, provides for an “extended confirmation phase” as an alternative to stopping the trial early for evidence of efficacy in stage I. Clin Cancer Res; 18(16); 4225–33. ©2012 AACR.
Liver-Specific Deletion of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Causes Hepatic Steatosis and Death
Authors: Nagashima Shuichi , Yagyu Hiroaki , Ohashi Ken , Tazoe Fumiko , Takahashi Manabu , Ohshiro Taichi , Bayasgalan Tumenbayar , Okada Kenta , Sekiya Motohiro , Osuga Jun-ichi , Ishibashi Shun 
Published: June 2012

Objective—
3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) catalyzes the rate-limiting step in cholesterol biosynthesis and has proven to be an effective target of lipid-lowering drugs, statins. The aim of this study was to understand the role of hepatic HMGCR in vivo.

Methods and Results—
To disrupt the HMGCR gene in liver, we generated mice homozygous for a floxed HMGCR allele and heterozygous for a transgene encoding Cre recombinase under the control of the albumin promoter (liver-specific HMGCR knockout mice). Ninety-six percent of male and 71% of female mice died by 6 weeks of age, probably as a result of liver failure or hypoglycemia. At 5 weeks of age, liver-specific HMGCR knockout mice showed severe hepatic steatosis with apoptotic cells, hypercholesterolemia, and hypoglycemia. The hepatic steatosis and death were completely reversed by providing the animals with mevalonate, indicating its essential role in normal liver function. There was a modest decrease in hepatic cholesterol synthesis in liver-specific HMGCR knockout mice. Instead, they showed a robust increase in the fatty acid synthesis, independent of sterol regulatory element binding protein-1c.

Conclusion—
Hepatocyte HMGCR is essential for the survival of mice, and its abrogation elicits hepatic steatosis with jaundice and hypoglycemia.
The Status of Telestroke in the United States
Authors: Silva Gisele S. , Farrell Shawn , Shandra Emma , Viswanathan Anand , Schwamm Lee H. 
Published: June 2012

Background and Purpose
Little is known about adoption or success of telestroke networks outside of published or federally funded programs. Under contract to the Health Resource Services Administration, we conducted an environmental scan of telestroke programs in the United States.

Methods
An analyst contacted all potential programs identified in comprehensive online searches, interviewed respondents, and collected response data about structural and functional components of currently operating telestroke programs.

Results

Among 97 potential programs contacted, 56 programs had confirmed telestroke activity, and 38 programs (68%) from 27 states participated. Hospital and community characteristics of nonparticipating programs were similar to those of participating ones. The top 3 clinical needs met by the telestroke were emergency department consultation (100%), patient triage (83.8%), and inpatient teleconsultation (46.0%). Telestroke programs were in operation a median of 2.44 years (interquartile range, 1.36–3.44 years); 94.6% used 2-way, real-time interactive video plus imaging, but only 44% used dedicated telemedicine consultation software. The mean number of spokes per hub increased significantly from 2007 to 2008 to 2009 (3.78 versus 7.60;
P
<0.05), and >80% of spoke sites were rural or small hospitals. Reimbursement was absent for >40% of sites. Sites rated inability to obtain physician licensure (27.77%), lack of program funds (27.77%), and lack of reimbursement (19.44%) as the most important barriers to program growth.

Conclusions
Telestroke is a widespread and growing practice model. Important barriers to expansion amenable to change relate to organizational, technical, and educational domains and external economic and regulatory forces.
A Parameterization for the Effects of Ozone on the Wave Driving Exerted by Equatorial Waves in the Stratosphere
Authors: Grogan Dustin F. P. , Nathan Terrence R. , Echols Robert S. , Cordero Eugene C. 
Published: June 2012

An equatorial β-plane model of the tropical stratosphere is used to examine the effects of ozone on Kelvin, Rossby–gravity, equatorial Rossby, inertia–gravity, and smaller-scale gravity waves. The model is composed of coupled equations for wind, temperature, and ozone volume mixing ratio, which are linearized about a zonally averaged background state. Using the Wentzel–Kramers–Brillouin (WKB) formalism, equations are obtained for the vertical spatial scale, spatial damping rate, and amplitude of the waves. These equations yield an analytical expression for the ozone-modified wave driving of the zonal-mean circulation. The expression for the wave driving provides an efficient parameterization that can be implemented into models that are unable to spontaneously generate the ozone-modified, convectively coupled waves that drive the quasi-biennial and semiannual oscillations of the tropical stratosphere. The effects of ozone on the wave driving, which are strongly modulated by the Doppler-shifted frequency, are maximized in the upper stratosphere, where ozone photochemistry and vertical ozone advection combine to augment Newtonian cooling. The ozone causes a contraction in spatial scale and an increase in the spatial damping rate. In the midstratosphere to lower mesosphere, the ozone-induced increase in wave driving is about 10%–30% for all wave types, but it can be as large as about 80% over narrow altitude regions and for specific wave types. In the dynamically controlled lower stratosphere, vertical ozone advection dominates over meridional ozone advection and opposes Newtonian cooling, causing, on average, a 10%–15% reduction in the damping rate.
Ocean Heat Transport and Its Projected Change in CanESM2
Authors: Yang Duo , Saenko Oleg A. 
Published: June 2012

Abstract
The meridional ocean heat transport (MOHT), its seasonal variability, and projected changes simulated by the second generation Canadian Earth System Model (CanESM2) are presented. The global mean MOHT is within the uncertainty of the observational estimates. However, a correct simulation of the MOHT for individual ocean basins is more challenging, and the Atlantic MOHT south of 30°N is underestimated. The partitioning of the MOHT into the overturning and gyre components is generally consistent with such partitioning in an observationally optimized ocean model. At low latitudes, the time-mean MOHT is dominated by its overturning component, whereas in the Southern Ocean and, especially, in the subpolar North Atlantic, it is the gyre component that plays a more important role. In the projected warmer climates, CanESM2 simulates a weakening of the poleward MOHT essentially in both hemispheres. The projected MOHT changes are largely determined by the overturning component, except in the subpolar Atlantic where it is dominated by the gyre component. Consistent with (the limited number of) previous studies, the seasonal variability of the MOHT is large and is mostly driven by the seasonal variability of the meridional Ekman transport. In the simulated warmer climates, the seasonal cycle of the MOHT is projected to change, mostly in the tropics and also in the Southern Hemisphere midlatitudes. The eddy contribution to the MOHT is broadly consistent with that in the observationally optimized eddy-permitting model. However, in the tropics a significant fraction of the eddy energy is converted back to the mean circulation, and the heat transports due to the parameterized and permitted eddies differ.
Wildfire Management and Forecasting Fire Potential: The Roles of Climate Information and Social Networks in the Southwest United States
Authors: Owen Gigi , McLeod Jonathan D. , Kolden Crystal A. , Ferguson Daniel B. , Brown Timothy J. 
Published: June 2012

Abstract
Continuing progress in the fields of meteorology, climatology, and fire ecology has enabled more proactive and risk-tolerant wildland fire management practices in the United States. Recent institutional changes have also facilitated the incorporation of more advanced climate and weather research into wildland fire management. One of the most significant changes was the creation of Predictive Services in 1998, a federal interagency group composed, in part, of meteorologists who create climate- and weather-based fire outlooks tailored to fire manager needs. Despite the numerous forecast products now available to fire managers, few studies have examined how these products have affected their practices. In this paper the authors assess how fire managers in the Southwest region of the United States perceive and incorporate different types of information into their management practices. A social network analysis demonstrates that meteorologists have become central figures in disseminating information in the regional interagency fire management network. Interviews and survey data indicate that person-to-person communication during planning phases prior to the primary fire season is key to Predictive Services’ success in supporting fire managers’ decision making. Over several months leading up to the fire season, predictive forecasts based on complex climate, fuels, and fire-risk models are explained to fire managers and updated through frequent communication. The study’s findings suggest that a significant benefit of the information sharing process is the dialogue it fosters among fire managers, locally, regionally, and nationally, which better prepares them to cooperate and strategically plan for the fire season.
The Randomized Shortened Dental Arch Study
Authors: Wolfart S. , Marré B. , Wöstmann B. , Kern M. , Mundt T. , Luthardt R.G. , Huppertz J. , Hannak W. , Reiber T. , Passia N. , Heydecke G. , Reinhardt W. , Hartmann S. , Busche E. , Mitov G. , Stark H. , Pospiech P. , Weber A. , Gernet W. , Walter M.H. 
Published: June 2012

The scientific evidence concerning prosthodontic care for the shortened dental arch (SDA) is sparse. This randomized multicenter study aimed to compare two common treatment options: removable partial dental prostheses (RPDPs) for molar replacement vs. no replacement (SDA). One of the hypotheses was that the follow-up treatment differs between patients with RPDPs and patients with SDAs during the 5-year follow-up period. Two hundred and fifteen patients with complete molar loss in one jaw were included in the study. Molars were either replaced by RPDPs or not replaced according to the SDA concept. A mean number of 4.2 (RPDP) and 2.8 (SDA) treatments for biological or technical reasons occurred during the 5-year observation time per patient. Concerning the biological aspect, no significant differences between the groups could be shown, whereas treatment arising from technical reasons was significantly more frequent for the RPDP group. When the severity of treatment was analyzed, a change over time was evident. When, at baseline, only follow-up treatment with minimal effort is required, over time there is a continuous increase to moderate and extensive effort observed for both groups ( Controlled-trials.com number ISRCTN97265367).
Heterozygosity for Roquinsan leads to angioimmunoblastic T-cell lymphoma-like tumors in mice
Authors: Ellyard Julia I. , Chia Tiongsun , Rodriguez-Pinilla Socorro-Maria , Martin Jaime L. , Hu Xin , Navarro-Gonzalez Manuel , Garcia Juan F. , Delfau-Larue Marie-Helene , Montes-Moreno Santiago , Gaulard Philippe , Cook Matthew C. , Walters Giles , Piris Miguel A. , Vinuesa Carola G. 
Published: June 2012

Abstract
Angioimmunoblastic T-cell lymphoma (AITL) is the second most common peripheral T-cell lymphoma with unusual clinical and pathologic features and a poor prognosis despite intensive chemotherapy. Recent studies have suggested AITL derives from follicular helper T (TFH) cells, but the causative molecular pathways remain largely unknown. Here we show that approximately 50% of mice heterozygous for the “san” allele of Roquin develop tumors accompanied by hypergammaglobulinemia by 6 months of age. Affected lymph nodes displayed the histologic features diagnostic of AITL, except for the presence of expanded FDC networks. Accumulation of TFH cells preceded tumor development, and clonal rearrangements in the TCR-β genes were present in most tumors. Furthermore, TFH cells exhibited increased clonality compared with non-TFH cells from the same lymph nodes, even in the absence of tumors. Genetic manipulations that prevent TFH development, such as deletion of ICOS, CD28, and SAP, partially or completely abrogated tumor development, confirming a TFH-derived origin. Roquinsan/+ mice emerge as a useful model to investigate the molecular pathogenesis of AITL and for preclinical testing of therapies aimed at targeting dysregulated TFH cells or their consequences.