bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II, Open-Label, Randomized Trial of the MEK1/2 Inhibitor Selumetinib as Monotherapy versus Temozolomide in Patients with Advanced Melanoma
Authors: Kirkwood John M. , Bastholt Lars , Robert Caroline , Sosman Jeff , Larkin James , Hersey Peter , Middleton Mark , Cantarini Mireille , Zazulina Victoria , Kemsley Karin , Dummer Reinhard 
Published: November 2011

Abstract
Purpose: To compare the efficacy and tolerability of the mitogen-activated protein (MAP)/extracellular signal-regulated (ERK) kinase (MEK) 1/2 inhibitor selumetinib versus temozolomide in chemotherapy-naive patients with unresectable stage III/IV melanoma.
Experimental Design: This phase II, open-label, multicenter, randomized, parallel-group study examined the effect of 100 mg oral selumetinib twice daily in 28-day cycles versus oral temozolomide (200 mg/m2/d for 5 days, then 23 days off-treatment). The primary endpoint was progression-free survival.
Results: Two hundred patients were randomized. Progression-free survival did not differ significantly between selumetinib and temozolomide (median time to event 78 and 80 days, respectively; hazard ratio, 1.07; 80% confidence interval, 0.86–1.32). Objective response was observed in six (5.8%) patients receiving selumetinib and nine (9.4%) patients in the temozolomide group. Among patients with BRAF mutations, objective responses were similar between selumetinib and temozolomide groups (11.1% and 10.7%, respectively). However, five of the six selumetinib partial responders were BRAF mutated. Frequently reported adverse events with selumetinib were dermatitis acneiform (papular pustular rash; 59.6%), diarrhea (56.6%), nausea (50.5%), and peripheral edema (40.4%), whereas nausea (64.2%), constipation (47.4%), and vomiting (44.2%) were reported with temozolomide.
Conclusions: No significant difference in progression-free survival was observed between patients with unresectable stage III/IV melanoma unselected for BRAF/NRAS mutations, who received therapy with selumetinib or temozolomide. Five of six patients with partial response to selumetinib had BRAF mutant tumors. Clin Cancer Res; 18(2); 555–67. ©2011 AACR.
The mRNA Stability Factor HuR Inhibits MicroRNA-16 Targeting of COX-2
Authors: Young Lisa E. , Moore Ashleigh E. , Sokol Lena , Meisner-Kober Nicole , Dixon Dan A. 
Published: November 2011

Abstract
Commonly observed in colorectal cancer is the elevated expression of the prostaglandin (PG) synthase COX-2. In normal intestinal epithelium, the COX-2 mRNA is targeted for rapid decay through the 3′-untranslated region (3′-UTR) adenylate- and uridylate (AU)-rich element (ARE), whereas in tumors ARE-mediated decay is compromised. Here we show that the COX-2 ARE can mediate degradation through microRNA (miRNA)-mediated regulation. We identified miR-16 to bind the COX-2 3′-UTR and inhibit COX-2 expression by promoting rapid mRNA decay. In colorectal cancer cells and tumors, miR-16 levels were decreased approximately twofold and miR-16 expression in cancer cells attenuated COX-2 expression and PG synthesis. The COX-2 ARE is also bound by the RNA-binding protein HuR. In colorectal cancer tumors, HuR is overexpressed and localized within the cytoplasm, where it promotes ARE-mRNA stabilization. Under conditions of HuR overexpression, miR-16 was unable to promote rapid mRNA decay through the COX-2 ARE. Ribonucleoprotein immunoprecipitation of HuR showed direct association with miR-16 that was reversed when cytoplasmic trafficking of HuR was inhibited. Furthermore, this interaction between HuR and miR-16 promoted the downregulation of miR-16. These new results identify miR-16 as a central posttranscriptional regulator of COX-2 and show the ability of elevated levels of HuR to antagonize miR-16 function. Along with insight into altered ARE-mediated mRNA decay observed in colorectal cancer, these findings provide a new explanation for tumor-derived loss of miR-16. Mol Cancer Res; 10(1); 167–80. ©2011 AACR.
How Do We Safely Get People to Stop Smoking?
Authors: Lam David C.L. , Minna John D. 
Published: November 2011

Abstract
Nicotine replacement therapy (NRT) is a valuable, proven, and U.S. Food and Drug Administration–approved tool for smoking cessation. However, the discoveries of functional nicotinic acetylcholine receptors (nAChR) on lung epithelial and cancer cells and of nAChR polymorphisms associated with lung cancer risk, in addition to a large number of preclinical studies indicating that nicotine may promote or facilitate cancer development and growth, have prompted concern that NRT, although important for smoking cessation, may actually augment lung carcinogenesis. Therefore, it is of great public health interest that two independent studies reported in this issue of the journal (Murphy and colleagues, beginning on page 1752, and Maier and colleagues, beginning on page 1743) showed that nicotine given in drinking water at a dose to achieve blood concentrations in mice similar to those achieved in people receiving NRT did not enhance lung carcinogenesis or tumor growth in several mouse models of lung cancer. Effective non-nicotine alternatives to NRT, such as varenicline and bupropion, are also available and perhaps better than NRT for smoking cessation therapy. In the near future, nicotine vaccines will likely be added to the smoking cessation armamentarium. However, the normal and pathophysiologic role of nicotine, nAChRs, and the signaling pathways they activate in lung epithelial cells and lung cancer still requires elucidation. Cancer Prev Res; 4(11); 1724–7. ©2011 AACR.
Long-term Nicotine Replacement Therapy: Cancer Risk in Context
Authors: Shields Peter G. 
Published: November 2011

Abstract
Nicotine replacement therapy (NRT) for up to 12 weeks is well established, safe and efficacious for fostering smoking cessation. Some smokers at a high risk of relapse may benefit from long-term use, and so long-term NRT safety and efficacy have become a paramount question for the FDA and others. Laboratory studies have indicated a carcinogenic potential of nicotine. Animal model studies reported in this issue of the journal by Maier and colleagues (beginning on page 1743) and Murphy and colleagues (beginning on page 1752), however, provide additional reassurance that NRT does not promote lung cancer. Very long-term studies of NRT effects do not yet exist and would be needed to definitively answer the question about NRT efficacy and cancer risk and some decision making will need to be made based on limited human data and experimental studies. The overall NRT safety question is complex and requires consideration of three contexts and comparator groups (long-term NRT/abstinence vs. smoking, long-term intermittent NRT/reduced smoking vs. smoking, and long-term NRT/abstinence vs. abstinence without long-term NRT). Although the data on these issues are insufficient, the first comparison seems intuitive and may be compelling enough to allow the FDA to approve a long-term indication for NRT. An important public health goal is to help smokers and their health care providers understand the implications of potential long-term NRT risks in the context of its potential benefits and the far greater risks of continued smoking. Cancer Prev Res; 4(11); 1719–23. ©2011 AACR.
An Exact Thickness-Weighted Average Formulation of the Boussinesq Equations
Authors: Young William R. 
Published: November 2011

Abstract
The author shows that a systematic application of thickness-weighted averaging to the Boussinesq equations of motion results in averaged equations of motion written entirely in terms of the thickness-weighted velocity; that is, the unweighted average velocity and the eddy-induced velocity do not appear in the averaged equations of motion. This thickness-weighted average (TWA) formulation is identical to the unaveraged equations, apart from eddy forcing by the divergence of three-dimensional Eliassen–Palm (EP) vectors in the two horizontal momentum equations. These EP vectors are second order in eddy amplitude and, moreover, the EP divergences can be expressed in terms of the eddy flux of the Rossby–Ertel potential vorticity derived from the TWA equations of motion. That is, there is a fully nonlinear and three-dimensional generalization of the one- and two-dimensional identities found by Taylor and Bretherton. The only assumption required to obtain this exact TWA formulation is that the buoyancy field is stacked vertically; that is, that the buoyancy frequency is never zero. Thus, the TWA formulation applies to nonrotating stably stratified turbulent flows, as well as to large-scale rapidly rotating flows. Though the TWA formulation is obtained by working on the equations of motion in buoyancy coordinates, the averaged equations of motion can then be translated into Cartesian coordinates, which is the most useful representation for many purposes.
Analysis of Tidal Straining as Driver for Estuarine Circulation in Well-Mixed Estuaries
Authors: Burchard Hans , Schuttelaars Henk M. 
Published: November 2011

Abstract
Tidal straining, which can mathematically be described as the covariance between eddy viscosity and vertical shear of the along-channel velocity component, has been acknowledged as one of the major drivers for estuarine circulation in channelized tidally energetic estuaries. In this paper, the authors investigate the role of lateral circulation for generating this covariance. Five numerical experiments are carried out, starting with a reference scenario including the full physics and four scenarios in which specific key physical processes are neglected. These processes are longitudinal internal pressure gradient forcing, lateral internal pressure gradient forcing, lateral advection, and the neglect of temporal variation of eddy viscosity. The results for the viscosity–shear covariance are correlated across different experiments to quantify the change due to neglect of these key processes. It is found that the lateral advection of vertical shear of the along-channel velocity component and its interaction with the tidally asymmetric eddy viscosity (which is also modified by the lateral circulation) is the major driving force for estuarine circulation in well-mixed tidal estuaries.
Annual Cycle and Depth Penetration of Wind-Generated Near-Inertial Internal Waves at Ocean Station Papa in the Northeast Pacific
Authors: Alford Matthew H. , Cronin Meghan F. , Klymak Jody M. 
Published: November 2011

Abstract
The downward propagation of near-inertial internal waves following winter storms is examined in the context of a 2-yr record of velocity in the upper 800 m at Ocean Station Papa. The long time series allow accurate estimation of wave frequency, whereas the continuous data in depth allow separation into upward- and downward-propagating components. Near-inertial kinetic energy (KEin) dominates the record. At all measured depths, energy in downgoing motions exceeds that of upward-propagating motions by factors of 3–7, whereas KEin is elevated by a factor of 3–5 in winter relative to summer. The two successive winters are qualitatively similar but show important differences in timing and depth penetration. Energy is seen radiating downward in a finite number of wave groups, which are tagged and catalogued to determine the vertical group velocity cgz, which has a mean of about 1.5 × 10−4 m s−1 (13 m day−1). Case studies of three of these are presented in detail.
Downward energy flux is estimated as cgz × KEin (i) by summing over the set of events, (ii) from time series near the bottom of the record, and (iii) from the wavenumber–frequency spectrum and the dispersion relationship. These estimates are compared to the work done on near-inertial motions in the mixed layer by the wind, which is directly estimated from mixed layer near-inertial currents and winds measured from a surface buoy 10 km away. All three methods yield similar values, indicating that 12%–33% of the energy input into the mixed layer transits 800 m toward the deep sea. This simple picture neglects lateral energy flux carried by the first few vertical modes, which was not measured. The substantial deep penetration implies that near-inertial motions may play a role in mixing the deep ocean, but the strong observed variability calls for a need to better understand the role of lateral mesoscale structures in modulating the vertical propagation.
A Political Ecology of “Water in Mind”: Attributing Perceptions in the Era of Global Climate Change
Authors: Crate Susan A. 
Published: November 2011

AbstractThis article explores how researchers can apply social science methods and theoretical frames to capture how place-based communities are perceiving and responding to the immediate effects of global climate change. The study focuses on research with Viliui Sakha—native horse and cattle breeders of northeastern Siberia, Russia, who are increasingly challenged by one of global climate change’s most prevalent effects: altered water regimes. By applying the theoretical framework of political ecology, the article shows how researchers can better understand how affected peoples have, in this case, “water in mind” via their histories, cosmologies, and management practices of water. Such awareness can inform research activities and findings, facilitate effective adaptation, and, ultimately, affect policy. Given the widespread emphasis on adaptation, including the urgent need for, increasing interest in, and funding support for transdisciplinary research projects on adaptation, and the facilitative role researchers and policymakers can play in adaptation, this move to understanding and integrating a population’s shifting perceptions—in this case, of water in mind—into research is fundamental.
Isolation of pectin-enriched products from red beet (Beta vulgaris L. var. conditiva) wastes: composition and functional properties
Authors: Fissore E.N. , Ponce N.M.A. , Matkovic L. , Stortz C.A. , Rojas A.M. , Gerschenson L.N. 
Published: November 2011

The present work was dedicated to the development of an extraction process for red beet ( Beta vulgaris L. var. conditiva) by-products that preserves the high molecular weight of the macromolecules with the primary aim of waste upgrading. Our study concerns the extraction of pectin-enriched products with potential thickening properties for their usage in food formulation, as well as with some healthy physiological effect, by using citrate buffer (pH = 5.2) either alone or with enzymes (hemicellulase or cellulase) active on cell wall polysaccharide networks. Considering that red beet tissue contains ferulic acid, which cross-links pectin macromolecules through arabinose residues to anchor them into the cell wall, an alkaline pretreatment was also evaluated in order to perform polysaccharide hydrolysis in the cell wall network to accomplish higher renderings. Chemical composition and yield, as well as the in vitro glucose retention exerted by the isolated fiber products were finally analyzed.
Antigen stored in dendritic cells after macropinocytosis is released unprocessed from late endosomes to target B cells
Authors: Le Roux Delphine , Le Bon Agnès , Dumas Audrey , Taleb Kahina , Sachse Martin , Sikora Romain , Julithe Marion , Benmerah Alexandre , Bismuth Georges , Niedergang Florence 
Published: November 2011

AbstractB lymphocytes can be triggered in lymph nodes by nonopsonized antigens (Ag), potentially in their native form. However, the mechanisms that promote encounter of B lymphocytes with unprocessed antigens in lymph nodes are still elusive. We show here that antigens are detected in B cells in the draining lymph nodes of mice injected with live, but not fixed, dendritic cells (DCs) loaded with antigens. This highlights active processes in DCs to promote Ag transfer to B lymphocytes. In addition, antigen-loaded DCs found in the draining lymph node were CD103+. Using 3 different model Ag, we then show that immature DCs efficiently take up Ag by macropinocytosis and store the internalized material in late endocytic compartments. We find that DCs have a unique ability to release antigens from these compartments in the extracellular medium, which is controlled by Rab27. B cells take up the regurgitated Ag and the chemokine CXCL13, essential to attract B cells in lymph nodes, enhances this transfer. Our results reveal a unique property of DCs to regurgitate unprocessed Ag that could play an important role in B-cell activation.
Cyclic AMP response element-binding protein prevents endothelial permeability increase through transcriptional controlling p190RhoGAP expression
Authors: Chava Koteswara Rao , Tauseef Mohammad , Sharma Tiffany , Mehta Dolly 
Published: November 2011

Abstract
Increased endothelial permeability contributes to the morbidity and mortality associated with chronic inflammatory diseases, including acute lung injury. Cyclic AMP response element-binding protein (CREB) transcriptional factor induces genes that regulate inflammation and vascular remodeling. However, the role of CREB in regulating endothelial barrier function is unknown. Here, we demonstrate that CREB maintains basal endothelial barrier function and suppresses endothelial permeability increase by diverse agonists such as thrombin, lipopolysaccharide, histamine, and VEGF. We show that CREB transcriptionally controls the expression of p190RhoGAP-A, a GTPase-activating protein that inhibits small GTPase RhoA. Impairing CREB function using small interfering RNA or dominant-negative (dn)–CREB mutant (dn-CREB) markedly suppressed p190RhoGAP-A expression, increased RhoA activity, induced actin stress fiber formation, and produced an amplified and protracted increase in endothelial permeability in response to thrombin. Rescuing p190RhoGAP-A expression restored the permeability defect in dn-CREB–transducing endothelial cells. These findings were recapitulated in vivo because dn-CREB expression in mice vasculature increased basal lung microvessel permeability and exaggerated permeability increase induced by thrombin and lipopolysaccharide. Inhibiting RhoA signaling restored endothelial barrier dysfunction in the dn-CREB–expressing lung microvasculature. These results uncover a pivotal role of CREB in regulating endothelial barrier function by restricting RhoA signaling through controlling p190RhoGAP-A expression.
Increased serum soluble IL-15Rα levels in T-cell large granular lymphocyte leukemia
Authors: Chen Jing , Petrus Mike , Bamford Richard , Shih Joanna H. , Morris John C. , Janik John E. , Waldmann Thomas A. 
Published: November 2011

AbstractLarge granular lymphocyte (LGL) leukemia is a clonal lymphoproliferative disease of mature T and natural killer cells. The etiology of LGL leukemia is unknown. IL-15 is an inflammatory cytokine that stimulates T and natural killer cells and is critical for their survival and proliferation. IL-15 signals through a heterotrimeric receptor that is composed of a private receptor, IL-15Rα and IL-2/IL-15Rβ and γc shared with IL-2. Using a newly developed assay, we demonstrated increased levels of soluble IL-15Rα in the serum of patients with T-LGL leukemia. Furthermore, IL-15Rα mRNA levels were also up-regulated in the PBMCs of these patients. FACS analysis indicated that IL-15Rα was expressed both on monocytes as well as on some CD8+ leukemic cells of the patients. Interestingly, the mRNA levels of IFN-γ, a known inducer of IL-15Rα, were also up-regulated in patients' PBMCs. Moreover, PBMCs of some T-LGL patients proliferated at higher levels in response to exogenously added IL-15 compared with those of normal donors. In summary, our study demonstrated increased expression of IL-15Rα in T-LGL leukemia. It is conceivable that higher IL-15Rα expression may lower IL-15 response threshold in vivo and, therefore, may contribute to the pathogenesis of the disease.
Increased BMI correlates with higher risk of disease relapse and differentiation syndrome in patients with acute promyelocytic leukemia treated with the AIDA protocols
Authors: Breccia Massimo , Mazzarella Luca , Bagnardi Vincenzo , Disalvatore Davide , Loglisci Giuseppina , Cimino Giuseppe , Testi Anna Maria , Avvisati Giuseppe , Petti Maria Concetta , Minotti Clara , Latagliata Roberto , Foà Robin , Pelicci Pier Giuseppe , Lo-Coco Francesco 
Published: November 2011

Abstract
We investigated whether body mass index (BMI) correlates with distinct outcomes in newly diagnosed acute promyelocytic leukemia (APL). The study population included 144 patients with newly diagnosed and genetically confirmed APL consecutively treated at a single institution. All patients received All-trans retinoic acid and idarubicin according to the GIMEMA protocols AIDA-0493 and AIDA-2000. Outcome estimates according to the BMI were carried out together with multivariable analysis for the risk of relapse and differentiation syndrome. Fifty-four (37.5%) were under/normal weight (BMI < 25), whereas 90 (62.5%) patients were overweight/obese (BMI ≥ 25). An increased BMI was associated with older age (P < .0001) and male sex (P = .02). BMI was the most powerful predictor of differentiation syndrome in multivariable analysis (odds ratio = 7.24; 95% CI, 1.50-34; P = .014). After a median follow-up of 6 years, the estimated cumulative incidence of relapse at 5 years was 31.6% (95% CI, 22.7%-43.8%) in overweight/obese and 11.2% (95% CI, 5.3%-23.8%) in underweight/normal weight patients (P = .029). Multivariable analysis showed that BMI was an independent predictor of relapse (hazard ratio = 2.45, 95% CI, 1.00-5.99, in overweight/obese vs under/normal weight patients, P = .049). An increased BMI at diagnosis is associated with a higher risk of developing differentiation syndrome and disease relapse in APL patients treated with AIDA protocols.
Aldose reductase deficiency in mice protects from ragweed pollen extract (RWE)-induced allergic asthma
Authors: Yadav Umesh CS , Aguilera-Aguirre Leopoldo , Boldogh Istvan , Ramana Kota V , Srivastava Satish K 
Published: November 2011

Abstract

Background
Childhood hospitalization related to asthma remains at historically high levels, and its incidence is on the rise world-wide. Previously, we have demonstrated that aldose reductase (AR), a regulatory enzyme of polyol pathway, is a major mediator of allergen-induced asthma pathogenesis in mouse models. Here, using AR null (AR-/-) mice we have investigated the effect of AR deficiency on the pathogenesis of ragweed pollen extract (RWE)-induced allergic asthma in mice and also examined the efficacy of enteral administration of highly specific AR inhibitor, fidarestat.

Methods
The wild type (WT) and AR-/- mice were sensitized and challenged with RWE to induce allergic asthma. AR inhibitor, fidarestat was administered orally. Airway hyper-responsiveness was measured in unrestrained animals using whole body plethysmography. Mucin levels and Th2 cytokine in broncho-alveolar lavage (BAL) were determined using mouse anti-Muc5A/C ELISA kit and multiplex cytokine array, respectively. Eosinophils infiltration and goblet cells were assessed by H&E and periodic acid Schiff (PAS)-staining of formalin-fixed, paraffin-embedded lung sections. T regulatory cells were assessed in spleen derived CD4+CD25+ T cells population.

Results
Deficiency of AR in mice led to significantly decreased PENH, a marker of airway hyper-responsiveness, metaplasia of airway epithelial cells and mucus hyper-secretion following RWE-challenge. This was accompanied by a dramatic decrease in infiltration of eosinophils into sub-epithelium of lung as well as in BAL and release of Th2 cytokines in response to RWE-challenge of AR-/- mice. Further, enteral administration of fidarestat significantly prevented eosinophils infiltration, airway hyper-responsiveness and also markedly increased population of T regulatory (CD4+CD25+FoxP3+) cells as compared to RWE-sensitized and challenged mice not treated with fidarestat.

Conclusion
Our results using AR-/- mice strongly suggest the role of AR in allergic asthma pathogenesis and effectiveness of oral administration of AR inhibitor in RWE-induced asthma in mice supports the use of AR inhibitors in the treatment of allergic asthma.