bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modulating Endogenous NQO1 Levels Identifies Key Regulatory Mechanisms of Action of β-Lapachone for Pancreatic Cancer Therapy
Authors: Li Long Shan , Bey Erik A. , Dong Ying , Meng Jieru , Patra Biswanath , Yan Jingsheng , Xie Xian-Jin , Brekken Rolf A. , Barnett Carlton C. , Bornmann William G. , Gao Jinming , Boothman David A. 
Published: January 2011

Abstract
Purpose: Pancreatic cancer is the fourth leading cause of cancer-related deaths, in which the 5-year survival rate is less than 5%. Current standard of care therapies offer little selectivity and high toxicity. Novel, tumor-selective approaches are desperately needed. Although prior work suggested that β-lapachone (β-lap) could be used for the treatment of pancreatic cancers, the lack of knowledge of the compound's mechanism of action prevented optimal use of this agent.
Experimental Design: We examined the role of NAD(P)H:quinone oxidoreductase-1 (NQO1) in β-lap–mediated antitumor activity, using a series of MIA PaCa-2 pancreatic cancer clones varying in NQO1 levels by stable shRNA knockdown. The antitumor efficacy of β-lap was determined using an optimal hydroxypropyl-β-cyclodextran (HPβ-CD) vehicle formulation in metastatic pancreatic cancer models.
Results: β-Lap–mediated cell death required ∼90 enzymatic units of NQO1. Essential downstream mediators of lethality were as follows: (i) reactive oxygen species (ROS); (ii) single-strand DNA breaks induced by ROS; (iii) poly(ADP-ribose)polymerase-1 (PARP1) hyperactivation; (iv) dramatic NAD+/ATP depletion; and (v) programmed necrosis. We showed that 1 regimen of β-lap therapy (5 treatments every other day) efficaciously regressed and reduced human pancreatic tumor burden and dramatically extended the survival of athymic mice, using metastatic pancreatic cancer models.
Conclusions: Because NQO1 enzyme activities are easily measured and commonly overexpressed (i.e., &gt;70%) in pancreatic cancers 5- to 10-fold above normal tissue, strategies using β-lap to efficaciously treat pancreatic cancers are indicated. On the basis of optimal drug formulation and efficacious antitumor efficacy, such a therapy should be extremely safe and not accompanied with normal tissue toxicity or hemolytic anemia. Clin Cancer Res; 17(2); 275–85. ©2011 AACR.
Unique Functional Status of Natural Killer Cells in Metastatic Stage IV Melanoma Patients and Its Modulation by Chemotherapy
Authors: Fregni Giulia , Perier Aurélie , Pittari Gianfranco , Jacobelli Simon , Sastre Xavier , Gervois Nadine , Allard Mathilde , Bercovici Nadège , Avril Marie Françoise , Caignard Anne 
Published: January 2011

AbstractPurpose: Immunotherapy is an alternative for metastatic melanoma patients resistant to chemotherapy. Natural killer (NK) cells are powerful antileukemia effectors and their role in solid tumors is suspected. NK cell activation is regulated by a balance between activating receptors, which detect stress molecules on tumor cells, and HLA-I specific inhibitory receptors. Here, we studied the phenotype and function of NK cells in stage IV metastatic melanoma patients.Experimental Design: Circulating NK cells from 35 healthy donors and 51 patients were studied: 24 patients before chemotherapy (prechemotherapy), 17 patients 1 month after 1 to 4 lines of chemotherapy (postchemotherapy), and 10 patients analyzed pre- and postchemotherapy. NK functionality was carried out toward 2 primary metastatic melanoma cell lines, analyzed for the expression of NK receptor ligands.Results: NK cells from prechemotherapy patients exhibit an NKp46dim/NKG2Adim phenotype. In contrast, NK cells from postchemotherapy patients display high expression of NKp46 and NKG2A receptors. Purified NK cells from patients are efficiently activated in response to melanoma cells. Melanoma cells express different level of NKG2D ligands and HLA-I molecules. In agreements with their phenotype, NK cells from pre- and postchemotherapy patients present distinct functional status toward these primary melanoma cells. A dynamic label free assay was used to determine the pathways involved in the lysis of melanoma cells by IL-2–activated NK cells. NKG2D, NCR (natural cytotoxicity receptor), and DNAM-1 are involved in the NK-mediated lysis of melanoma cells.Conclusions: These results provide new arguments and clues to design NK cell–based immunotherapeutic strategies for melanoma patients. Clin Cancer Res; 17(9); 2628–37. ©2011 AACR.
Pretreatment Transcriptional Profiling for Predicting Response to Neoadjuvant Chemoradiotherapy in Rectal Adenocarcinoma
Authors: Brettingham-Moore Kate H. , Duong Cuong P. , Greenawalt Danielle M. , Heriot Alexander G. , Ellul Jason , Dow Christopher A. , Murray William K. , Hicks Rodney J. , Tjandra Joe , Chao Michael , Bui Andrew , Joon Daryl Lim , Thomas Robert J. S. , Phillips Wayne A. 
Published: January 2011

AbstractPurpose: Patients presenting with locally advanced rectal cancer currently receive preoperative radiotherapy with or without chemotherapy. Although pathologic complete response is achieved for approximately 10% to 30% of patients, a proportion of patients derive no benefit from this therapy while being exposed to toxic side effects of treatment. Therefore, there is a strong need to identify patients who are unlikely to benefit from neoadjuvant therapy to help direct them toward alternate and ultimately more successful treatment options.Experimental Design: In this study, we obtained expression profiles from pretreatment biopsies for 51 rectal cancer patients. All patients underwent preoperative chemoradiotherapy, followed by resection of the tumor 6 to 8 weeks posttreatment. Gene expression and response to treatment were correlated, and a supervised learning algorithm was used to generate an original predictive classifier and validate previously published classifiers.Results: Novel predictive classifiers based on Mandard's tumor regression grade, metabolic response, TNM (tumor node metastasis) downstaging, and normal tissue expression profiles were generated. Because there were only 7 patients who had minimal treatment response (&gt;80% residual tumor), expression profiles were used to predict good tumor response and outcome. These classifiers peaked at 82% sensitivity and 89% specificity; however, classifiers with the highest sensitivity had poor specificity, and vice versa. Validation of predictive classifiers from previously published reports was attempted using this cohort; however, sensitivity and specificity ranged from 21% to 70%.Conclusions: These results show that the clinical utility of microarrays in predictive medicine is not yet within reach for rectal cancer and alternatives to microarrays should be considered for predictive studies in rectal adenocarcinoma. Clin Cancer Res; 17(9); 3039–47. ©2011 AACR.
Bortezomib Induces Nuclear Translocation of IκBα Resulting in Gene-Specific Suppression of NF-κB–Dependent Transcription and Induction of Apoptosis in CTCL
Authors: Juvekar Ashish , Manna Subrata , Ramaswami Sitharam , Chang Tzu-Pei , Vu Hai-Yen , Ghosh Chandra C. , Celiker Mahmut Y. , Vancurova Ivana 
Published: January 2011

Abstract
Cutaneous T-cell lymphoma (CTCL) is characterized by constitutive activation of nuclear factor κB (NF-κB), which plays a crucial role in the survival of CTCL cells and their resistance to apoptosis. NF-κB activity in CTCL is inhibited by the proteasome inhibitor bortezomib; however, the mechanisms remained unknown. In this study, we investigated mechanisms by which bortezomib suppresses NF-κB activity in CTCL Hut-78 cells. We demonstrate that bortezomib and MG132 suppress NF-κB activity in Hut-78 cells by a novel mechanism that consists of inducing nuclear translocation and accumulation of IκBα (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha), which then associates with NF-κB p65 and p50 in the nucleus and inhibits NF-κB DNA binding activity. Surprisingly, however, while expression of NF-κB–dependent antiapoptotic genes cIAP1 and cIAP2 is inhibited by bortezomib, expression of Bcl-2 is not suppressed. Chromatin immunoprecipitation indicated that cIAP1 and cIAP2 promoters are occupied by NF-κB p65/50 heterodimers, whereas Bcl-2 promoter is occupied predominantly by p50/50 homodimers. Collectively, our data reveal a novel mechanism of bortezomib function in CTCL and suggest that the inhibition of NF-κB–dependent gene expression by bortezomib is gene specific and depends on the subunit composition of NF-κB dimers recruited to NF-κB–responsive promoters. Mol Cancer Res; 9(2); 183–94. ©2011 AACR.
Haemostatic effects of a new combined oral contraceptive, nomegestrol acetate/17β-estradiol, compared with those of levonorgestrel/ethinyl estradiol
Authors: Alhenc-Gelas Martine , Thomas Jean-Louis , Bachelot-Loza Christilla , Remones Veronique , Dali Ali Fouad , Aiach Martine , Scarabin Pierre-Yves , Gaussem Pascale 
Published: January 2011

SummaryUse of oral contraceptives (OC) that combine a progestogen with synthetic ethinyl estradiol (EE) is associated with increased risk of venous thromboembolism. NOMAC/E2 is a new monophasic OC that combines nomegestrol acetate (NOMAC), a highly selective progestogen, with 17β-estradiol (E2). The study objective was to compare the effects on markers of haemostasis of NOMAC/E2 (2.5 mg/1.5 mg) versus the second-generation OC, levonorgestrel (LNG)/EE (100 μg/20 μg). Healthy women (age 18–38 years) received once-daily treatment for three consecutive 28-day cycles in a double-blind, randomised study: either NOMAC/E2 for 24 days with a four-day placebo interval (n=45) or LNG/ EE for 21 days with a seven-day placebo interval (n=45) per cycle. Mean changes from baseline to end-of-treatment in coagulation markers, including prothrombin fragment 1+2 (primary endpoint), fibrinolysis markers and platelet functions were assessed. Mean prothrombin fragment 1+2 levels (primary endpoint) did not increase with NOMAC/E2 compared with LNG/EE ( –0.02 vs. +0.08 nM, p<0.01). Other significant differences between NOMAC/E2 and LNG/EE were mean changes in antithrombin (+0.3% vs. –4.4%, p<0.001), activated protein C resistance – normalised ratio (+0.20 vs. +0.46, p<0.01), D-dimer ( –53 vs. +43 ng/ml, p<0.001), plasminogen (+6% vs. +30%, p<0.0001) and plasminogen activator inhibitor-1 ( –3.1 vs. –8.0 ng/ml, p<0.001). There was no effect of either treatment on platelet aggregation. The NOMAC/E2 pill regimen has fewer adverse effects on blood biological coagulation and fibrinolysis markers than LNG/EE. This suggests that NOMAC/E2 could have a more favourable venous thromboembolism risk profile than LNG/EE; further epidemiological data are required to confirm this.
Simultaneous intravital imaging of macrophage and neutrophil behaviour during inflammation using a novel transgenic zebrafish
Authors: Gray Caroline , Loynes Catherine , Whyte Moira , Crossman David , Renshaw Stephen , Chico Timothy 
Published: January 2011

SummaryThe zebrafish is an outstanding model for intravital imaging of inflammation due to its optical clarity and the ability to express fluorescently labelled specific cell types by transgenesis. However, although several transgenic labelling myeloid cells exist, none allow distinction of macrophages from neutrophils. This prevents simultaneous imaging and examination of the individual contributions of these important leukocyte subtypes during inflammation. We therefore used Bacterial Artificial Chromosome (BAC) recombineering to generate a transgenic Tg(fms:GAL4.VP16)i186, in which expression of the hybrid transcription factor Gal4-VP16 is driven by the fms (CSF1R) promoter. This was then crossed to a second transgenic expressing a mCherry-nitroreductase fusion protein under the control of the Gal4 binding site (the UAS promoter), allowing intravital imaging of mCherry-labelled macrophages. Further crossing this compound transgenic with the neutrophil transgenic Tg(mpx:GFP)i114 allowed clear distinction between macrophages and neutrophils and simultaneous imaging of their recruitment and behaviour during inflammation. Compared with neutrophils, macrophages migrate significantly more slowly to an inflammatory stimulus. Neutrophil number at a site of tissue injury peaked around 6 hours post injury before resolving, while macrophage recruitment increased until at least 48 hours. We show that macrophages were effectively ablated by addition of the prodrug metronidazole, with no effect on neutrophil number. Crossing with Tg(Fli1:GFP)y1 transgenic fish enabled intravital imaging of macrophage interaction with endothelium for the first time, revealing that endothelial contact is associated with faster macrophage migration. Tg(fms:GAL4.VP16)i186 thus provides a powerful tool for intravital imaging and functional manipulation of macrophage behaviour during inflammation.
Association between the Pulmonary Embolism Severity Index (PESI) and short-term clinical deterioration
Authors: Hariharan Praveen , Takayesu James Kimo , Kabrhel Christopher 
Published: January 2011

SummaryThe Pulmonary Embolism Severity Index (PESI) has been shown to predict 30 and 90 day mortality after PE. However, whether the PESI predicts patients who will be free of clinically adverse outcomes during a typical hospitalisation is not known. Retrospective analysis of Emergency Department patients with PE from May 2006 to April 2008. We compiled demographics, data to calculate the PESI and a composite outcome. Patients were considered to have a negative PESI if they were in category I or II (≤85 points). Patients were considered to have the composite outcome if, within five days of diagnosis, they: A) had recurrent PE; B) developed a new cardiac dysrhythmia; C) required advanced cardiac life support; D) required respiratory support; E) required vasopressors; F) received thrombolysis; G) had major bleeding; H) returned to the ED; I) died. We enrolled 245 patients with PE. Of these, 115 (47%) were male, 204 (83%) were white. The mean age was 57 ± 17 years. The PESI identified 109 (44%) as low risk and 136 (56%) as high risk. Sixty-one (26%) patients had the outcome, of whom nine (14%) were char-acterised as low risk by the PESI. Test characteristics were: sensitivity 86% (95% confidence interval [CI]: 75%-93%), specificity 55% (95% CI: 47%-62%), NPV 63% (95% CI: 55%-70%), PPV 40% (95% CI: 31%-49%), LR(+) 1.9 (95% CI: 1.57–2.30) and LR(-) 0.26 (95% CI: 0.14–0.48). Of the patients categorised by the PESI as safe for discharge, 14% had an adverse clinical event or required a hospital-based intervention within the first five days after PE diagnosis. Improvements in the risk stratification of patients with PE are still needed.* Presented at the American College of Emergency Physicians, Scientific Assembly, Boston, 2009.
Molecular imaging of macrophage protease activity in cardiovascular inflammation in vivo
Authors: Quillard Thibaut , Croce Kevin , Jaffer Farouc , Weissleder Ralph , Libby Peter 
Published: January 2011

SummaryMacrophages contribute pivotally to cardiovascular diseases (CVD), notably to atherosclerosis. Imaging of macrophages in vivo could furnish new tools to advance evaluation of disease and therapies. Proteolytic enzymes serve as key effectors of many macrophage contributions to CVD. Therefore, intravital imaging of protease activity could aid evaluation of the progress and outcome of atherosclerosis, aortic aneurysm formation, or rejection of cardiac allografts. Among the large families of proteases, matrix metalloproteinases (MMPs) and cysteinyl cathepsins have garnered the most interest because of their participation in extra-cellular matrix remodelling. These considerations have spurred the development of dedicated imaging agents for protease activity detection. Activatable fluorescent probes, radiolabelled inhibitors, and nanoparticles are currently under exploration for this purpose. While some agents and technologies may soon see clinical use, others will require further refinement. Imaging of macrophages and protease activity should provide an important adjunct to understanding pathophysiology in vivo, evaluating the effects of interventions, and ultimately aiding clinical care.
Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II)
Authors: Dahl Ola , Huo Michael , Kurth Andreas , Hantel Stefan , Hermansson Karin , Schnee Janet , Friedman Richard , Eriksson Bengt ,   for the RE-NOVATE II Study Group
Published: January 2011

SummaryThis trial compared the efficacy and safety of oral dabigatran, a direct thrombin inhibitor, versus subcutaneous enoxaparin for extended thromboprophylaxis in patients undergoing total hip arthroplasty. A total of 2,055 patients were randomised to 28–35 days treatment with oral dabigatran, 220 mg once-daily, starting with a half-dose 1–4 hours after surgery, or subcutaneous enoxaparin 40 mg once-daily, starting the evening before surgery. The primary efficacy outcome was a composite of total venous thromboembolism [VTE] (venographic or symptomatic) and death from all-causes. The main secondary composite outcome was major VTE (proximal deep-vein thrombosis or non-fatal pulmonary embolism) plus VTE-related death. The main safety outcome was major bleeding. In total, 2,013 were treated, of whom 1,577 operated patients were included in the primary efficacy analysis. The primary efficacy outcome occurred in 7.7% of the dabigatran group versus 8.8% of the enoxaparin group, risk difference (RD) –1.1% (95%CI –3.8 to 1.6%); p<0.0001 for the pre-specified non-inferiority margin. Major VTE plus VTE-related death occurred in 2.2% of the dabigatran group versus 4.2% of the enoxaparin group, RD –1.9% (-3.6% to –0.2%); p=0.03. Major bleeding occurred in 1.4% of the dabigatran group and 0.9% of the enoxaparin group (p=0.40). The incidence of adverse events, including liver enzyme elevations and cardiac events, during treatment was similar between the groups. Extended prophylaxis with oral dabigatran 220 mg once-daily was as effective as sub-cutaneous enoxaparin 40 mg once-daily in reducing the risk of VTE after total hip arthroplasty, and superior to enoxaparin for reducing the risk of major VTE. The risk of bleeding and safety profiles were similar.
Venous and arterial thrombosis – pathogenesis and the rationale for anticoagulation
Authors: Esmon Charles , Turpie Alexander 
Published: January 2011

SummaryThromboembolic disorders are major causes of morbidity and mortality. It is well-recognised that the pathogenesis is different for arterial and venous thrombosis; however, both involve coagulation activation. Anticoagulants are used for the prevention and treatment of a wide variety of thromboembolic and related conditions. Agents with anti-inflammatory properties in addition to anticoagulation may be particularly beneficial. Traditional anticoagulants, although effective, are associated with certain limitations. Understanding the pathological processes associated with thrombosis and the rational target for anticoagulation is essential, not only for the development of safer and more effective agents, but also for better clinical management of patients who require anticoagulation therapy. In recent years, new oral agents that target single enzymes of the coagulation cascade have been developed – some of those are in advanced stages of clinical development. Based on scientific rationale, both factor Xa and thrombin are viable targets for effective anticoagulation.
Cross-Cultural Variations in Naïve Psychology among 2-year-olds: A Comparison of Children in the United Kingdom and Singapore
Authors: Lim Ai Keow , Williams Joanne M. , Cebula Katie R. , Annaz Dagmara 
Published: January 2011

Abstract
Children’s understanding of naïve psychology is the main focus of this study. Research evidence suggests that 2- and 3-year-olds understand some aspects of naïve psychology. By 4 years, they develop internal representations of mental states. Previous studies have also reported cross-cultural variations in naïve psychology development. The majority of this research has focused on Western individualistic societies such as Australia, Europe and North America, and Eastern collectivism societies such as China and Japan. Singapore with its blend of Eastern and Western values represents a unique case for comparison with Western societies. This paper reports a cross-cultural study of young children’s developing understanding of naïve psychology in Edinburgh, UK and Singapore. It addresses three main questions: (a) Are there cross-cultural differences in the development of naïve psychology?; (b) What are children’s performance sequences on naïve psychology tasks?; and (c) Are naïve psychology concepts coherent? The participants were 87 children from the UK (n=43, mean age 2 years 4 months) and Singapore (n=44, mean age 2 years 5 months). This study incorporated several established tasks of pretence, desires, emotions, perceptions, appearance-reality and false-beliefs to investigate children’s understanding of non-representational and representational mental states. The results showed no gross cross-cultural differences. However, significant cultural differences in performance on two tasks and differences in the coherence of naïve psychology concepts were identified. The results highlight the importance of considering subtle cultural influences on children’s developing understanding of various aspects of naïve psychology.
Intuitive Moral Judgments are Robust across Variation in Gender, Education, Politics and Religion: A Large-Scale Web-Based Study
Authors: Banerjee Konika , Huebner Bryce , Hauser Marc 
Published: January 2011

AbstractResearch on moral psychology has frequently appealed to three, apparently consistent patterns: (1) Males are more likely to engage in transgressions involving harm than females; (2) educated people are likely to be more thorough in their moral deliberations because they have better resources for rationally navigating and evaluating complex information; (3) political affiliations and religious ideologies are an important source of our moral principles. Here, we provide a test of how four factors ‐ gender, education, politics and religion ‐ affect intuitive moral judgments in unfamiliar situations. Using a large-scale sample of participants (n=8778) who voluntarily logged on to the internet-based Moral Sense Test (available online at <ext-link ext-link-type="url" xlink:href="http://moral.wjh.harvard.edu">http://moral.wjh.harvard.edu</ext-link>), we analyzed responses to 145 unique moral and conventional scenarios that varied widely in content. Although each demographic or cultural factor sometimes yielded a statistically significant difference in the predicted direction (e.g., men giving more utilitarian judgments than women; religious individuals giving more deontological/rule-based judgments than atheists), these differences were consistently associated with extremely small effect sizes. We conclude that gender, education, politics and religion are likely to be relatively insignificant for moral judgments of unfamiliar scenarios. We discuss these results in light of current debates concerning the mechanisms underlying our moral judgments and, especially, the idea that we share a universal moral sense that constrains the range of cross-cultural variation.