bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synergistic Effects of Metformin Treatment in Combination with Gefitinib, a Selective EGFR Tyrosine Kinase Inhibitor, in LKB1 Wild-type NSCLC Cell Lines
Authors: Morgillo Floriana , Sasso Ferdinando Carlo , Della Corte Carminia Maria , Vitagliano Donata , D'Aiuto Elena , Troiani Teresa , Martinelli Erika , De Vita Ferdinando , Orditura Michele , De Palma Raffaele , Ciardiello Fortunato 
Published: May 2013

Abstract
Purpose: EGF receptor (EGFR) tyrosine kinase inhibitors (TKI) have been found to be effective against lung cancer, but clinical resistance to these agents has developed as their usage has increased. Metformin is a widely used antidiabetic drug and also displays significant growth-inhibitory and proapoptotic effects in several cancer models, alone or in combination with chemotherapeutic drugs.
Experimental Design: The effects of gefitinib, a selective EGFR-TKI, and metformin on a panel of non–small cell lung cancer (NSCLC) cell lines were assessed by using MTT, bromide assay, flow cytometry, anchorage-independent growth, coimmunoprecipitation, and Western blot analysis.
Results: The combination of metformin with gefitinib induced a strong antiproliferative and proapoptotic effect in NSCLC cell lines that harbored wild-type LKB1 gene. Treatment with metformin as single agent, however, induced an activation and phosphorylation of mitogen-activated protein kinase (MAPK) through an increased C-RAF/B-RAF heterodimerization. The inhibition of EGFR phosphorylation and of downstream signaling by adding gefitinib to metformin treatment abrogated this phenomenon and induced a strong apoptotic effect in vitro and in vivo.
Conclusions: Metformin and gefitinib are synergistic in LKB1 wild-type NSCLC cells. However, further studies are required to investigate better the effect of metformin action on the RAS/RAF/MAPK pathway and the best context in which to use metformin in combination with molecular targeted agents. Clin Cancer Res; 19(13); 3508–19. ©2013 AACR.
Anti-HDGF Targets Cancer and Cancer Stromal Stem Cells Resistant to Chemotherapy
Authors: Zhao Jun , Ma Mark Z. , Ren Hening , Liu Zhenqiu , Edelman Martin J. , Pan Hong , Mao Li 
Published: May 2013

Abstract
Purpose: Approximately one third of the patients with advanced non–small cell lung carcinoma (NSCLC) will initially respond to platinum-based chemotherapy, but virtually all tumors will progress (acquired resistance). The remainder will progress during initial treatment (primary resistance). In this study, we test whether the treatment can be improved by inhibiting hepatoma-derived growth factor (HDGF).
Experimental Design: Thirteen primary NSCLC heterotransplant models were used to test four treatment regimens, including platinum-based chemotherapy with and without bevacizumab (VEGF-neutralizing antibody) or HDGF-H3 (HDGF-neutralizing antibody) and chemotherapy with bevacizumab and HDGF-H3. Expression of stem cell–related genes was measured using quantitative reverse transcription PCR (qRT-PCR) and immunohistochemistry.
Results: Among 13 primary NSCLC heterotransplant models, three (23%) responded to chemotherapy but all relapsed within 20 days. The residual tumors after response to the chemotherapy exhibited an increased expression in 51 (61%) of 84 genes related with stem cell proliferation and maintenance, particularly those in Notch and Wnt pathways, suggesting enrichment for stem cell populations in the residual tumors. Interestingly, tumors from two of three models treated with HDGF-H3, bevacizumab, and chemotherapy combination did not relapse during 6 months of posttreatment observation. Importantly, this treatment combination substantially downregulated expression levels in 57 (68%) of 84 stem cell–related genes, including 34 (67%) of 51 genes upregulated after the chemotherapy.
Conclusion: These data support the hypothesis that cancer stem cells (CSC) are a mechanism for chemotherapy resistance and suggest HDGF may be a target for repressing CSCs to prevent relapse of NSCLC sensitive to chemotherapy. Clin Cancer Res; 19(13); 3567–76. ©2013 AACR.
Downregulation of miR-452 Promotes Stem-Like Traits and Tumorigenicity of Gliomas
Authors: Liu Liping , Chen Kun , Wu Jueheng , Shi Ling , Hu Bo , Cheng Shiyuan , Li Mengfeng , Song Libing 
Published: May 2013

Abstract
Purpose: miR-452 is reported to be required for neural crest stem cell differentiation during neural crest development. However, the biologic role of miR-452 in gliomas remains unclear. The aim of the present study was to evaluate the effect of miR-452 on the stem-like properties and tumorigenesis of glioma cells.
Experimental Design: The expression of miR-452 was examined in glioma cells and glioma tissues using real-time PCR. The effects of miR-452 on stem-like traits and tumorigenesis were investigated in vitro and in vivo using patient-derived glioma cells and glioma cell lines. Western blotting and luciferase reporter assays were conducted to examine the negative regulation of Bmi-1, LEF1, and TCF4 by miR-452. The methylation of the miR-452 promoter region was examined by bisulfite genomic sequencing PCR.
Results: miR-452 was markedly downregulated in glioma cells and clinical glioma tissues. miR-452 levels were inversely correlated with World Health Organization (WHO) grades and patient survival. miR-452 directly targeted and suppressed multiple stemness regulators, including Bmi-1, LEF1, and TCF4, resulting in reduced stem-like traits and tumorigenesis of glioma cells in vitro and in vivo. Furthermore, we showed that downregulation of miR-452 in gliomas was caused by hypermethylation of its promoter region.
Conclusions: Downregulation of miR-452 plays an important role in promoting the stem-like traits and tumorigenesis of gliomas and may represent a novel prognostic biomarker and therapeutic target for the disease. Clin Cancer Res; 19(13); 3429–38. ©2013 AACR.
PG545, an Angiogenesis and Heparanase Inhibitor, Reduces Primary Tumor Growth and Metastasis in Experimental Pancreatic Cancer
Authors: Ostapoff Katherine T. , Awasthi Niranjan , Kutluk Cenik Bercin , Hinz Stefan , Dredge Keith , Schwarz Roderich E. , Brekken Rolf A. 
Published: May 2013

Abstract
Aggressive tumor progression, metastasis, and resistance to conventional therapies lead to an extremely poor prognosis for pancreatic ductal adenocarcinoma (PDAC). Heparanase, an enzyme expressed by multiple cell types, including tumor cells in the tumor microenvironment, has been implicated in angiogenesis and metastasis, and its expression correlates with decreased overall survival in PDAC. We evaluated the therapeutic potential of PG545, an angiogenesis and heparanase inhibitor, in experimental PDAC. PG545 inhibited the proliferation, migration, and colony formation of pancreatic cancer cells in vitro at pharmacologically relevant concentrations. Heparanase inhibition also reduced the proliferation of fibroblasts but had only modest effects on endothelial cells in vitro. Furthermore, PG545 significantly prolonged animal survival in intraperitoneal and genetic models (mPDAC: LSL-KrasG12D; Cdkn2alox/lox; p48Cre) of PDAC. PG545 also inhibited primary tumor growth and metastasis in orthotopic and genetic endpoint studies. Analysis of tumor tissue revealed that PG545 significantly decreased cell proliferation, increased apoptosis, reduced microvessel density, disrupted vascular function, and elevated intratumoral hypoxia. Elevated hypoxia is a known driver of collagen deposition and tumor progression; however, tumors from PG545-treated animals displayed reduced collagen deposition and a greater degree of differentiation compared with control or gemcitabine-treated tumors. These results highlight the potent antitumor activity of PG545 and support the further exploration of heparanase inhibitors as a potential clinical strategy for the treatment of PDAC. Mol Cancer Ther; 12(7); 1190–201. ©2013 AACR.
Remote Ischemic Preconditioning Improves Outcome at 6 Years After Elective Percutaneous Coronary Intervention
Authors: Davies William R. , Brown Adam J. , Watson William , McCormick Liam M. , West Nick E.J. , Dutka David P. , Hoole Stephen P. 
Published: May 2013

Background—
Postprocedural myocardial infarction (type 4a) has been shown to be an adverse prognostic indicator after elective percutaneous coronary intervention (PCI). The Cardiac Remote Ischemic Preconditioning in Coronary Stenting (CRISP Stent) study demonstrated that remote ischemic preconditioning reduced procedural symptoms, ECG ST-segment deviation, and cardiac troponin I release after elective PCI and reduced the major adverse cardiac and cerebral event (MACCE) rate at 6 months. We were interested to confirm if this early benefit in MACCE rate in the remote ischemic preconditioning group was sustained long-term.

Methods and Results—

Patients were telephoned by researchers blinded to the randomization details. MACCE, defined as all-cause mortality, nonfatal myocardial infarction, transient ischemic attack or stroke, and heart failure requiring hospital admission, were adjudicated by case note and national database review. One hundred ninety-two (89.3%) of the 225 patients with elective PCI randomized in the original study were available for long-term follow-up (mean time to event or last follow-up: 1579.7±603.6 days). There were a total of 59 (30.7%) MACCEs. Patients with an MACCE had a higher mean cardiac troponin I after PCI (±SD): 2.07±6.99 versus 0.91±2.07 ng/mL (
P
=0.05). The MACCE rate at 6 years remained lower in the remote ischemic preconditioning group (hazard ratio, 0.58; 95% confidence interval, 0.35–0.97;
P
=0.039; absolute risk reduction=0.13 and number needed to treat=8 to prevent the MACCE at 6 years).

Conclusions—
Remote ischemic preconditioning reduces the incidence of postprocedural cardiac troponin I after elective PCI and confers an MACCE-free survival benefit at both short- and long-term follow-up.

Clinical Trial Registration—

URL:
http://www.ukcrn.org.uk
. Unique identifier: UKCRN 4074
Axonal Remodeling of the Corticospinal Tract in the Spinal Cord Contributes to Voluntary Motor Recovery After Stroke in Adult Mice
Authors: Liu Zhongwu , Chopp Michael , Ding Xiaoshuang , Cui Yisheng , Li Yi 
Published: May 2013

Background and Purpose—
We sought to demonstrate the contribution of axonal remodeling of the corticospinal tract (CST) in the spinal cord to functional outcome after stroke.

Methods—
Bilateral pyramidotomy (BPT) or sham-BPT was performed in mice with transgenic yellow fluorescent protein labeling in the CST subjected to middle cerebral artery occlusion (MCAo). Foot-fault and single pellet reaching tests were performed 3 days after MCAo and weekly thereafter. Mice were euthanized at day 14 or 28 after stroke. Immunofluorescent staining for growth-associated protein-43 and Synaptophysin was performed on cervical sections.

Results—

Functional improvements were evident during the initial 14 days in both MCAo-sham-BPT and MCAo-BPT mice (
P
<0.01, versus day 3). Progressive recovery was present during the subsequent 14 days in MCAo-sham-BPT mice (
P
<0.001, versus day 14) but not in MCAo-BPT mice. In the stroke-affected cervical gray matter of MCAo-sham-BPT mice, growth-associated protein-43-Cy3 staining on CST axons were significantly increased at day 14 after stroke compared with normal mice (
P
<0.001), and CST axonal density and Synaptophysin-Cy3 staining of CST-yellow fluorescent protein axonal terminals were significantly increased at day 28 compared with day 14 after MCAo (
P
<0.001).

Conclusions—
Our data demonstrate that voluntary motor recovery is associated with CST axonal outgrowth and synaptic formation in the denervated side of the spinal gray matter during the later phase after stroke, suggesting that the CST axonal plasticity in the spinal cord contributes to neurological recovery.
Does Perceptual Learning Require Consciousness or Attention?
Authors: Meuwese Julia D. I. , Post Ruben A. G. , Scholte H. Steven , Lamme Victor A. F. 
Published: May 2013

Abstract
It has been proposed that visual attention and consciousness are separate [Koch, C., & Tsuchiya, N. Attention and consciousness: Two distinct brain processes. Trends in Cognitive Sciences, 11, 16–22, 2007] and possibly even orthogonal processes [Lamme, V. A. F. Why visual attention and awareness are different. Trends in Cognitive Sciences, 7, 12–18, 2003]. Attention and consciousness converge when conscious visual percepts are attended and hence become available for conscious report. In such a view, a lack of reportability can have two causes: the absence of attention or the absence of a conscious percept. This raises an important question in the field of perceptual learning. It is known that learning can occur in the absence of reportability [Gutnisky, D. A., Hansen, B. J., Iliescu, B. F., & Dragoi, V. Attention alters visual plasticity during exposure-based learning. Current Biology, 19, 555–560, 2009; Seitz, A. R., Kim, D., & Watanabe, T. Rewards evoke learning of unconsciously processed visual stimuli in adult humans. Neuron, 61, 700–707, 2009; Seitz, A. R., & Watanabe, T. Is subliminal learning really passive? Nature, 422, 36, 2003; Watanabe, T., Náñez, J. E., & Sasaki, Y. Perceptual learning without perception. Nature, 413, 844–848, 2001], but it is unclear which of the two ingredients—consciousness or attention—is not necessary for learning. We presented textured figure-ground stimuli and manipulated reportability either by masking (which only interferes with consciousness) or with an inattention paradigm (which only interferes with attention). During the second session (24 hr later), learning was assessed neurally and behaviorally, via differences in figure-ground ERPs and via a detection task. Behavioral and neural learning effects were found for stimuli presented in the inattention paradigm and not for masked stimuli. Interestingly, the behavioral learning effect only became apparent when performance feedback was given on the task to measure learning, suggesting that the memory trace that is formed during inattention is latent until accessed. The results suggest that learning requires consciousness, and not attention, and further strengthen the idea that consciousness is separate from attention.
The Banished God: Concerning Faith and Doubt in Lohengrin
Authors: Kienzle Ulrike , Gawlick Ralf Yusuf 
Published: May 2013

Abstract
In his Lohengrin, Wagner contrasts the medieval piety of Wolfram’s Parzival with the tragedy of doubt, which ends without reconciliation. The conflict between faith and doubt essentially forms the spiritual substance of Wagner’s Lohengrin, from the first conception to the completed score, although in the earliest prose draft—the Prosaentwurf (Prose-sketch) of 1845—a variety of political and historical motives unfold around the main idea. These, however, become increasingly relegated to the background in successive compositional stages of the work. The final score, completed in 1847, accentuates the psychological aspect of the drama through the expressive power of the music.
Significations of Religious Desire in Louise Talma’s The Alcestiad
Authors: Leonard Kendra Preston 
Published: May 2013

Abstract
American composer Louise Talma’s opera The Alcestiad can be read as a highly autobiographical work; its themes can be understood as crucial elements of Talma’s own life. These correlations include: the demands and restrictions of society upon women’s behavior and desires, particularly its emphasis upon conforming to heteronormative performance, represented by Alcestis’s hesitant acceptance of marriage and motherhood, and Talma’s reluctant career as a pedagogue and internal conflict over her relationship with Nadia Boulanger; and the yearning for a life of devotion to a religion and a single art, in which Alcestis’s desire to serve as an oracular priestess of Apollo and Talma’s desire to dedicate herself to her work as a Catholic and as a composer are parallel tropes. This essay explores these parallels and demonstrates the ways in which the close relationships between The Alcestiad and Talma’s life are manifested in Talma’s use of rhythm in text-setting within the work.
Predictors of Recurrence and Survival for Head and Neck Mucoepidermoid Carcinoma
Authors: Byrd Serena A. , Spector Matthew E. , Carey Thomas E. , Bradford Carol R. , McHugh Jonathan B. 
Published: May 2013

ObjectiveTo describe the epidemiology and determine the clinicopathologic predictors of recurrence and survival in patients with head and neck mucoepidermoid carcinoma (MEC).Study DesignCase series with chart review.SettingTertiary care hospital.Subjects and MethodsThe medical records of 101 patients who underwent surgical treatment at the University of Michigan for head and neck MEC between 1985 and 2010 were reviewed. Main outcome measures were disease‐free survival (DFS), disease‐specific survival (DSS), and overall survival. Clinicopathologic parameters evaluated were age, sex, subsite, histological grade, adjuvant therapy, T stage, nodal status with/without extracapsular spread, and margin status.ResultsOf the 101 patients, 38 parotid, 33 palate, 17 oral, 8 submandibular/sublingual, 4 orbital, and 1 parapharyngeal carcinomas were identified. All patients underwent surgical resection, 23 had postoperative radiation, and 2 had postoperative chemoradiation. The 5‐year OS and DSS was 79% and 95% with a median follow‐up of 72 and 45 months, respectively. Five‐year DFS was 76%. On univariate analysis, histological grade was a statistically significant predictor of disease‐free survival (P =. 001) and overall survival (P =. 04). Positive nodal status was a significant predictor of DSS (P =. 004). There was no statistically significant difference in DFS, DSS, or OS based on sex, age, anatomic subsite, T stage, adjuvant therapy, and margin status.ConclusionAdvanced histological grade and positive nodal status are the strongest independent predictors of prognosis in head and neck MEC patients. Further studies into the molecular biology of MEC that may account for such clinicopathological features are currently underway.
MORECare research methods guidance development: Recommendations for ethical issues in palliative and end-of-life care research
Authors: Gysels Marjolein , Evans Catherine J , Lewis Penney , Speck Peter , Benalia Hamid , Preston Nancy J , Grande Gunn E , Short Vicky , Owen-Jones Eleanor , Todd Chris J , Higginson Irene J 
Published: May 2013

Background: There is little guidance on the particular ethical concerns that research raises with a palliative care population. Aim: To present the process and outcomes of a workshop and consensus exercise on agreed best practice to accommodate ethical issues in research on palliative care. Design: Consultation workshop using the MORECare Transparent Expert Consultation approach. Prior to workshops, participants were sent overviews of ethical issues in palliative care. Following the workshop, nominal group techniques were used to produce candidate recommendations. These were rated online by participating experts. Descriptive statistics were used to analyse agreement and consensus. Narrative comments were collated. Setting/participants: Experts in ethical issues and palliative care research were invited to the Cicely Saunders Institute in London. They included senior researchers, service providers, commissioners, researchers, members of ethics committees and policy makers. Results: The workshop comprised 28 participants. A total of 16 recommendations were developed. There was high agreement on the issue of research participation and high to moderate agreement on applications to research ethics committees. The recommendations on obtaining and maintaining consent from patients and families were the most contentious. Nine recommendations were refined on the basis of the comments from the online consultation. Conclusions: The culture surrounding palliative care research needs to change by fostering collaborative approaches between all those involved in the research process. Changes to the legal framework governing the research process are required to enhance the ethical conduct of research in palliative care. The recommendations are relevant to all areas of research involving vulnerable adults.
Biomechanical Comparison of Anatomic Single- and Double-Bundle Anterior Cruciate Ligament Reconstructions
Authors: Goldsmith Mary T. , Jansson Kyle S. , Smith Sean D. , Engebretsen Lars , LaPrade Robert F. , Wijdicks Coen A. 
Published: May 2013

Background: Arthroscopic identification of the anteromedial (AM) and posterolateral (PL) bundle locations of the anterior cruciate ligament (ACL) has facilitated an improved quantitative description of ACL anatomy. Few studies have directly compared the biomechanical laxity of anatomic single-bundle (SB) versus anatomic double-bundle (DB) ACL reconstruction techniques based on precise anatomic descriptions. Hypothesis: Anatomic tunnel positioning for SB and DB reconstructions would produce comparable anterior-posterior and rotatory knee laxity. Study Design: Controlled laboratory study. Methods: Nine matched pairs of cadaveric knees were evaluated for the kinematics of intact, ACL-deficient, and either anatomic SB or anatomic DB ACL-reconstructed knees. Reconstruction tunnels were placed either centrally in the ACL footprint or within the AM and PL footprints. A 6 degrees of freedom robotic system was used to assess knee laxity with an 88-N anterior tibial load and a simulated pivot-shift test of combined 10-N·m valgus and 5-N·m internal tibial torques. Rotational motion was measured with internal and external torques of 5 N·m along with varus and valgus torques of 10 N·m. One-sample and 2-sample independent t tests were used to compare between groups ( P < .05). Results: No significant differences were found between anatomic SB and DB reconstruction groups during anterior tibial loading. Anterior tibial translations during simulated pivot shift had no significant differences between anatomic reconstruction groups. Tibial rotation for internal/external and varus/valgus torques showed no significant differences between anatomic reconstructions, with the exception of small (<3°) but statistically significant differences in internal rotation at 20° and 30° of flexion. Despite the similar behavior between the 2 anatomic reconstruction groups, neither technique was able to reproduce the intact state during an anterior tibial load. Conclusion: No significant differences in anterior translation were found between the anatomic SB and anatomic DB ACL reconstructions for simulated pivot shift or anterior tibial loading. Clinical Relevance: Although significant differences between reconstructions were observed for internal rotation, the small magnitude of these differences (<3°) may not have clinical significance.