bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ran Is a Potential Therapeutic Target for Cancer Cells with Molecular Changes Associated with Activation of the PI3K/Akt/mTORC1 and Ras/MEK/ERK Pathways
Authors: Yuen Hiu-Fung , Chan Ka-Kui , Grills Claire , Murray James T. , Platt-Higgins Angela , Eldin Osama Sharaf , O'Byrne Ken , Janne Pasi , Fennell Dean A. , Johnston Patrick G. , Rudland Philip S. , El-Tanani Mohamed 
Published: November 2011

Abstract
Purpose: Cancer cells have been shown to be more susceptible to Ran knockdown than normal cells. We now investigate whether Ran is a potential therapeutic target of cancers with frequently found mutations that lead to higher Ras/MEK/ERK [mitogen-activated protein/extracellular signal-regulated kinase (ERK; MEK)] and phosphoinositide 3-kinase (PI3K)/Akt/mTORC1 activities.
Experimental Design: Apoptosis was measured by flow cytometry [propidium iodide (PI) and Annexin V staining] and MTT assay in cancer cells grown under different conditions after knockdown of Ran. The correlations between Ran expression and patient survival were examined in breast and lung cancers.
Results: Cancer cells with their PI3K/Akt/mTORC1 and Ras/MEK/ERK pathways inhibited are less susceptible to Ran silencing–induced apoptosis. K-Ras–mutated, c-Met–amplified, and Pten-deleted cancer cells are also more susceptible to Ran silencing–induced apoptosis than their wild-type counterparts and this effect is reduced by inhibitors of the PI3K/Akt/mTORC1 and MEK/ERK pathways. Overexpression of Ran in clinical specimens is significantly associated with poor patient outcome in both breast and lung cancers. This association is dramatically enhanced in cancers with increased c-Met or osteopontin expression, or with oncogenic mutations of K-Ras or PIK3CA, all of which are mutations that potentially correlate with activation of the PI3K/Akt/mTORC1 and/or Ras/MEK/ERK pathways. Silencing Ran also results in dysregulation of nucleocytoplasmic transport of transcription factors and downregulation of Mcl-1 expression, at the transcriptional level, which are reversed by inhibitors of the PI3K/Akt/mTORC1 and MEK/ERK pathways.
Conclusion: Ran is a potential therapeutic target for treatment of cancers with mutations/changes of expression in protooncogenes that lead to activation of the PI3K/Akt/mTORC1 and Ras/MEK/ERK pathways. Clin Cancer Res; 18(2); 380–91. ©2011 AACR.
TP53 Disruptive Mutations Lead to Head and Neck Cancer Treatment Failure through Inhibition of Radiation-Induced Senescence
Authors: Skinner Heath D. , Sandulache Vlad C. , Ow Thomas J. , Meyn Raymond E. , Yordy John S. , Beadle Beth M. , Fitzgerald Alison L. , Giri Uma , Ang K. Kian , Myers Jeffrey N. 
Published: November 2011

Abstract
Purpose: Mortality of patients with head and neck squamous cell carcinoma (HNSCC) is primarily driven by tumor cell radioresistance leading to locoregional recurrence (LRR). In this study, we use a classification of TP53 mutation (disruptive vs. nondisruptive) and examine impact on clinical outcomes and radiation sensitivity.
Experimental Design: Seventy-four patients with HNSCC treated with surgery and postoperative radiation and 38 HNSCC cell lines were assembled; for each, TP53 was sequenced and the in vitro radioresistance measured using clonogenic assays. p53 protein expression was inhibited using short hairpin RNA (shRNA) and overexpressed using a retrovirus. Radiation-induced apoptosis, mitotic cell death, senescence, and reactive oxygen species (ROS) assays were carried out. The effect of the drug metformin on overcoming mutant p53-associated radiation resistance was examined in vitro as well as in vivo, using an orthotopic xenograft model.
Results: Mutant TP53 alone was not predictive of LRR; however, disruptive TP53 mutation strongly predicted LRR (P = 0.03). Cell lines with disruptive mutations were significantly more radioresistant (P &lt; 0.05). Expression of disruptive TP53 mutations significantly decreased radiation-induced senescence, as measured by SA-β-gal staining, p21 expression, and release of ROS. The mitochondrial agent metformin potentiated the effects of radiation in the presence of a disruptive TP53 mutation partially via senescence. Examination of our patient cohort showed that LRR was decreased in patients taking metformin.
Conclusions: Disruptive TP53 mutations in HNSCC tumors predicts for LRR, because of increased radioresistance via the inhibition of senescence. Metformin can serve as a radiosensitizer for HNSCC with disruptive TP53, presaging the possibility of personalizing HNSCC treatment. Clin Cancer Res; 18(1); 290–300. ©2011 AACR.
Single-Chain Antibody-Based Immunotoxins Targeting Her2/neu: Design Optimization and Impact of Affinity on Antitumor Efficacy and Off-Target Toxicity
Authors: Cao Yu , Marks James D. , Huang Qian , Rudnick Stephen I. , Xiong Chiyi , Hittelman Walter N. , Wen Xiaoxia , Marks John W. , Cheung Lawrence H. , Boland Kim , Li Chun , Adams Gregory P. , Rosenblum Michael G. 
Published: November 2011

AbstractRecombinant immunotoxins, consisting of single-chain variable fragments (scFv) genetically fused to polypeptide toxins, represent potentially effective candidates for cancer therapeutics. We evaluated the affinity of various anti-Her2/neu scFv fused to recombinant gelonin (rGel) and its effect on antitumor efficacy and off-target toxicity. A series of rGel-based immunotoxins were created from the human anti-Her2/neu scFv C6.5 and various affinity mutants (designated ML3-9, MH3-B1, and B1D3) with affinities ranging from 10−8 to 10−11 mol/L. Against Her2/neu-overexpressing tumor cells, immunotoxins with increasing affinity displayed improved internalization and enhanced autophagic cytotoxicity. Targeting indices were highest for the highest affinity B1D3/rGel construct. However, the addition of free Her2/neu extracellular domain (ECD) significantly reduced the cytotoxicity of B1D3/rGel because of immune complex formation. In contrast, ECD addition had little impact on the lower affinity constructs in vitro. In vivo studies against established BT474 M1 xenografts showed growth suppression by all immunotoxins. Surprisingly, therapy with the B1D3-rGel induced significant liver toxicity because of immune complex formation with shed Her2/neu antigen in circulation. The MH3-B1/rGel construct with intermediate affinity showed effective tumor growth inhibition without inducing hepatotoxicity or complex formation. These findings show that while high-affinity constructs can be potent antitumor agents, they may also be associated with mistargeting through the facile formation of complexes with soluble antigen leading to significant off-target toxicity. Constructs composed of intermediate-affinity antibodies are also potent agents that are more resistant to immune complex formation. Therefore, affinity is an exceptionally important consideration when evaluating the design and efficacy of targeted therapeutics. Mol Cancer Ther; 11(1); 143–53. ©2011 AACR.
Curing “Incurable” Cancer
Authors: Watson James D. 
Published: November 2011

Abstract
Cancer cells are preferentially killed by anticancer agents because key signals for growth and cell division are “always on” as opposed to the alternative “on” and “off” signaling of normal cells. Too much of today's anticancer drug discovery effort may go toward reversing genetically promoted “always on” signals. More effective anticancer drug targets may be found through use of RNAi technologies that pinpoint the key gene regulatory and metabolic weakness of the “always on” cancer cells. Cancer Discovery; 1(6); 477–80. ©2011 AACR.
mTORC 2:1 for Chemotherapy Sensitization in Glioblastoma
Authors: Wick Wolfgang , Blaes Jonas , Weiler Markus 
Published: November 2011

Abstract
mTOR signaling is frequently deregulated in cancer, including brain tumors. Although the signaling of mTOR complex 1 (mTORC1) has been subject to intensive investigations and mTORC1 itself has been a well-established cancer drug target for years, the role of the second complex, mTORC2, remains elusive. Tanaka et al. reveal an EGFRvIII-mTORC2-NFκB signaling cascade and demonstrate that mTORC2 mediates cisplatin resistance through NF-κB in an Akt-independent manner in glioblastoma. Uncovering the role of mTORC2 in chemotherapy resistance in glioblastoma highlights the need for further investigations of mTORC2 inhibition. Cancer Discovery; 1(6); 475–76. ©2011 AACR.
Commentary on Tanaka et al., p. 524.
Construction of Stratospheric Temperature Data Records from Stratospheric Sounding Units
Authors: Wang Likun , Zou Cheng-Zhi , Qian Haifeng 
Published: November 2011

AbstractIn recognizing the importance of Stratospheric Sounding Unit (SSU) onboard historical NOAA polar-orbiting satellites in assessment of long-term stratospheric temperature changes and limitations in previous available SSU datasets, this study constructs a fully documented, publicly accessible, and well-merged SSU time series for climate change investigations. Focusing on methodologies, this study describes the details of data processing and bias corrections in the SSU observations for generating consistent stratospheric temperature data records, including 1) removal of the instrument gas leak effect in its CO2 cell; 2) correction of the atmospheric CO2 increase effect; 3) adjustment for different observation viewing angles; 4) removal of diurnal sampling biases due to satellite orbital drift; and 5) statistical merging of SSU observations from different satellites. After reprocessing, the stratospheric temperature records are composed of nadirlike, gridded brightness temperatures that correspond to identical weighting functions and a fixed local observation time. The 27-yr reprocessed SSU data record comprises global monthly and pentad layer temperatures, with grid resolution of 2.5° latitude by 2.5° longitude, of the midstratosphere (TMS), upper stratosphere (TUS), and top stratosphere (TTS), which correspond to the three SSU channel observations. For 1979–2006, the global mean trends for TMS, TUS, and TTS, are respectively −1.236 ± 0.131, −0.926 ± 0.139, and −1.006 ± 0.194 K decade−1. Spatial trend pattern analyses indicated that this cooling occurred globally with larger cooling over the tropical stratosphere.
A pilot study of a crossover trial with randomized use of ankle-foot orthoses for people with Charcot–Marie–Tooth disease
Authors: Phillips Margaret F , Robertson Zoe , Killen Brian , White Barney 
Published: November 2011

Objectives: This was a pilot and feasibility study of a crossover trial with randomized use of ankle-foot orthoses by people with Charcot–Marie–Tooth (CMT) disease, investigating the effects of these on gait parameters, practical aspects of use and achievement of goals. Design: A randomized crossover trial. Setting: The community and ambulatory care. Participants: Eight adults with CMT disease type 1 or 2. Interventions: Ligaflex™, custom-made polypropylene and silicone ankle-foot orthoses worn in randomized order for three weeks each, with a washout week in-between; the orthoses of each participant’s choice were then worn until 28 weeks. Main outcome measures: The primary outcome measure was gait velocity; other outcome measures included Goal Attainment Scaling; Likert scores, concerning aspects of orthosis use and gait analysis parameters. Results: Gait velocity was greatest wearing polypropylene orthoses, median 0.96 (interquartile range (IQR) 0.75–1.18) ms−1, compared with silicone orthoses, median 0.88 (0.71–1.12) ms−1, and no orthosis, median 0.79 (0.56–0.84) ms−1, P=0.006. The silicone orthoses met goals more successfully and scored more favourably for comfort, 5.0 (5.0–6.0), P=0.003 and pain, 5.5 (4.0–7.0), P=0.015. Future modifications to study methodology were identified, such as a longer period of wear and measurement of walking in different situations. Conclusions: This study confirmed the feasibility of a larger trial. It indicated differences in walking velocity and parameters concerning wear of the orthoses that could be explored further. A further crossover trial would require 27 participants in order to show a clinically meaningful difference in velocity of 0.13 ms−1 with 90% power and alpha of 5%.
Initial Fixation Strength of Transosseous-Equivalent Suture Bridge Rotator Cuff Repair Is Comparable With Transosseous Repair
Authors: Behrens Steve B. , Bruce Benjamin , Zonno Alan J. , Paller David , Green Andrew 
Published: November 2011

Background: The outcome of rotator cuff repair correlates with tendon healing. Early studies of arthroscopic rotator cuff repair demonstrate lower healing rates than traditional open techniques. Transosseous-equivalent repair techniques (suture bridge) were developed to improve the initial fixation strength. Purpose: To compare the initial in vitro tensile fixation strength of a transosseous-equivalent suture bridge (TOE-SB) rotator cuff repair construct to a traditional transosseous (TO) suture construct. Study Design: Controlled laboratory study. Methods: Identical simulated rotator cuff tears were created on 8 matched pairs of humeri. Each matched pair underwent repair with 4 sutures using either the TOE-SB or TO technique. Initial fixation strength was tested in a custom testing jig. Each shoulder underwent 1000 cycles each of low and then high load testing. Gap displacement was measured at anterior and posterior sites of the repair with digital video tracking of paired reflective markers and recorded at predetermined cycle intervals. Results: There were no statistically significant differences in gap formation at the repair sites under low or high load conditions between TOE-SB and TO techniques. The mean maximal gap formation of the repairs during low load testing in the TOE-SB and TO constructs was 0.93 ± 0.88 mm and 0.55 ± 0.22 mm, respectively ( P = .505). The mean maximal gap formation during high load testing in the TOE-SB and TO constructs was 2.04 ± 1.10 mm and 2.28 ± 1.62 mm, respectively ( P = .517). The most significant increase in gap distance occurred at the transition from low load to high load in both constructs. Most of the incremental displacement occurred within the first 100 cycles for both high and low load testing ( P < .001). Conclusion: The arthroscopic TOE-SB technique is comparable in initial fixation strength to the traditional TO simple suture repair technique. Clinical Relevance: Arthroscopic techniques can achieve initial fixation strength comparable with traditional TO techniques performed without suture anchors.
Biomechanical and Histological Evaluations of the Doubled Semitendinosus Tendon Autograft After Anterior Cruciate Ligament Reconstruction in Sheep
Authors: Kondo Eiji , Yasuda Kazunori , Katsura Taro , Hayashi Riku , Kotani Yoshihisa , Tohyama Harukazu 
Published: November 2011

Background: A sheep or goat anterior cruciate ligament (ACL) reconstruction model with the semitendinosus tendon autograft has not as of yet been established. Hypothesis: The semitendinosus tendon graft may be necrotized after ACL reconstruction until 12 weeks. Structural properties of the femur-graft-tibia complex may not be restored to the normal ACL level even at 12 months after surgery. Study Design: Controlled laboratory study. Methods: Thirty-eight mature sheep were used. In each animal, the right knee underwent ACL reconstruction using the semitendinosus tendon autograft. Two of them were not tested because of pneumonia. Twenty of 36 sheep were used for biomechanical evaluations. Five randomly selected animals were sacrificed at 0, 12, 24, or 52 weeks after surgery. In each animal, both the knees were harvested, and the left knee was used to obtain the control data. The remaining 16 sheep were used for histological evaluation. Two or 3 randomly selected animals were sacrificed at 0, 2, 6, 12, 24, or 52 weeks after surgery. Results: The tendon graft was predominantly acellular at 2 weeks. Although cell infiltration increased at 6 weeks, the core portion remained necrotic even at 12 weeks. At 24 and 52 weeks, the necrotic lesion disappeared in the core portion. In each period, the anteroposterior translation of the reconstructed knee remained significantly greater than that of the control ( P < .0001). At 52 weeks, the maximum load of the femur-graft-tibia complex was significantly lower than that of the femur-ACL-tibia complex ( P < .0001), although there was no significant difference in the cell density, the tissue dimensions, the stiffness, and the elongation at failure between the 2 complexes. Conclusion: The sheep ACL reconstruction model showed predominant intrinsic fibroblast necrosis in the tendon autograft until 12 weeks. Although the structural properties of the femur-graft-tibia complex gradually improved, they were not completely restored to the femur-ACL-tibia complex level even at 52 weeks. Clinical Relevance: Remodeling of the semitendinosus tendon autograft after ACL reconstruction is not different from that of the bone-tendon-bone graft. This study has suggested that vigorous activity should not be permitted for patients in the early periods after ACL reconstruction using semitendinosus tendon autografts, which are necrotized and weakened after surgery.
Strategies of legitimization in political discourse: From words to actions
Authors: Reyes Antonio 
Published: November 2011

From an interdisciplinary framework anchored theoretically in Critical Discourse Analysis and using analytical tools from Systemic Functional Linguistics, this article accounts for a crucial use of language in society: the process of legitimization. This article explains specific linguistic ways in which language represents an instrument of control (Hodge and Kress, 1993: 6) and manifests symbolic power (Bourdieu, 2001) in discourse and society. Taking into account previous studies on legitimization (i.e. Martín Rojo and Van Dijk, 1997; Van Dijk, 2005; Van Leeuwen, 1996, 2007, 2008; Van Leeuwen and Wodak, 1999), this particular work develops and proposes some key strategies of legitimization employed by social actors to justify courses of action. The strategies of legitimization can be used individually or in combination with others, and justify social practices through: (1) emotions (particularly fear), (2) a hypothetical future, (3) rationality, (4) voices of expertise and (5) altruism. This article explains how these strategies are linguistically constructed and shaped. This study explains the use of these discursive structures and strategies through examples of speeches given by leaders with differing ideologies, specifically George W. Bush and Barack Obama, in two different armed conflicts, Iraq (2007) and Afghanistan (2009), to underline their justifications of military presence in the notorious ‘War on Terror’.
Lack of involvement of type 7 phosphodiesterase in an experimental model of asthma
Authors: Chevalier E. , Lagente V. , Dupont M. , Fargeau H. , Palazzi X. , Richard V. , Dassaud M. , Fric M. , Coupe M. , Carré C. , Leduc S. , Bernardelli P. , Vergne F. , Berna P. , Bertrand C.P. 
Published: November 2011

Type 7 phosphodiesterases (PDE7) are responsible for the decrease of intracellular cyclic AMP (cAMP) in many cells involved in allergic asthma by suppressing their potential to respond to many activating stimuli. The elevation of intracellular cAMP has been associated with immunosuppressive and anti-inflammatory activities and represents a potential treatment of asthma.Our aim was to evaluate the impact of the deletion of the murine phosphodiesterase (PDE)7B gene and then to evaluate the efficacy of a newly described selective PDE7A and -B inhibitor on an ovalbumin (OVA)-induced airway inflammation and airway hyperreactivity (AHR) model in mice.Inflammation was determined 72 h after single OVA challenge or 24 h after multiple challenges by the relative cell influx and cytokine content in bronchoalveolar lavage fluid. AHR and immunoglobulin E levels in serum were determined after multiple challenges.For the first time, we have demonstrated that the deletion of the PDE7B gene or the pharmacological inhibition of PDE7A and -B had no effect on all the parameters looked at in this model. These results highlight the absence of any implication of the PDE7 enzyme in our model.
TBX3 over-expression causes mammary gland hyperplasia and increases mammary stem-like cells in an inducible transgenic mouse model
Authors: Liu Jing , Esmailpour Taraneh , Shang Xiying , Gulsen Gultekin , Liu Andy , Huang Taosheng 
Published: November 2011

Abstract

Background
The T-box transcription factor TBX3 is necessary for early embryonic development and for the normal development of the mammary gland. Homozygous mutations, in mice, are embryonic lethal while heterozygous mutations result in perturbed mammary gland development. In humans, mutations that result in the haploinsufficiency of TBX3 causes Ulnar Mammary Syndrome (UMS) characterized by mammary gland hypoplasia as well as other congenital defects. In addition to its role in mammary gland development, various studies have also supported a role for Tbx3 in breast cancer development. TBX3 is over-expressed in various breast cancer cell lines as well as cancer tissue and has been found to contribute to breast cancer cell migration. Previous studies have suggested that TBX3 contributes to cancer development by its ability to bypass senescence by repressing the expression of p14ARF-tumor suppressor. Although many studies have shown that a dysregulation of TBX3 expression may contribute to cancer progression, no direct evidence shows TBX3 causes breast cancer.

Results
In this study, we created doxycycline inducible double transgenic mice (MMTV-rtTA;tet-myc-TBX3-IRES-Luciferase) to test whether TBX3 over-expression can induce tumor formation within the mammary gland. Although over-expression of TBX3, alone, did not induce tumor formation it did promote accelerated mammary gland development by increasing mammary epithelial cell proliferation. We also show that TBX3 directly binds to and represses NFκBIB, an inhibitor of the NF-κB pathway known to play a role in regulating cell proliferation. Lastly, we also show that the over-expression of TBX3 is associated with an increase in mammary stem-like cells.

Conclusions
Overall, our data suggests that over-expression of TBX3 may contribute to breast cancer development by promoting accelerated mammary gland development through the inhibition of the NF-κB pathway and stimulation of both mammary epithelial cell and stem-like cell proliferation.