bluuebunny/crossref_metadata_2025_split huggingface dataset:
Survivin-3B Potentiates Immune Escape in Cancer but Also Inhibits the Toxicity of Cancer Chemotherapy
Authors: Végran Frédérique , Mary Romain , Gibeaud Anne , Mirjolet Céline , Collin Bertrand , Oudot Alexandra , Charon-Barra Céline , Arnould Laurent , Lizard-Nacol Sarab , Boidot Romain 
Published: July 2013

Abstract
Dysregulation in patterns of alternative RNA splicing in cancer cells is emerging as a significant factor in cancer pathophysiology. In this study, we investigated the little known alternative splice isoform survivin-3B (S-3B) that is overexpressed in a tumor-specific manner. Ectopic overexpression of S-3B drove tumorigenesis by facilitating immune escape in a manner associated with resistance to immune cell toxicity. This resistance was mediated by interaction of S-3B with procaspase-8, inhibiting death-inducing signaling complex formation in response to Fas/Fas ligand interaction. We found that S-3B overexpression also mediated resistance to cancer chemotherapy, in this case through interactions with procaspase-6. S-3B binding to procaspase-6 inhibited its activation despite mitochondrial depolarization and caspase-3 activation. When combined with chemotherapy, S-3B targeting in vivo elicited a nearly eradication of tumors. Mechanistic investigations identified a previously unrecognized 7-amino acid region as responsible for the procancerous properties of survivin proteins. Taken together, our results defined S-3B as an important functional actor in tumor formation and treatment resistance. Cancer Res; 73(17); 5391–401. ©2013 AACR.
Estrogen Receptor α Regulates ATM Expression through miRNAs in Breast Cancer
Authors: Guo Xiaojing , Yang Chunying , Qian Xiaolong , Lei Ting , Li Yaqing , Shen Haifa , Fu Li , Xu Bo 
Published: July 2013

Abstract
Purpose: Estrogen receptor α (ERα) is an essential element regulating mammary gland development and it contributes to breast cancer development and progression. Most of the ER-negative breast cancers display more aggressive clinical behaviors and are resistant to antiestrogen therapies. In addition, many ER-negative tumors show insensitivity to many chemotherapeutic drugs and radiotherapy, although mechanisms underlying this phenotype are less clear.
Experimental Design: We conducted immunohistochemistry on 296 cases of breast cancer tissues using a variety of antibodies. On the basis of the clinical data, we conducted siRNA knockdown to study the role of ERα on ATM expression in breast cancer cell lines. Furthermore, we used antisense oligonucleotides against micro RNAs (miRNA) or miRNA overexpression plasmids to study the role of miR-18a and -106a on ATM expression. Finally we used in situ hybridization to assess miR-18a and -106a expression in breast cancer tissues.
Results: We found that in ER-negative breast cancer tissues, expression of the ATM kinase, a critical DNA damage-response protein, is aberrantly upregulated. We also found that the locoregional recurrence rate after radiotherapy positively correlates with ATM expression. On the cellular level, we showed that ERα, but not ERβ, negatively regulates ATM expression. Furthermore, we identified that ERα activates miR-18a and -106a to downregulate ATM expression. We also showed that miR-18a and -106a were significantly underexpressed in ER-negative breast cancer tissues.
Conclusions: We reveal a novel mechanism involving ERα and miR-18a and -106a regulation of ATM in breast cancer. Clin Cancer Res; 19(18); 4994–5002. ©2013 AACR.
The Translocation t(4;14) Can Be Present Only in Minor Subclones in Multiple Myeloma
Authors: Hébraud Benjamin , Caillot Denis , Corre Jill , Marit Gérald , Hulin Cyrille , Leleu Xavier , Lodé Laurence , Wetterwald Marc , Dib Mamoun , Rodon Philippe , Voillat Laurent , Royer Bruno , Voog Eric , Fitoussi Olivier , Stoppa Anne-Marie , Garderet Laurent , Kolb Brigitte , Maigre Michel , Boullanger Nadine , Allangba Olivier , Karlin Lionel , Daguindau Nicolas , Legros Laurence , Sohn Claudine , Joubert Marie-Véronique , Lenain Pascal , Facon Thierry , Attal Michel , Moreau Philippe , Avet-Loiseau Hervé 
Published: July 2013

Abstract
Purpose: Although the translocation t(4;14) is supposed to be a primary event in multiple myeloma, we have been surprised to observe that in large relapse series of patients, the t(4;14) can be observed only in subpopulations of plasma cells, in contrast to what is seen at diagnosis. This observation raised the question of possible subclones harboring the translocation that would be observable only at the time of relapse.
Experimental Design: To address this issue, we analyzed by FISH a cohort of 306 patients for whom we had at least two samples obtained at different disease phases.
Results: We observed a “gain” of the t(4;14) in 14 patients, and conversely, a “loss” of the translocation in 11 patients. Two hypotheses were raised: either an acquisition of the translocation during evolution or the existence of small t(4;14)-positive subclones at the time of diagnosis. To address this question, we had the opportunity to analyze two patients at the time of diagnosis by RT-PCR (reverse transcription-polymerase chain reaction) to look for the chimeric Eμ-MMSET transcript, and one patient positive at diagnosis, but negative at relapse. The samples were positive, supporting the second hypothesis. Furthermore, the IGH sequences of two patients who “lose” the t(4;14) were identical at diagnosis and relapse, confirming the existence of a common ancestral clone.
Conclusion: Thus, the conclusion of this study is that the t(4;14) is not a primary event in multiple myeloma and that it can be present in silent subclones at diagnosis, but also at relapse. Clin Cancer Res; 19(17); 4634–7. ©2013 AACR.
IL-17A Stimulates the Progression of Giant Cell Tumors of Bone
Authors: Xu Meng , Song Zhi-Gang , Xu Cheng-Xiong , Rong Guang-Hua , Fan Ke-Xing , Chen Ji-Ying , Zhang Wei , Jia Jin-Peng , Han Gang , Wang Wei , Chai Wei , Liang Wen-Tao , Bi Wen-Zhi , Wang Yan 
Published: July 2013

Abstract
Purpose: Giant cell tumors of bone (GCTB) exhibit aggressive bone lytic behavior. Studies have shown that interleukin 17A (IL-17A) is involved pathologic bone resorption in various skeletal disorders. Thus, we have investigated the role of IL-17A in GCTBs.
Experimental Design: We evaluated the progression of GCTBs using Campanacci grading and Enneking staging systems in 74 patients with GCTB. The expression of IL-17A and the IL-17A receptor A (IL-17RA) was assessed in GCTB tissues and in both multinucleated giant cells (MNGC) and stromal cells cultured in vitro using immunostaining and reverse transcription PCR (RT-PCR). The effects of IL-17A on the osteolytic activity of the MNGCs and the proliferation of the stromal cells were investigated using the “pit” formation and MTT assays, respectively. The effects of IL-17A on the expression of proosteolytic factors were examined in primary cultured MNGCs and stromal cells using RT-PCR, Western blotting, and gene expression microarrays.
Results: In GCTBs, we detected abundant levels of IL-17A, which were associated with tumor extension and grade. IL-17A is predominantly produced by MNGCs, whereas IL-17RA is expressed by both MNGCs and stromal cells in GCTBs. In the MNGCs, the IL-17A increased the mRNA expression of IL-17A and proosteolytic enzymes, and also enhanced osteolytic ability. In the stromal cells, the IL-17A stimulated cellular proliferation and the expression of proosteolytic factors, including RANKL through myc and STAT3, respectively. In addition, IL-17A stimulated in vivo tumor growth and the extent of angiogenesis in GCTBs.
Conclusion: IL-17A stimulates the progression of GCTBs and might represent a useful candidate marker for progression and as a therapeutic target for GCTBs. Clin Cancer Res; 19(17); 4697–705. ©2013 AACR.
RETRACTED: Minocycline Targets the NF-κB Nexus through Suppression of TGF-β1-TAK1-IκB Signaling in Ovarian Cancer
Authors: Ataie-Kachoie Parvin , Badar Samina , Morris David L. , Pourgholami Mohammad H. 
Published: July 2013

Abstract
Substantial evidence supports the critical role of NF-κB in ovarian cancer. Minocycline, a tetracycline, has been shown to exhibit beneficial effects in this malignancy through regulation of a cohort of genes that overlap significantly with the NF-κB transcriptome. Here, it was examined whether or not the molecular mechanism could be attributed to modulation of NF-κB signaling using a combination of in vitro and in vivo models. Minocycline suppressed constitutive NF-κB activation in OVCAR-3 and SKOV-3 ovarian carcinoma cells and was correlated with attenuation of IκBα kinase (IKK) activation, IκBα phosphorylation and degradation, and p65 phosphorylation and nuclear translocation. The inhibition of IKK was found to be associated with suppression of TGF-β-activated-kinase-1 (TAK1) activation and its dissociation from TAK1-binding-protein-1 (TAB1), an indispensable functional mediator between TGF-β and TAK1. Further studies demonstrated that minocycline downregulated TGF-β1 expression. Enforced TGF-β1 expression induced NF-κB activity, and minocycline rescued this effect. Consistent with this finding, TGF-β1 knockdown suppressed NF-κB activation and abrogated the inhibitory effect of minocycline on this transcription factor. These results suggest that the minocycline-induced suppression of NF-κB activity is mediated, in part, through inhibition of TGF-β1. Furthermore, the influence of minocycline on NF-κB pathway activation was examined in female nude mice harboring intraperitoneal OVCAR-3 tumors. Both acute and chronic administration of minocycline led to suppression of p65 phosphorylation and nuclear translocation accompanied by downregulation of NF-κB activity and endogenous protein levels of its target gene products. These data reveal the therapeutic potential of minocycline as an agent targeting the pro-oncogenic TGF-β—NF-κB axis in ovarian cancer.
Implications: This preclinical study lends support to the notion that ovarian cancer management would benefit from administration of minocycline. Mol Cancer Res; 11(10); 1279–91. ©2013 AACR.
Oral Administration of a Gemini Vitamin D Analog, a Synthetic Triterpenoid and the Combination Prevents Mammary Tumorigenesis Driven by ErbB2 Overexpression
Authors: So Jae Young , Wahler Joseph E. , Yoon Taesook , Smolarek Amanda K. , Lin Yong , Shih Weichung Joe , Maehr Hubert , Uskokovic Milan , Liby Karen T. , Sporn Michael B. , Suh Nanjoo 
Published: July 2013

Abstract
HER2 (or ErbB2), a member of ErbB receptor tyrosine kinases, is overexpressed in approximately 20% of human breast cancer, and the ErbB2 signaling pathway is a critical therapeutic target for ErbB2-overexpressing breast cancer. We investigated the inhibitory effects of the Gemini vitamin D analog BXL0124, the synthetic triterpenoid CDDO-Im and the combination on the tumorigenesis of ErbB2-overexpressing breast cancer. MMTV-ErbB2/neu transgenic mice were treated with BXL0124, CDDO-Im, or the combination from three months of age until the end of the experiment. Formation and growth of MMTV-ErbB2/neu mammary tumors were monitored every week, and all three treatments delayed the development of mammary tumors without significant toxicity. Decreased activation of ErbB2 as well as other ErbB receptors, ErbB1 and ErbB3, in MMTV-ErbB2/neu mammary tumors was shown by all treatments. Protein levels of downstream targets of the ErbB2 signaling pathway, including activated-Erk1/2, activated-Akt, c-Myc, CycD1, and Bcl2, were repressed by all three treatments, with the combination treatment exhibiting the strongest effects. To investigate therapeutic efficacy, the combination of BXL0124 and CDDO-Im was given to MMTV-ErbB2/neu mice after mammary tumors were established between 23 and 30 weeks of age. Short-term treatment with the combination did not show effects on tumor growth nor the ErbB2 signaling pathway. The present study shows BXL0124, CDDO-Im, and the combination as potential agents for prevention, but not treatment, against the tumorigenesis of ErbB2-overexpressing breast cancer. Cancer Prev Res; 6(9); 959–70. ©2013 AACR.
Rosiglitazone and Outcomes for Patients With Diabetes Mellitus and Coronary Artery Disease in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial
Authors: Bach Richard G. , Brooks Maria Mori , Lombardero Manuel , Genuth Saul , Donner Thomas W. , Garber Alan , Kennedy Laurence , Monrad E. Scott , Pop-Busui Rodica , Kelsey Sheryl F. , Frye Robert L. 
Published: July 2013

Background—
Rosiglitazone improves glycemic control for patients with type 2 diabetes mellitus, but there remains controversy regarding an observed association with cardiovascular hazard. The cardiovascular effects of rosiglitazone for patients with coronary artery disease remain unknown.

Methods and Results—
To examine any association between rosiglitazone use and cardiovascular events among patients with diabetes mellitus and coronary artery disease, we analyzed events among 2368 patients with type 2 diabetes mellitus and coronary artery disease in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. Total mortality, composite death, myocardial infarction, and stroke, and the individual incidence of death, myocardial infarction, stroke, congestive heart failure, and fractures, were compared during 4.5 years of follow-up among patients treated with rosiglitazone versus patients not receiving a thiazolidinedione by use of Cox proportional hazards and Kaplan–Meier analyses that included propensity matching. After multivariable adjustment, among patients treated with rosiglitazone, mortality was similar (hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.58–1.18), whereas there was a lower incidence of composite death, myocardial infarction, and stroke (HR, 0.72; 95% CI, 0.55–0.93) and stroke (HR, 0.36; 95% CI, 0.16–0.86) and a higher incidence of fractures (HR, 1.62; 95% CI, 1.05–2.51); the incidence of myocardial infarction (HR, 0.77; 95% CI, 0.54–1.10) and congestive heart failure (HR, 1.22; 95% CI, 0.84–1.82) did not differ significantly. Among propensity-matched patients, rates of major ischemic cardiovascular events and congestive heart failure were not significantly different.

Conclusions—
Among patients with type 2 diabetes mellitus and coronary artery disease in the BARI 2D trial, neither on-treatment nor propensity-matched analysis supported an association of rosiglitazone treatment with an increase in major ischemic cardiovascular events.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00006305.
Going beyond Inferior Prefrontal Involvement in Semantic Control: Evidence for the Additional Contribution of Dorsal Angular Gyrus and Posterior Middle Temporal Cortex
Authors: Noonan Krist A. , Jefferies Elizabeth , Visser Maya , Lambon Ralph Matthew A. 
Published: July 2013

AbstractSemantic cognition requires a combination of semantic representations and executive control processes to direct activation in a task- and time-appropriate fashion [Jefferies, E., & Lambon Ralph, M. A. Semantic impairment in stroke aphasia versus semantic dementia: A case-series comparison. Brain, 129, 2132–2147, 2006]. We undertook a formal meta-analysis to investigate which regions within the large-scale semantic network are specifically associated with the executive component of semantic cognition. Previous studies have described in detail the role of left ventral pFC in semantic regulation. We examined 53 studies that contrasted semantic tasks with high &gt; low executive requirements to determine whether cortical regions beyond the left pFC show the same response profile to executive semantic demands. Our findings revealed that right pFC, posterior middle temporal gyrus (pMTG) and dorsal angular gyrus (bordering intraparietal sulcus) were also consistently recruited by executively demanding semantic tasks, demonstrating patterns of activation that were highly similar to the left ventral pFC. These regions overlap with the lesions in aphasic patients who exhibit multimodal semantic impairment because of impaired regulatory control (semantic aphasia)—providing important convergence between functional neuroimaging and neuropsychological studies of semantic cognition. Activation in dorsal angular gyrus and left ventral pFC was consistent across all types of executive semantic manipulation, regardless of whether the task was receptive or expressive, whereas pMTG activation was only observed for manipulation of control demands within receptive tasks. Second, we contrasted executively demanding tasks tapping semantics and phonology. Our findings revealed substantial overlap between the two sets of contrasts within left ventral pFC, suggesting this region underpins domain-general control mechanisms. In contrast, we observed relative specialization for semantic control within pMTG as well as the most ventral aspects of left pFC (BA 47), consistent with our proposal of a distributed network underpinning semantic control.
Rejection Sensitivity Polarizes Striatal–Medial Prefrontal Activity When Anticipating Social Feedback
Authors: Powers Katherine E. , Somerville Leah H. , Kelley William M. , Heatherton Todd F. 
Published: July 2013

AbstractAs a social species, humans are acutely aware of cues that signal inclusionary status. This study characterizes behavioral and neural responses when individuals anticipate social feedback. Across two fMRI studies, participants (n = 42) made social judgments about supposed peers and then received feedback from those individuals. Of particular interest was the neural activity occurring when participants were awaiting social feedback. During this anticipatory period, increased neural activity was observed in the ventral striatum, a central component of the brain's reward circuitry, and dorsomedial pFC, a brain region implicated in mentalizing about others. Individuals high in rejection sensitivity exhibited greater responses in both the ventral striatum and dorsomedial pFC when anticipating positive feedback. These findings provide initial insight into the neural mechanisms involved in anticipating social evaluations as well as the cognitive processes that underlie rejection sensitivity.
Brain Activation during Masked and Unmasked Semantic Priming: Commonalities and Differences
Authors: Ulrich Martin , Hoenig Klaus , Grön Georg , Kiefer Markus 
Published: July 2013

Abstract
Using fMRI during a lexical decision task, we investigated the neural correlates of semantic priming under masked and unmasked prime presentation conditions in a repeated measurement design of the same group of 24 participants (14 women). The task was to discriminate between pseudowords and words. Masked and unmasked prime words differed in their degree of semantic relatedness with target stimuli. Neural correlates of priming were defined as significantly different neural activations upon semantically unrelated minus related trials. Left fusiform gyrus, left posterior inferior frontal gyrus, and bilateral pre-SMA showed priming effects independent of the masking condition. By contrast, bilateral superior temporal gyri, superior parietal lobules, and the SMA proper demonstrated greater neural priming in the unmasked compared with the masked condition. The inverted contrast (masked priming minus unmasked priming) did not show significant differences even at lowered thresholds of significance. The conjoint effects of priming in the left fusiform gyrus suggest its involvement as a direct consequence of the neural organization of semantic memory. Activity in brain regions showing significantly more neural priming in the unmasked condition possibly reflected participants' evaluation of the prime–target relationship, presumably in the context of semantic matching. The present results therefore indicate that masked and unmasked semantic priming partially depend on dissociable mechanisms at the neural and most likely also at the functional level.
Physical Mechanisms of Tropopause Polar Vortex Intensity Change
Authors: Cavallo Steven M. , Hakim Gregory J. 
Published: July 2013

Abstract
Characterized by radii as large as 800 km and lifetimes up to months, cyclonic tropopause polar vortices (TPVs) are coherent circulation features over the Arctic that are important precursors for surface cyclogenesis in high and middle latitudes. TPVs have been shown to be maintained by radiative processes over the Arctic owing to limited amounts of latent heating. This study explores the hypothesis that a downward extension of dry stratospheric air associated with TPVs results in an increase in longwave radiative cooling that intensifies the vortex.
Idealized numerical modeling experiments are performed to isolate physical interactions, beginning with radiative forcing in a dry atmosphere and culminating with multiple physical interactions between radiation and clouds that more accurately represent the observed environment of TPVs. Results show that longwave radiative cooling associated with a rapid decrease in water vapor concentration near the tropopause is primarily responsible for observed TPV intensification. These enhanced water vapor gradients result from a lower tropopause within the vortex that places dry stratospheric air above relatively moist tropospheric air. Cloud-top radiative cooling enhances this effect and also promotes the maintenance of clouds by destabilizing the region near cloud top. Shortwave radiation and latent heating offset the longwave intensification mechanism. Heating from shortwave radiation reduces the cloud water mixing ratio by preferentially warming levels above cloud tops.
Nonlinear Climate Responses to Changes in Antarctic Intermediate Water
Authors: Graham Jennifer A. , Stevens David P. , Heywood Karen J. 
Published: July 2013

AbstractThe global impact of changes in Antarctic Intermediate Water (AAIW) properties is demonstrated using idealized perturbation experiments in a coupled climate model. Properties of AAIW were altered between 10° and 20°S in the Atlantic, Pacific, and Indian Oceans separately. Potential temperature was changed by ±1°C, along with density-compensating changes in salinity. For each of the experiments, sea surface temperature responds to changes in AAIW when anomalies surface at higher latitudes (>30°). Anomalous sea-to-air heat fluxes leave density anomalies in the ocean, resulting in nonlinear responses to opposite-sign perturbations. In the Southern Ocean, these affect the meridional density gradient, leading to changes in Antarctic Circumpolar Current transport. The response to cooler, fresher AAIW is both greater in magnitude and significant over a larger area than that for warmer, saltier AAIW. The North Atlantic is particularly sensitive to cool, fresh perturbations, with density anomalies causing reductions in the meridional overturning circulation of up to 1 Sv (1 Sv ≡ 106 m3 s−1). Resultant changes in meridional ocean heat transport, along with surfacing anomalies, cause basinwide changes in the surface ocean and overlying atmosphere on multidecadal time scales.
Why Tropical Sea Surface Temperature is Insensitive to Ocean Heat Transport Changes
Authors: Koll Daniel D. B. , Abbot Dorian S. 
Published: July 2013

AbstractPrevious studies have shown that increases in poleward ocean heat transport (OHT) do not strongly affect tropical SST. The goal of this paper is to explain this observation. To do so, the authors force two atmospheric global climate models (GCMs) in aquaplanet configuration with a variety of prescribed OHTs. It is found that increased OHT weakens the Hadley circulation, which decreases equatorial cloud cover and shortwave reflection, as well as reduces surface winds and evaporation, which both limit changes in tropical SST. The authors also modify one of the GCMs by alternatively setting the radiative effect of clouds to zero and disabling wind-driven evaporation changes to show that the cloud feedback is more important than the wind–evaporation feedback for maintaining constant equatorial SST as OHT changes. This work highlights the fact that OHT can reduce the meridional SST gradient without affecting tropical SST and could therefore serve as an additional degree of freedom for explaining past warm climates.