bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epithelial Cell Organization Suppresses Myc Function by Attenuating Myc Expression
Authors: Simpson David R. , Yu Min , Zheng Siyuan , Zhao Zhongming , Muthuswamy Senthil K. , Tansey William P. 
Published: May 2011

Abstract
c-Myc is an oncogene transcription factor that causes cancer in many settings, including solid tumors that arise in the context of organized tissue structures. Given that disruption of tissue architecture frequently occurs in cancer, there is considerable interest in how cell organization impacts oncogene function. A previous report found that organization of mammary epithelial cells into defined 3-dimensional structures renders them insensitive to the effects of retrovirus-mediated overexpression of Myc, leading to the notion that organization tempers the sensitivity of individual cells to Myc activity. In this article, we report that epithelial cell organization does not profoundly alter Myc activity but, instead, suppresses Myc by modulating its expression. We show that the morphogenesis of mammary epithelial cells into organized acinar structures in vitro is accompanied by widespread changes in gene expression patterns, including a substantial decrease in the expression of Myc. Concomitant with the decrease in endogenous Myc expression, we observe a decrease in transcription from retroviral vectors during morphogenesis and find that Myc transgene expression in acini is much lower than in unorganized cells. This decrease in Myc transgene activity is responsible for the apparent recalcitrance of organized cells to ectopic Myc, as adenovirus-mediated expression of Myc in organized structures potently induces apoptosis. These observations reveal that organization does not alter the inherent response of epithelial cells to Myc and suggest that other tumor suppression mechanisms, apart from structure, antagonize Myc in the development of solid tumors. Cancer Res; 71(11); 3822–30. ©2011 AACR.
6-Bromoindirubin-3′-Oxime Inhibits JAK/STAT3 Signaling and Induces Apoptosis of Human Melanoma Cells
Authors: Liu Lucy , Nam Sangkil , Tian Yan , Yang Fan , Wu Jun , Wang Yan , Scuto Anna , Polychronopoulos Panos , Magiatis Prokopios , Skaltsounis Leandros , Jove Richard 
Published: May 2011

Abstract
STAT3 is persistently activated and contributes to malignant progression in various cancers. Janus activated kinases (JAK) phosphorylate STAT3 in response to stimulation by cytokines or growth factors. The STAT3 signaling pathway has been validated as a promising target for development of anticancer therapeutics. Small-molecule inhibitors of JAK/STAT3 signaling represent potential molecular-targeted cancer therapeutic agents. In this study, we investigated the role of JAK/STAT3 signaling in 6-bromoindirubin-3′-oxime (6BIO)-mediated growth inhibition of human melanoma cells and assessed 6BIO as a potential anticancer drug candidate. We found that 6BIO is a pan-JAK inhibitor that induces apoptosis of human melanoma cells. 6BIO directly inhibited JAK-family kinase activity, both in vitro and in cancer cells. Apoptosis of human melanoma cells induced by 6BIO was associated with reduced phosphorylation of JAKs and STAT3 in both dose- and time-dependent manners. Consistent with inhibition of STAT3 signaling, expression of the antiapoptotic protein Mcl-1 was downregulated. In contrast to the decreased levels of phosphorylation of JAKs and STAT3, phosphorylation levels of the Akt and mitogen-activated protein kinase (MAPK) signaling proteins were not inhibited in cells treated with 6BIO. Importantly, 6BIO suppressed tumor growth in vivo with low toxicity in a mouse xenograft model of melanoma. Taken together, these results show that 6BIO is a novel pan-JAK inhibitor that can selectively inhibit STAT3 signaling and induces tumor cell apoptosis. Our findings support further development of 6BIO as a potential anticancer therapeutic agent that targets JAK/STAT3 signaling in tumor cells. Cancer Res; 71(11); 3972–9. ©2011 AACR.
NEMO-Binding Domain Peptide Inhibits Constitutive NF-κB Activity and Reduces Tumor Burden in a Canine Model of Relapsed, Refractory Diffuse Large B-Cell Lymphoma
Authors: Gaurnier-Hausser Anita , Patel Reema , Baldwin Albert S. , May Michael J. , Mason Nicola J. 
Published: May 2011

AbstractPurpose: Activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL) is an aggressive, poorly chemoresponsive lymphoid malignancy characterized by constitutive canonical NF-κB activity that promotes lymphomagenesis and chemotherapy resistance via overexpression of antiapoptotic NF-κB target genes. Inhibition of the canonical NF-κB pathway may therefore have therapeutic relevance in ABC-DLBCL. Here, we set out to determine whether dogs with spontaneous DLBCL have comparative aberrant constitutive NF-κB activity and to determine the therapeutic relevance of NF-κB inhibition in dogs with relapsed, resistant DLBCL.Experimental Design: Canonical NF-κB activity was evaluated by electrophoretic mobility shift assays and immunoblot analyses, and NF-κB target gene expression was measured by quantitative real time PCR. Primary malignant canine B lymphocytes were treated with the selective IKK complex inhibitor NF-κB essential modulator-binding domain (NBD) peptide and evaluated for NF-κB activity and apoptosis. NBD peptide was administered intranodally to dogs with relapsed B-cell lymphoma and NF-κB target gene expression and tumor burden were evaluated pre- and post-treatment.Results: Constitutive canonical NF-κB activity and increased NF-κB target gene expression were detected in primary DLBCL tissue. NBD peptide inhibited this activity and induced apoptosis of primary malignant B cells in vitro. Intratumoral injections of NBD peptide to dogs with relapsed DLBCL inhibited NF-κB target gene expression and reduced tumor burden.Conclusions: This work shows that dogs with spontaneous DLBCL represent a clinically relevant, spontaneous, large animal model for human ABC-DLBCL and shows the therapeutic relevance of NF-κB inhibition in the treatment of ABC-DLBCL. These results have important translational relevance for ABC-DLBCL treatment in human patients. Clin Cancer Res; 17(14); 4661–71. ©2011 AACR.
BRAF-KIAA1549 Fusion Predicts Better Clinical Outcome in Pediatric Low-Grade Astrocytoma
Authors: Hawkins Cynthia , Walker Erin , Mohamed Nequesha , Zhang Cindy , Jacob Karine , Shirinian Margret , Alon Noa , Kahn Daniel , Fried Iris , Scheinemann Katrin , Tsangaris Elena , Dirks Peter , Tressler Robert , Bouffet Eric , Jabado Nada , Tabori Uri 
Published: May 2011

Abstract
Purpose: Recent studies have revealed that the majority of pediatric low-grade astrocytomas (PLGA) harbor the BRAF-KIAA1549 (B-K) fusion gene resulting in constitutive activation of the RAS/MAPK pathway. However, the clinical significance of this genetic alteration is yet to be determined. We aimed to test the prognostic role of the B-K fusion in progression of incompletely resected PLGA.
Experimental Design: We retrospectively identified 70 consecutive patients with incompletely resected “clinically relevant” PLGA. We added 76 tumors diagnosed at our institution between 1985 and 2010 as controls. We examined BRAF alterations by reverse transcriptase PCR, FISH, and single-nucleotide polymorphism array analysis and correlated that with progression-free survival (PFS).
Results: Overall, 60% of tumors were B-K fusion positive. All patients with B-K fused PLGA are still alive. Five-year PFS was 61% ± 8% and 18% ± 8% for fusion positive and negative patients, respectively (P = 0.0004). B-K fusion resulted in similarly significant favorable PFS for patients who received chemotherapy. Multivariate analysis revealed that B-K fusion was the most significant favorable prognostic factor in incompletely resected PLGA and was independent of location, pathology, and age. In vitro, BRAF overexpression resulted in growth arrest associated with DNA damage (γH2AX expression). Five-year PFS was 68% ± 15% and 0% for patients with B-K fused and γH2AX-expressing PLGA versus negative tumors (P = 0.001).
Conclusion: These data suggest that B-K fusion confers a less aggressive clinical phenotype on PLGA and may explain their tendency to growth arrest. Combined analysis of B-K fusion and γH2AX expression can determine prognosis and may be a powerful tool to tailor therapy for these patients. Clin Cancer Res; 17(14); 4790–8. ©2011 AACR.
MicroRNA-146a Downregulates NFκB Activity via Targeting TRAF6 and Functions as a Tumor Suppressor Having Strong Prognostic Implications in NK/T Cell Lymphoma
Authors: Paik Jin Ho , Jang Ji-Young , Jeon Yoon Kyung , Kim Wook Youn , Kim Tae Min , Heo Dae Seog , Kim Chul-Woo 
Published: May 2011

Abstract
Purpose: We investigated prognostic implications of microRNAs in extranodal NK/T cell lymphoma (NKTL).
Experimental Design: We measured miRNA expression in NKTL tissues and cell lines, using real-time PCR, and analyzed its role in NKTL, using cell lines.
Results: Multivariate analysis showed low miR-146a expression (P &lt; 0.001; HR = 13.110), primary non–upper aerodigestive tract lesion (non-UAT; P = 0.008; HR = 5.376) and high International Prognostic Index (IPI; ≥3; P = 0.013; HR = 3.584) to be independent poor prognostic factors. miR-146a expression could subdivide UAT-NKTL into 2 prognostic groups, resulting in the following prognostic groups: (i) UATLow-146a, (ii) UATHigh-146a, and (iii) non-UAT. Compared with UATHigh-146a, UATLow-146a showed distinctively poor prognosis (P &lt; 0.001; HR = 15.620), similar to the non-UAT group. In vitro, miR-146a overexpression in NKTL cell lines, SNK6 and YT, inhibited nuclear factor κB (NFκB) activity, suppressed cell proliferation, induced apoptosis, and enhanced chemosensitivity. TNF receptor–associated factor 6, a target of miR-146a and a known NFκB activator, was downregulated by miR-146a in SNK6 and YT cells. Promoter methylation of miR-146a gene was observed in SNK6 and YT cells, as well as in NKTL tissues with low miR-146a expression, and miR-146a expression was induced by the conversion of methylation status with a demethylating agent in SNK6 and YT cells.
Conclusions: These results suggest that miR-146a might function as a potent tumor suppressor in NKTL and be useful for patient assessment and therapeutic targeting. Clin Cancer Res; 17(14); 4761–71. ©2011 AACR.
Making Forecasts Meaningful: Explanations of Problematic Predictions in Northeast Brazil
Authors: Pennesi Karen 
Published: May 2011

AbstractThis study illustrates the need to consider the multiple interpretations and experiences that influence how climate forecasts are evaluated in local contexts when assessing how useful forecasts can be for increasing the resilience of rural communities. Video clips of predictions made by scientific and traditional forecasters were shown in interviews and focus groups to elicit explanations for why the predictions are sometimes judged to be inaccurate, not useful, or inappropriately communicated by different sectors of the rural population in Ceará, Northeast Brazil. Results indicate that climate forecasts are not simply a decision-making tool that provides information in a one-way transfer from forecaster to user. The meanings and values of predictions are jointly created by both forecasters and their audiences. Predictions and the discussions that surround them are also an important part of expressing social identities and ideas about how the world works. Ineffective predictions are explained here in terms of religious beliefs, environmental change, forecaster identity, interactional context, and cultural practices.
Double-Bundle versus Single-Bundle Anterior Cruciate Ligament Reconstruction
Authors: Suomalainen Piia , Moisala Anna-Stina , Paakkala Antti , Kannus Pekka , Järvelä Timo 
Published: May 2011

Background One aspect of the debate over the reconstruction of the anterior cruciate ligament is whether it should be carried out with the single-bundle or double-bundle technique. Hypothesis The double-bundle technique results in fewer graft failures than the single-bundle technique in anterior cruciate ligament reconstruction. Study Design Randomized controlled trial; Level of evidence, 1. Methods A total of 153 patients were prospectively randomized into 2 groups of anterior cruciate ligament reconstruction with hamstring autografts using aperture interference screw fixation: single-bundle technique (SB group, n = 78) and double-bundle technique (DB group, n = 75). The evaluation methods were clinical examination, KT-1000 arthrometric measurement, the International Knee Documentation Committee (IKDC) and the Lysholm knee scores, and magnetic resonance imaging (MRI) evaluation. All of the operations were performed by 1 experienced orthopaedic surgeon, and all clinical assessments were made by 2 blinded and independent examiners. A musculoskeletal radiologist blinded to the clinical data made the MRI interpretation. Results There were no differences between the study groups preoperatively. Ninety percent of patients (n = 138) were available at a minimum 2-year follow-up (range, 24-37 months). Eight patients (7 in the SB group and 1 in the DB group) had graft failure during the follow-up and had anterior cruciate ligament revision surgery ( P = .04). In addition, 7 patients (5 in the SB group and 2 in the DB group) had an invisible graft on the MRI assessment at the 2-year follow-up. Also, the anteromedial bundle was partially invisible in 2 patients and the posterolateral bundle in 9 patients. Together, the total number of failures and invisible grafts were significantly higher in the SB group (12 patients, 15%) than the DB group (3 patients, 4%) ( P = .024). No significant group differences were found in the knee scores or stability evaluations at the follow-up. Conclusion This 2-year randomized trial showed that the revision rate of the anterior cruciate ligament reconstruction was significantly lower with the double-bundle technique than that with the single-bundle technique. However, additional years of follow-up are needed to reveal the long-term results.
Long-term Survivorship of Rotator Cuff Repairs Using Ultrasound and Magnetic Resonance Imaging Analysis
Authors: Kluger Rainer , Bock Peter , Mittlböck Martina , Krampla Wolfgang , Engel Alfred 
Published: May 2011

Background: Important differences in clinical outcomes likely exist between patients with healed and nonhealed rotator cuff repairs. The survival probability of rotator cuff repairs has not been published in a time-dependent manner up to now. Hypotheses: Recurrent tears occur more frequently in the early postoperative period. Early failures of the repair are a prognostic factor for the long-term outcome. Study Design: Cohort study; Level of evidence, 3. Methods: A series of 107 consecutive patients undergoing arthroscopically assisted mini-open repair of the rotator cuff between 1998 and 2002 were evaluated in a prospective study. Of these, 95 patients finished the study after a maximum follow-up of 11 years. The evaluation included 1 postoperative magnetic resonance imaging scan as well as multiple ultrasonographies and determinations of the American Shoulder and Elbow Surgeons (ASES) and Constant scores at 3 months, 6 months, 1 year, and then yearly with a median follow-up of 96 months. Results: The overall failure rate was 33% (35 of 107). The survivorship analysis revealed that 74% of all failures occurred atraumatically in the first 3 months and 11% occurred between the third and the sixth month after the repair. The remaining reruptures (14%) happened 2 to 5 years postoperatively and were related to sports activities or direct trauma. The overall clinical results did not deteriorate over time. The parameters healed tendon, rerupture of less than 2 cm2, and rerupture of more than 2 cm2 at 6 months were predictors of the gender- and age-adjusted (normalized) Constant score at 84 months ( P < .0001). Conclusion: The majority of recurrent tears occurred in the first 3 months after surgical repair. The parameters “recurrent tear” as well as “healed tendon” evaluated at 6 months postoperatively appear to be predictors for the clinical outcomes at 7 years. Efforts to improve healing during the initial 3 months have long-term implications for maintenance of cuff integrity and clinical outcomes.
Confounding due to changing background risk in adaptively randomized trials
Authors: Lipsky Ari M , Greenland Sander 
Published: May 2011

Background While adaptive trials tend to improve efficiency, they are also subject to some unique biases. Purpose We address a bias that arises from adaptive randomization in the setting of a time trend in disease incidence. Methods We use a potential-outcome model and directed acyclic graphs to illustrate the bias that arises from a changing subject allocation ratio with a concurrent change in background risk. Results In a trial that uses adaptive randomization, time trends in risk can bias the crude effect estimate obtained by naively combining the data from the different stages of the trial. We illustrate how the bias arises from an interplay of departures from exchangeability among groups and the changing randomization proportions. Limitations We focus on risk-ratio and risk-difference analysis. Conclusions Analysis of trials using adaptive randomization should involve attention to or adjustment for possible trends in background risk. Numerous modeling strategies are available for that purpose, including stratification, trend modeling, inverse-probability-of-treatment weighting, and hierarchical regression.
Investigation of performance characteristics and water flooding in the cathode flow channel of a polymer electrolyte membrane fuel cell
Authors: Seo S H , Lee C S 
Published: May 2011

This study was experimentally carried out to investigate the relationship between fuel-cell performance and the water flooding phenomena at the cathode, which is an important research area of water management in the polymer electrolyte membrane fuel cell. A transparent fuel cell was fabricated to observe the water flooding phenomenon in the cathode channel. Images of the flooding phenomena were obtained by digital and high-speed cameras under various operating conditions involving cell temperature, cathode flowrate, humidifying temperature, cathode backpressure, and oxygen concentration. At the same time, performance was measured at the potentiostatic mode. In this study, investigations for the effects of operating parameters on the water flooding phenomenon, as well as water droplet generation and removal in the cathode flow channel were made. As time elapsed, it was seen that small water droplets formed and then grew into larger water droplets, when the flooding phenomena occurred. It was also observed that when the cell temperature increased the occurrence of flooding phenomena decreased due to evaporation, and performance was significantly improved. The water droplets in the cathode channel were found to be almost zero at high cathode flowrates, and the instances of the flooding phenomenon were decreased by evaporation as the humidified temperature was increased. On account of increasing cathode backpressure, the flooding phenomenon due to high partial pressure was reduced and as compared to air when oxygen was used as an oxidant, the water distribution was increased. Based on this experimental study, it is seen that the flooding phenomenon is closely related to fuel-cell performance.
Theoretical model for the hot-melt-drawn fabrication of optical fibre probes and analysis of fabrication parameters
Authors: Lin Z-C , Yang C-B , Lee K-P 
Published: May 2011

Optical fibre probes made by manually operated hot-melt-drawn methods may have unreliable production quality. This can result in unreliable results during use of the probes. This article presents a theoretical model for the construction of optical fibre probes by a hot-melt-drawn method, intending to simulate the optical fibre melt-drawing process using the P-2000 Sutter melt-drawing installation, and investigates changes in length, radius, and geometric profile of the optical fibre. Using preset processing parameters, the study simulates the profile, size, and shape of an optical fibre probe, and the geometric shape and diameter of the probe tip. Additionally, the article presents an analysis of fabrication parameters to determine which of the three processing parameters, probe diameter, melt-drawing rate, and hard-drawn value, is most significant in determining the length and profile of a simulation model probe.
Evolution of endogenous retroviruses in the Suidae: evidence for different viral subpopulations in African and Eurasian host species
Authors: Nascimento Fabrícia F , Gongora Jaime , Charleston Michael , Tristem Michael , Lowden Stewart , Moran Chris 
Published: May 2011

Abstract

Background
Porcine endogenous retroviruses (PERVs) represent remnants of an exogenous form that have become integrated in the domestic pig (Sus scrofa) genome. Although they are usually inactive, the capacity of γ1 ERVs to infect human cells in vitro has raised concerns about xenotransplantation because the viruses could cross the species barrier to humans. Here we have analyzed the evolution of γ1 ERVs in ten species of Suidae (suids, pigs and hogs) from Eurasia and Africa using DNA sequences for their coding domains (gag, pro/pol and env genes). For comparison with γ1 PERVs, we have also analysed γ2 ERVs which in domestic pigs are known to be inactive and do not pose a risk to xenotransplantation.

Results
Phylogenetic analysis using Bayesian inference showed that γ1 and γ2 ERVs have distinctive evolutionary histories. Firstly, two different viral lineages of γ1 ERVs were found and a coevolutionary analysis demonstrated that they correspond broadly to their host phylogeny, one of Eurasian and another of African species, and show no evidence of horizontal transmission. γ2 ERVs, however, show a bush-like evolution, suggesting a rapid viral radiation from a single common ancestor with no correspondence between host and viral evolutionary trees. Furthermore, though γ1 ERV env genes do not possess frequent stop codons, γ2 env genes do. To understand whether γ1 suid ERVs may be still replicating, we have also evaluated their likely mechanism of proliferation by statistically testing internal to terminal branches using nonsynonymous versus synonymous substitution ratios. Our results suggest that γ1 ERVs are increasing in copy number by reinfection, which requires the translocation of the virus from one cell to another.

Conclusions
Evidence of at least two viral subpopulations was observed in γ1 ERVs from Eurasian and African host species. These results should be taken into account in xenotransplantation since γ1 ERVs appear to be codiverging with their host and maintaining ongoing capacity to infect somatic and germ cells.