bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Peptide-Based Positron Emission Tomography Probe for In Vivo Detection of Caspase Activity in Apoptotic Cells
Authors: Hight Matthew R. , Cheung Yiu-Yin , Nickels Michael L. , Dawson Eric S. , Zhao Ping , Saleh Samir , Buck Jason R. , Tang Dewei , Washington M. Kay , Coffey Robert J. , Manning H. Charles 
Published: February 2014

Abstract
Purpose: Apoptosis, or programmed cell death, can be leveraged as a surrogate measure of response to therapeutic interventions in medicine. Cysteine aspartic acid–specific proteases, or caspases, are essential determinants of apoptosis signaling cascades and represent promising targets for molecular imaging. Here, we report development and in vivo validation of [18F]4-fluorobenzylcarbonyl–Val–Ala–Asp(OMe)–fluoromethylketone ([18F]FB-VAD-FMK), a novel peptide-based molecular probe suitable for quantification of caspase activity in vivo using positron emission tomography (PET).
Experimental Design: Supported by molecular modeling studies and subsequent in vitro assays suggesting probe feasibility, the labeled pan-caspase inhibitory peptide, [18F]FB-VAD-FMK, was produced in high radiochemical yield and purity using a simple two-step, radiofluorination. The biodistribution of [18F]FB-VAD-FMK in normal tissue and its efficacy to predict response to molecularly targeted therapy in tumors was evaluated using microPET imaging of mouse models of human colorectal cancer.
Results: Accumulation of [18F]FB-VAD-FMK was found to agree with elevated caspase-3 activity in response to Aurora B kinase inhibition as well as a multidrug regimen that combined an inhibitor of mutant BRAF and a dual PI3K/mTOR inhibitor in V600EBRAF colon cancer. In the latter setting, [18F]FB-VAD-FMK PET was also elevated in the tumors of cohorts that exhibited reduction in size.
Conclusions: These studies illuminate [18F]FB-VAD-FMK as a promising PET imaging probe to detect apoptosis in tumors and as a novel, potentially translatable biomarker for predicting response to personalized medicine. Clin Cancer Res; 20(8); 2126–35. ©2014 AACR.
High-Throughput Detection of Clinically Relevant Mutations in Archived Tumor Samples by Multiplexed PCR and Next-Generation Sequencing
Authors: Bourgon Richard , Lu Shan , Yan Yibing , Lackner Mark R. , Wang Weiru , Weigman Victor , Wang David , Guan Yinghui , Ryner Lisa , Koeppen Hartmut , Patel Rajesh , Hampton Garret M. , Amler Lukas C. , Wang Yulei 
Published: February 2014

Abstract
Purpose: Tailoring cancer treatment to tumor molecular characteristics promises to make personalized medicine a reality. However, reliable genetic profiling of archived clinical specimens has been hindered by limited sensitivity and high false-positive rates. Here, we describe a novel methodology, MMP-seq, which enables sensitive and specific high-throughput, high-content genetic profiling in archived clinical samples.
Experimental Design: We first validated the technical performance of MMP-seq in 66 cancer cell lines and a Latin square cross-dilution of known somatic mutations. We next characterized the performance of MMP-seq in 17 formalin-fixed paraffin-embedded (FFPE) clinical samples using matched fresh-frozen tissue from the same tumors as benchmarks. To demonstrate the potential clinical utility of our methodology, we profiled FFPE tumor samples from 73 patients with endometrial cancer.
Results: We demonstrated that MMP-seq enabled rapid and simultaneous profiling of a panel of 88 cancer genes in 48 samples, and detected variants at frequencies as low as 0.4%. We identified DNA degradation and deamination as the main error sources and developed practical and robust strategies for mitigating these issues, and dramatically reduced the false-positive rate. Applying MMP-seq to a cohort of endometrial tumor samples identified extensive, potentially actionable alterations in the PI3K (phosphoinositide 3-kinase) and RAS pathways, including novel PIK3R1 hotspot mutations that may disrupt negative regulation of PIK3CA.
Conclusions: MMP-seq provides a robust solution for comprehensive, reliable, and high-throughput genetic profiling of clinical tumor samples, paving the way for the incorporation of genomic-based testing into clinical investigation and practice. Clin Cancer Res; 20(8); 2080–91. ©2014 AACR.
Androgen Receptor Promotes the Oncogenic Function of Overexpressed Jagged1 in Prostate Cancer by Enhancing Cyclin B1 Expression via Akt Phosphorylation
Authors: Yu Yongjiang , Zhang Yu , Guan Wenbin , Huang Tao , Kang Jian , Sheng Xujun , Qi Jun 
Published: February 2014

AbstractThe Jagged1, a Notch signaling pathway ligand, had been shown to have a positive correlation with prostate cancer development. Our study for Jagged1 expression in 218 prostate cancer tissue samples also supports this conclusion. However, the detailed molecular mechanism of Jagged1 in promoting the progression of prostate cancer is still unclear. Through cell proliferation examination, androgen receptor (AR) was found to promote the oncogenic function of Jagged1 to enhance the cell proliferation rate by comparing four prostate cancer cell lines, LNCaP, LAPC4, DU145, and PC3, which was further validated through analyzing the survival of 118 patients treated with androgen-deprivation therapy (ADT) with different expression levels of Jagged1 and AR. More importantly, our data showed that Jagged1 combined with AR could increase the phosphorylation level of Akt and, in turn, phosphorylated Akt plays an important role in regulating the expression level of cyclin B1 by interacting with AR and increasing the transcriptional activity of AR. These data indicate that prostate cancer progression regulated by Jagged1 can be dramatically enhanced by combining with AR through promoting Akt activity.Implications: This study could benefit our clinical treatments for patients with prostate cancer with overexpressed Jagged1 by targeting AR and Akt. Mol Cancer Res; 12(6); 830–42. ©2014 AACR.
DDB2 Suppresses Tumorigenicity by Limiting the Cancer Stem Cell Population in Ovarian Cancer
Authors: Han Chunhua , Zhao Ran , Liu Xingluo , Srivastava Amit , Gong Li , Mao Hsiaoyin , Qu Meihua , Zhao Weiqiang , Yu Jianhua , Wang Qi-En 
Published: February 2014

AbstractOvarian cancer is an extremely aggressive disease associated with a high percentage of tumor recurrence and chemotherapy resistance. Understanding the underlying mechanism of tumor relapse is crucial for effective therapy of ovarian cancer. DNA damage-binding protein 2 (DDB2) is a DNA repair factor mainly involved in nucleotide excision repair. Here, a novel role was identified for DDB2 in the tumorigenesis of ovarian cancer cells and the prognosis of patients with ovarian cancer. Overexpressing DDB2 in human ovarian cancer cells suppressed its capability to recapitulate tumors in athymic nude mice. Mechanistic investigation demonstrated that DDB2 is able to reduce the cancer stem cell (CSC) population characterized with high aldehyde dehydrogenase activity in ovarian cancer cells, probably through disrupting the self-renewal capacity of CSCs. Low DDB2 expression correlates with poor outcomes among patients with ovarian cancer, as revealed from the analysis of publicly available gene expression array datasets. Given the finding that DDB2 protein expression is low in ovarian tumor cells, enhancement of DDB2 expression is a promising strategy to eradicate CSCs and would help to halt ovarian cancer relapse.Implications: DDB2 status has prognostic potential, and elevating its expression eradicates CSCs and could reduce ovarian cancer relapse. Mol Cancer Res; 12(5); 784–94. ©2014 AACR.
NEDD9 Regulates Actin Dynamics through Cortactin Deacetylation in an AURKA/HDAC6–Dependent Manner
Authors: Kozyreva Varvara K. , McLaughlin Sarah L. , Livengood Ryan H. , Calkins Robin A. , Kelley Laura C. , Rajulapati Anuradha , Ice Ryan J. , Smolkin Matthew B. , Weed Scott A. , Pugacheva Elena N. 
Published: February 2014

Abstract
The prometastatic protein NEDD9 (neural precursor cell expressed, developmentally downregulated 9) is highly expressed in many cancers and is required for mesenchymal individual cell migration and progression to the invasive stage. Nevertheless, the molecular mechanisms of NEDD9-driven migration and the downstream targets effecting metastasis are not well defined. In the current study, knockdown of NEDD9 in highly metastatic tumor cells drastically reduces their migratory capacity due to disruption of actin dynamics at the leading edge. Specifically, NEDD9 deficiency leads to a decrease in the persistence and stability of lamellipodial protrusions similar to knockdown of cortactin (CTTN). Mechanistically, it was shown that NEDD9 binds to and regulates acetylation of CTTN in an Aurora A kinase (AURKA)/HDAC6–dependent manner. The knockdown of NEDD9 or AURKA results in an increase in the amount of acetylated CTTN and a decrease in the binding of CTTN to F-actin. Overexpression of the deacetylation mimicking (9KR) mutant of CTTN is sufficient to restore actin dynamics at the leading edge and migration proficiency of the tumor cells. Inhibition of AURKA and HDAC6 activity by alisertib and Tubastatin A in xenograft models of breast cancer leads to a decrease in the number of pulmonary metastases. Collectively, these findings identify CTTN as the key downstream component of NEDD9-driven migration and metastatic phenotypes.
Implications: This study provides a mechanistic platform for therapeutic interventions based on AURKA and HDAC6 inhibition for patients with metastatic breast cancer to prevent and/or eradicate metastases. Mol Cancer Res; 12(5); 681–93. ©2014 AACR.
Proteome-Based Systems Biology Analysis of the Diabetic Mouse Aorta Reveals Major Changes in Fatty Acid Biosynthesis as Potential Hallmark in Diabetes Mellitus–Associated Vascular Disease
Authors: Husi Holger , Van Agtmael Tom , Mullen William , Bahlmann Ferdinand H. , Schanstra Joost P. , Vlahou Antonia , Delles Christian , Perco Paul , Mischak Harald 
Published: February 2014

Background—
Macrovascular complications of diabetes mellitus are a major risk factor for cardiovascular morbidity and mortality. Currently, studies only partially described the molecular pathophysiology of diabetes mellitus–associated effects on vasculature. However, better understanding of systemic effects is essential in unraveling key molecular events in the vascular tissue responsible for disease onset and progression.

Methods and Results—
Our overall aim was to get an all-encompassing view of diabetes mellitus–induced key molecular changes in the vasculature. An integrative proteomic and bioinformatics analysis of data from aortic vessels in the low-dose streptozotocin-induced diabetic mouse model (10 animals) was performed. We observed pronounced dysregulation of molecules involved in myogenesis, vascularization, hypertension, hypertrophy (associated with thickening of the aortic wall), and a substantial reduction of fatty acid storage. A novel finding is the pronounced downregulation of glycogen synthase kinase-3β (Gsk3β) and upregulation of molecules linked to the tricarboxylic acid cycle (eg, aspartate aminotransferase [Got2] and hydroxyacid-oxoacid transhydrogenase [Adhfe1]). In addition, pathways involving primary alcohols and amino acid breakdown are altered, potentially leading to ketone-body production. A number of these findings were validated immunohistochemically. Collectively, the data support the hypothesis that in this diabetic model, there is an overproduction of ketone-bodies within the vessels using an alternative tricarboxylic acid cycle-associated pathway, ultimately leading to the development of atherosclerosis.

Conclusions—
Streptozotocin-induced diabetes mellitus in animals leads to a reduction of fatty acid biosynthesis and an upregulation of an alternative ketone-body formation pathway. This working hypothesis could form the basis for the development of novel therapeutic intervention and disease management approaches.
Norms Matter! The Role of International Norms in EU Policies on Asylum and Immigration
Authors: Roos Christof , Zaun Natascha 
Published: February 2014

Abstract
This Article investigates how international norms impact on eu asylum and immigration policy. To this end we scrutinize the assumption that the robustness of international norms indicates the quality of eu integration. Drawing on international norms literature we argue that four characters define an international norms’ robustness: specificity in definition, binding force, coherence with domestic law and international law, and concordant understanding among actors. Our analysis covers three eu policy areas, asylum policy, family reunification policy, and labour migration policy. Across the three areas international norms had varying degrees of robustness at the time of eu negotiations. The findings show that presence and robustness of international norms on asylum or immigration regulation are reflected in eu legislation. Given that there are more robust norms available on questions of status than on reception conditions or asylum procedures, the qualification directive was much easier to agree on than the reception conditions or the asylum procedures directive which were much more characterized by hard bargaining. The international norm, right to family life, was sufficiently robust and was codified in eu law. However, both the international norm and the eu law do not provide for clear admission criteria. On labour migration, robust international norms with regard to equality provisions for migrant workers are mirrored in eu legislation on residence rights of migrants. With regard to conditions of admission, the absence of international norms indicates little to no eu legislation.
Channelled Policy Transfers: EU-Tunisia Interactions on Migration Matters
Authors: Cassarino Jean-Pierre 
Published: February 2014

Abstract
This study analyses how the migration policy options of the Government of Tunisia have been codified by repeated interactions with the European Union (eu) and its Member States. It argues that these interactions have been shaped by the gradual consolidation of a hierarchy of priorities where the drive for operability and security predominates. A hierarchy of priorities delineates the contours of the perceived top priorities that should be tackled first and foremost, while hiding or dismissing others. Having historicized the origins of this hierarchy, the study sets out to show that the prioritization of security concerns in bilateral and multilateral migration talks allowed the leadership of former President Ben Ali to skilfully readjust or channel transferred rules and policies on migration matters with a view to strengthening its own domination. This had serious implications for human rights observance in Tunisia. Today, after (or despite) the radical transformations that took place in Tunisia in early 2011, the same hierarchy of priorities continues to exist. However, its resilience may raise a host of complicated issues, given the empowered advocacy role of civil society organizations and the manifest alertness of Tunisian population.
Rhetorical Traditions of Public Diplomacy and the Internet
Authors: Rolfe Mark 
Published: February 2014

Summary
Many calls have been made since 2001 for a ‘new public diplomacy’ of the information age that utilizes the internet to reach public opinion. They have been especially forthcoming from the Obama administration, although they have been just as popular with the political classes in the United States and elsewhere. However, such recent calls form only the latest instalment of a rhetorical tradition of public diplomacy that stretches back to Woodrow Wilson and beyond to the 1790s. There is a thematic recurrence in the rhetoric of public diplomacy, as there is in the rhetoric of democracy, and for the same reason: representative democracy has always involved a complex tension between, on the one hand, the political class of politicians and diplomats and, on the other, public opinion, which needs to be appeased since it confers legitimacy on representatives. This results in a recurring pattern of language involving suspicions of the political class, declarations of a new era of diplomacy and claims to credibility. There are hence frequent bouts of anti-politics politics and anti-diplomacy politics, sometimes utilizing a discourse of technological optimism, which politicians and diplomats attempt to assuage with similar calls for new political dawns.
Belgian Multinationals and Public–Private Partnerships in Economic Diplomacy
Authors: Kesteleyn Jennifer 
Published: February 2014

Summary
This article analyses public–private partnerships in Belgium’s economic diplomacy from the perspective of multinational companies (mncs). The concept of corporate political activity (cpa) is therefore introduced. cpa is seen as a part of business diplomacy (bd), which companies use in order to defend their interests. Eight stock-listed Belgian multinationals (bmncs) were interviewed using single, semi-structured interviews. This exploratory study focused on whether or not companies contact public officials, which strategies they use and how these strategies are organized in order to defend their interests abroad. The empirical data revealed that bmncs enter into relationships with national and supranational actors. Information-sharing is the central aim of these relationships, because of the mutual realization that these contacts are important. This was less so, however, at the international level. In short, bmncs will, depending on the subject and/or the institutional context, rely on the services offered by Belgian economic diplomacy. They will initially, however, also include diplomatic functions of their own.
Israeli Diplomacy: The Effects of Cultural Trauma
Authors: Yair Gad , Odom-Weiss Sharona 
Published: February 2014

Summary
Israeli politicians are diplomatic agents provocateurs. Presidents, prime ministers and foreign office executives craft diplomatic scenes that betray diplomatic protocol. This article exposes the deep cultural codes that explain the unique behaviour of Israeli diplomacy. It documents different occasions of Israeli exceptional diplomacy and suggests that they reflect the cultural traumas that underlie Israeli culture. The analyses apply a new theoretical framework that dwells on the cultural codes of ‘Israeliness’ while suggesting that the unique style of Israeli diplomacy reflects four such codes: existential anxiety; upright defiance; a dugri (frank) speech culture and a fear of seeming to be a sucker (‘fraier’). By interpreting prominent cases with a cultural lens, the authors provide new insights into Israeli unilateralism, its seeming ‘paranoid’ character, and the reason for Israeli ignorance of international diplomatic codes. Essentially, they suggest that: (a) there is a cultural mismatch between diplomatic protocol and the Israeli national habitus; (b) the more that Israel’s strategic interests are threatened, the more locked it becomes to its post-traumatic habitus and the further its politicians move away from protocol. Israel’s persistent cultural trauma is thus likely to maintain the deviation of Israeli diplomacy from diplomatic protocol.
Equal Opportunities in the Slovene Diplomatic Service
Authors: Jazbec Milan 
Published: February 2014

Summary
A survey on equal opportunities in the Slovene diplomatic service was conducted during 2009. A thorough empirical research, where the sample included 630 persons employed in the Slovene diplomatic service, of whom 235 (37.3 per cent) responded to the questionnaire, indicated five main determinants of inequality: political affiliation; personal grudges; personal preference; age/generation grouping; and gender. The determinants that affect employees and are based on their gender include a combination of professional and private life, working abroad, and time spent working. The project produced a number of policy recommendations, which were gradually taken into account within the Slovene diplomatic system.
Chronic Cervical Esophageal Foreign Bodies in Children
Authors: Schramm Jordan C. , Sewell Ryan K. , Azarow Kenneth S. , Raynor Stephen C. , Abdessalam Shahab F. 
Published: February 2014

Objectives: We reviewed the surgical management of chronic cervical esophageal foreign bodies (CCEFBs) in a pediatric population after failed endoscopic retrieval. Methods: A descriptive analysis via a retrospective chart review of patients with CCEFBs who failed initial endoscopic management was performed between 2008 and 2013. Details were recorded regarding presenting symptoms, time from symptom onset to diagnosis of the CCEFB, surgical approach, and complications. Results: Three patients with CCEFBs unsuccessfully managed with endoscopy were identified. The range of ages at diagnosis was 14 months to 4.5 years. The foreign bodies (FBs) were present for at least 1 month before diagnosis (range, 1 to 10 months). Respiratory symptoms were predominant in all cases. Neck exploration with removal of the FB was performed in each case. Complications included esophageal stricture necessitating serial dilations (patient 1), left true vocal fold paresis that resolved spontaneously (patient 3), and tracheoesophageal fistula with successful endoscopic closure (patient 3). No long-term sequelae were experienced. Conclusions: A high index of suspicion is required to recognize CCEFBs in children with respiratory distress. Although endoscopic management remains the first-line treatment, it may fail or may not be possible because of transmural FB migration. In this setting, neck exploration with FB removal is a safe and effective alternative.
Inflammatory Protein Expression in Human Subglottic Stenosis Tissue Mirrors That in a Murine Model
Authors: Haft Sunny , Lee Jennifer Y. , Ghosh Ankona , Philiponis Genevieve , Malaisrie Nora , Leahy Kevin P. , Singhal Sunil , Cohen Noam A. , Mirza Natasha 
Published: February 2014

Objectives: We undertook to describe the genetic and protein composition of subglottic stenosis (SGS) by measuring an array of protein expression and messenger RNA levels within human SGS tissue. We also sought to compare this human array to cytokine expression from a murine model of SGS in order to confirm the effective translational nature of our animal model. Methods: Human granulation tissue from 10 patients with early symptomatic SGS was compared to control bronchus. The expression levels of 24 different cytokines were measured by a Luminex protein assay and real-time polymerase chain reaction. Results: The protein expression in human SGS mirrors that seen in murine SGS. Transforming growth factor β1, interleukin 1β, and matrix metalloproteinase 9 were markedly elevated in both human and mouse SGS tissues. The protein array showed a statistically significant elevation in the proinflammatory cytokines tumor necrosis factor α, interleukin 1, granulocyte macrophage colony-stimulating factor, and interferon γ. Conclusions: This is the first study, to our knowledge, to measure an array of protein expression within human SGS tissue. The expression profile suggests that symptomatic tracheal granulation tissue is mostly within the early inflammatory phase of wound healing and has only begun fibrotic and angiogenic remodeling. This study validates our murine model of SGS, and also helps to define the exact pathways of tissue injury, in the hope of leading to new treatments for this difficult condition.