bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular Profiling of Patient-Matched Brain and Extracranial Melanoma Metastases Implicates the PI3K Pathway as a Therapeutic Target
Authors: Chen Guo , Chakravarti Nitin , Aardalen Kimberly , Lazar Alexander J. , Tetzlaff Michael T. , Wubbenhorst Bradley , Kim Sang-Bae , Kopetz Scott , Ledoux Alicia A. , Gopal Y.N. Vashisht , Pereira Cristiano Goncalves , Deng Wanleng , Lee Ju-Seog , Nathanson Katherine L. , Aldape Kenneth D. , Prieto Victor G. , Stuart Darrin , Davies Michael A. 
Published: May 2014

AbstractPurpose: An improved understanding of the molecular pathogenesis of brain metastases, one of the most common and devastating complications of advanced melanoma, may identify and prioritize rational therapeutic approaches for this disease. In particular, the identification of molecular differences between brain and extracranial metastases would support the need for the development of organ-specific therapeutic approaches.Experimental Design: Hotspot mutations, copy number variations (CNV), global mRNA expression patterns, and quantitative analysis of protein expression and activation by reverse-phase protein array (RPPA) analysis were evaluated in pairs of melanoma brain metastases and extracranial metastases from patients who had undergone surgical resection for both types of tumors.Results: The status of 154 previously reported hotspot mutations, including driver mutations in BRAF and NRAS, were concordant in all evaluable patient-matched pairs of tumors. Overall patterns of CNV, mRNA expression, and protein expression were largely similar between the paired samples for individual patients. However, brain metastases demonstrated increased expression of several activation-specific protein markers in the PI3K/AKT pathway compared with the extracranial metastases.Conclusions: These results add to the understanding of the molecular characteristics of melanoma brain metastases and support the rationale for additional testing of the PI3K/AKT pathway as a therapeutic target in these highly aggressive tumors. Clin Cancer Res; 20(21); 5537–46. ©2014 AACR.
The Microenvironment Matters: Estrogen Deficiency Fuels Cancer Bone Metastases
Authors: Wright Laura E. , Guise Theresa A. 
Published: May 2014

Abstract
Factors released during osteoclastic bone resorption enhance disseminated breast cancer cell progression by stimulating invasiveness, growth, and a bone-resorptive phenotype in cancer cells. Postmenopausal bone loss may accelerate progression of breast cancer growth in bone, explaining the anticancer benefit of the bone-specific antiresorptive agent zoledronic acid in the postmenopausal setting. Clin Cancer Res; 20(11); 2817–9. ©2014 AACR.
BET Bromodomain Inhibitors Block Growth of Pancreatic Cancer Cells in Three-Dimensional Collagen
Authors: Sahai Vaibhav , Kumar Krishan , Knab Lawrence M. , Chow Christina R. , Raza Sania S. , Bentrem David J. , Ebine Kazumi , Munshi Hidayatullah G. 
Published: May 2014

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is associated with pronounced fibrosis that contributes to chemoresistance, in part, through increased histone acetylation. Because bromodomain (BRD) and extra terminal domain (BET) proteins are “readers” of histone acetylation marks, we targeted BET proteins in PDAC cells grown in three-dimensional collagen. We show that treatment with BET inhibitors decreases growth of PDAC cells (AsPC1, CD18, and Panc1) in collagen. Transfection with siRNA against BRD4, which is increased in human PDAC tumors, also decreases growth of PDAC cells. BET inhibitors additionally decrease growth in collagen of PDAC cells that have undergone epithelial-to-mesenchymal transition or have become resistant to chemotherapy. Although BET inhibitors and BRD4 siRNA repress c-MYC only in AsPC1 and CD18 cells, downregulating c-MYC decreases growth of all three PDAC cell lines in collagen. FOSL1, which is also targeted by BET inhibitors and BRD4 siRNA in AsPC1, CD18, and Panc1 cells, additionally regulates growth of all three PDAC cell lines in collagen. BET inhibitors and BRD4 siRNA repress HMGA2, an architectural protein that modulates chromatin state and also contributes to chemoresistance, in PDAC cells grown in collagen. Importantly, we show that there is a statistically significant correlation between BRD4 and HMGA2 in human PDAC tumors. Significantly, overexpression of HMGA2 partially mitigates the effect of BET inhibitors on growth and c-MYC and/or FOSL1 expression in collagen. Overall, these results demonstrate that BET inhibitors block growth of PDAC cells in collagen and that BET proteins may be potential targets for the treatment of pancreatic cancer. Mol Cancer Ther; 13(7); 1907–17. ©2014 AACR.
CAF-Secreted IGFBPs Regulate Breast Cancer Cell Anoikis
Authors: Weigel Kelsey J. , Jakimenko Ana , Conti Brooke A. , Chapman Sarah E. , Kaliney William J. , Leevy W. Matthew , Champion Matthew M. , Schafer Zachary T. 
Published: May 2014

Abstract
Carcinoma-associated fibroblasts (CAFs) are now widely appreciated for their contributions to tumor progression. However, the ability of CAFs to regulate anoikis, detachment-induced cell death, has yet to be investigated. Here, a new role for CAFs in blocking anoikis in multiple cell lines, facilitating luminal filling in three-dimensional cell culture, and promoting anchorage-independent growth is defined. In addition, a novel mechanism underlying anoikis inhibition is discovered. Importantly, it was demonstrated that CAFs secrete elevated quantities of insulin-like growth factor–binding proteins (IGFBPs) that are both necessary for CAF-mediated anoikis inhibition and sufficient to block anoikis in the absence of CAFs. Furthermore, these data reveal a unique antiapoptotic mechanism for IGFBPs: the stabilization of the antiapoptotic protein Mcl-1. In aggregate, these data delineate a novel role for CAFs in promoting cell survival during detachment and unveil an additional mechanism by which the tumor microenvironment contributes to cancer progression. These results also identify IGFBPs as potential targets for the development of novel chemotherapeutics designed to eliminate detached cancer cells.
Implications: The ability of CAF-secreted IGFBPs to block anoikis in breast cancer represents a novel target for the development of therapeutics aimed at specifically eliminating extracellular matrix–detached breast cancer cells. Mol Cancer Res; 12(6); 855–66. ©2014 AACR.
Emerging Functions of SRSF1, Splicing Factor and Oncoprotein, in RNA Metabolism and Cancer
Authors: Das Shipra , Krainer Adrian R. 
Published: May 2014

Abstract
Serine/Arginine Splicing Factor 1 (SRSF1) is the archetype member of the SR protein family of splicing regulators. Since its discovery over two decades ago, SRSF1 has been repeatedly surprising and intriguing investigators by the plethora of complex biologic pathways it regulates. These include several key aspects of mRNA metabolism, such as mRNA splicing, stability, and translation, as well as other mRNA-independent processes, such as miRNA processing, protein sumoylation, and the nucleolar stress response. In this review, the structural features of SRSF1 are discussed as they relate to the intricate mechanism of splicing and the multiplicity of functions it performs. Similarly, a list of relevant alternatively spliced transcripts and SRSF1 interacting proteins is provided. Finally, emphasis is given to the deleterious consequences of overexpression of the SRSF1 proto-oncogene in human cancers, and the complex mechanisms and pathways underlying SRSF1-mediated transformation. The accumulated knowledge about SRSF1 provides critical insight into the integral role it plays in maintaining cellular homeostasis and suggests new targets for anticancer therapy. Mol Cancer Res; 12(9); 1195–204. ©2014 AACR.
Effectiveness of a Clinical Decision Support System for Reducing the Risk of QT Interval Prolongation in Hospitalized Patients
Authors: Tisdale James E. , Jaynes Heather A. , Kingery Joanna R. , Overholser Brian R. , Mourad Noha A. , Trujillo Tate N. , Kovacs Richard J. 
Published: May 2014

Background—
We evaluated the effectiveness of a computer clinical decision support system (CDSS) for reducing the risk of QT interval prolongation in hospitalized patients.

Methods and Results—

We evaluated 2400 patients admitted to cardiac care units at an urban academic medical center. A CDSS incorporating a validated risk score for QT
c
prolongation was developed and implemented using information extracted from patients’ electronic medical records. When a drug associated with torsades de pointes was prescribed to a patient at moderate or high risk for QT
c
interval prolongation, a computer alert appeared on the screen to the pharmacist entering the order, who could then consult the prescriber on alternative therapies and implement more intensive monitoring. QT
c
interval prolongation was defined as QT
c
interval >500 ms or increase in QT
c
of ≥60 ms from baseline; for patients who presented with QT
c
>500 ms, QT
c
prolongation was defined solely as increase in QT
c
≥60 ms from baseline. End points were assessed before (n=1200) and after (n=1200) implementation of the CDSS. CDSS implementation was independently associated with a reduced risk of QT
c
prolongation (adjusted odds ratio, 0.65; 95% confidence interval, 0.56–0.89;
P
<0.0001). Furthermore, CDSS implementation reduced the prescribing of noncardiac medications known to cause torsades de pointes, including fluoroquinolones and intravenous haloperidol (adjusted odds ratio, 0.79; 95% confidence interval, 0.63–0.91;
P
=0.03).

Conclusions—

A computer CDSS incorporating a validated risk score for QT
c
prolongation influences the prescribing of QT-prolonging drugs and reduces the risk of QT
c
interval prolongation in hospitalized patients with torsades de pointes risk factors.
Statins Improve Survival in Patients With Cardioembolic Stroke
Authors: Choi Jeong-Yoon , Seo Woo-Keun , Kang Sung Hoon , Jung Jin-Man , Cho Kyung-Hee , Yu Sungwook , Oh Kyungmi 
Published: May 2014

Background and Purpose—
The objective of this study was to investigate the potential benefits of statin therapy on mortality and stroke recurrence after cardioembolic stroke.

Methods—
In this retrospective observational study, we analyzed data from 535 patients with first-ever cardioembolic stroke. Patients were classified into nonstatin, low-potency statin, and high-potency statin groups. The primary outcomes were time to mortality and time to recurrent stroke.

Results—
The mean duration of follow-up was 22.2 months. The cumulative mortality rate was 7% at the end of the first year and 10% at the end of the third year. Statin therapy was independently associated with reduced mortality (hazard ratio, 0.237; 95% confidence interval, 0.080–0.703 for nonstatin versus low-potency statin; hazard ratio, 0.158; 95% confidence interval, 0.037–0.686 for nonstatin versus high-potency statin). Statin treatment did not affect the incidence of recurrent stroke in patients with cardioembolic stroke.

Conclusions—
Statin therapy could be associated with reduced mortality in patients with cardioembolic stroke.
Interaction between WSSV envelope protein VP31 and triosephosphate isomerase in haemocytes of the Chinese shrimp, Fenneropenaeus chinensis (Osbeck, 1765) (Decapoda, Penaeoidea)
Authors: Zhao J. M. , Tang X. Q. , Zhan W. B. 
Published: May 2014

To investigate the interaction between white spot syndrome virus (WSSV) envelope protein VP31 and haemocytes of the Chinese shrimp, Fenneropenaeus chinensis (Osbeck, 1765), the VP31 protein was recombinantly expressed in Escherichia coli (Migula, 1895) as a fusion protein with glutathione S-transferase tag (GST-tag). By Far Western Blotting, a prominent protein band of 26 kDa in haemocytes of F. chinensis was recognized by the recombinant VP31 (rVP31), which was identified as triosephosphate isomerase (TPI) by mass spectrometric analysis. Then, the TPI gene of F. chinensis was cloned and expressed as a fusion protein with thioredoxin/Histone/S-protein tag (Trx/His/S-tag) using the pET-32(a)+ vector, and the binding interaction between the recombinant TPI (rTPI) and rVP31 was further confirmed by pull-down assay. The expression of the TPI gene in haemocytes was significantly down-regulated in response to WSSV challenge. Moreover, the rTPI appeared to be able to partially block the WSSV infection and delay the death of infected shrimp in in vivo neutralization assay. These results indicate that TPI might play an important role in WSSV infection in F. chinensis.
Reflections on the Indictment of Sitting Heads of State and Government and Its Consequences for Peace and Stability and Reconciliation in Africa
Authors: Jalloh Charles Chernor 
Published: May 2014

Abstract
In these remarks, the author considers the most recent challenge to the application of international criminal justice in Africa: Kenya’s controversial November 2013 proposal to amend the Rome Statute of the International Criminal Court to temporarily exempt from prosecution sitting presidents accused of involvement with international crimes. He examines several legal and practical reasons why such a proposal is untenable. Instead, citing the principle of complementarity and urging the principled use of judicial and prosecutorial discretion, he contends that much of the African Union’s current concerns about the Kenya Situation can be addressed within the confines of existing Rome Law. This is important because, even if it is possible for African countries to secure amendments to the Rules of Procedure and Evidence, African States Parties are unlikely able to secure the global consensus required to effect substantive amendments to the 1998 treaty. On the other hand, the author suggests that the International Criminal Court officials, especially the judges and the chief prosecutor, can help bridge the apparent gap between the Court and its African supporters. Towards that end, they should consider taking a more flexible and more nuanced approach to their interpretations and application of several important provisions contained in their founding statute. Eschewing a one-size fits all approach, it is submitted that each African situation is unique – both in the scope of the problem, and in the solution required in the necessary fight against impunity in Africa.
Legitimacy of Regional Economic Integration Courts in Africa
Authors: Oppong Richard Frimpong 
Published: May 2014

Abstract
The expansion of economic integration initiatives in Africa has been accompanied by an increase in the number of regional courts currently operating on the continent. Four of these courts have been particularly active, spinning off judgments on issues ranging from the legality of national elections to the free movement of persons. There is a modest but growing body of scholarship on the jurisprudence of the courts. However, to date, there has been little or no attempt in the academic literature to examine the legitimacy of the courts. The issue of the courts’ legitimacy is important because of the potential impact of their judgments on national legal systems and policies. This paper examines that issue. While acknowledging that the concept of legitimacy is not free of debate, it identifies a number of factors that influence the legitimacy of international courts and applies them to the regional courts. An earlier draft of this paper was presented at a workshop on the legitimacy of international courts at the Centre for International and Comparative Law, Duke University School of Law.
Pope John XXII and the Michaelists
Authors: Brunner Melanie 
Published: May 2014

The theoretical poverty controversy in 1322–1323 concerned the question of the Franciscan doctrine that Christ and the apostles had renounced both individual and communal property. This article examines Pope John XXII’s final and often neglected text on the question of Franciscan poverty, the bull Quia vir reprobus published in 1329. It was only in this late bull that the pope addressed the question of the scriptural title of Franciscan poverty, and he used the bull to establish the (temporal) dominion of Christ through biblical exegesis. The middle section of John’s bull constitutes an almost completely self-contained treatise on the role of dominion in Scripture, and it is therefore as close as we can get to a personal statement of the pope on his own definition of both the dominion and the poverty of Christ. The pope’s preoccupation with the reconstruction of Christ’s lordship and poverty from biblical texts shows a different aspect of John XXII’s relationship with the Franciscans from the primarily legal argumentation in his earlier bulls, and it illustrates that his dissatisfaction with the Franciscan poverty ideal went beyond legal and administrative concerns.
Three-Way Chess
Authors: Krabbendam Hans 
Published: May 2014

By following the career and networks of Dutch missionary and diplomat Arie Kok (1883–1951), this essay explores the motives for creating a transatlantic fundamentalist network after World War II. Using private correspondence, interviews, institutional records, and periodicals, the essay demonstrates that the goal, means, and strategy of American fundamentalists tied them closely to other American Protestant groups active in postwar Europe. Apart from the exclusivist doctrine and antithetical style, which burdened the chances for positive cooperation among traditional Protestants, it was the national agenda of Carl McIntire, the American father of international fundamentalism that nullified Kok’s transnational endeavors. Despite these limitations, Kok succeeded briefly in captivating a group of Europeans, shaping the discourse and the religious activities of the Americans on the European continent, and causing the emerging evangelicals serious concern.
الخط الكوفي الهندسي الشكل حلية زخرفية بجامع البرديني بالقاهرة "دراسة تحليلية مقارنة" (Geometric Kufic Script A Decorative Ornament in al-Bardini Mosque in Cairo ‘A Comparative Analysis Study’)
Authors: محمد زكي أحمد احمد 
Published: May 2014

The Mosque of al-Khawaja Karim al-Din ibn Ahmad al-Bardini al-Shafei (1025-1038 AH/1616-1629 CE) monument no. 201, Daudi street, (previously Darb al-Fawakhir), north of Queen Safeya Mosque, Darb al-Ahmar, south of Cairo, in Mamluk style and its layout comprises a lounge perpendicular to it from the south-east is the Qibla Iwan (Mecca direction locator), with a curtain/drape on the inner left-side of its main door. It is perpendicular north- west to the lounge. The sheath is marble inlaid with mother-of-pearl in different areas, decorated with rectangular fillings including 12 star-shaped plates, and other various geometric motifs. This paper deals with the geometric kufic script in the Mosque. The author reads each inscription, carefully analyzes it, measures it, and compares it to other similar samples from previous historical periods.
(Please note that this article is in Arabic)
How Well Are the Distribution and Extreme Values of Daily Precipitation over North America Represented in the Community Climate System Model? A Comparison to Reanalysis, Satellite, and Gridded Station Data
Authors: Gervais Melissa , Gyakum John R. , Atallah Eyad , Tremblay L. Bruno , Neale Richard B. 
Published: May 2014

AbstractAn intercomparison of the distribution and extreme values of daily precipitation between the National Center for Atmospheric Research Community Climate System Model, version 4 (CCSM4) and several observational/reanalysis data sources are conducted over the contiguous United States and southern Canada. The use of several data sources, from gridded station, satellite, and reanalysis products, provides a measure of errors in the reference datasets. An examination of specific locations shows that the global climate model (GCM) distributions closely match the observations along the East and West Coasts, with larger discrepancies in the Great Plains and Rockies. In general, the distribution of model precipitation is more positively skewed (more light and less heavy precipitation) in the Great Plains and the eastern United States compared to gridded station observations, a recurring error in GCMs. In the Rocky Mountains the GCMs generally overproduce precipitation relative to the observations and furthermore have a more negatively skewed distribution, with fewer lower daily precipitation values relative to higher values. Extreme precipitation tends to be underestimated in regions and time periods typically characterized by large amounts of convective precipitation. This is shown to be the result of errors in the parameterization of convective precipitation that have been seen in previous model versions. However, comparison against several data sources reveals that model errors in extreme precipitation are approaching the magnitude of the disparity between the reference products. This highlights the existence of large errors in some of the products employed as observations for validation purposes.
Midlatitude Moisture Contribution to Recent Arctic Tropospheric Summertime Variability*
Authors: Laliberté Frédéric , Kushner Paul J. 
Published: May 2014

AbstractThe dynamics of late summer Arctic tropospheric heat content variability is studied using reanalyses. In both trends and interannual variability, much of the August heat content variability in the Arctic midtroposphere can be explained by the total—sensible plus latent—heat content variability at the midlatitude near surface in July. Climate models suggest that this connection is part of the global warming signal in September–November, but in reanalyses the connection is most strongly present in July–August variability and trends. It is argued that heat content signals are propagated from the midlatitude near surface to the Arctic midtroposphere approximately along climatological moist isentropes. High-frequency data reveal that the propagating signal is primarily driven by a few strong meridional heat flux events each summer season. Composite analysis on these events shows that August meridional heat fluxes into the Arctic midtroposphere are succeeded by positive heat content anomalies in the lower troposphere a few days later. This second connection between the Arctic midtroposphere and the Arctic lower troposphere could be sufficient to explain some of the recent Arctic 850-hPa temperature variability north of 75°N.
Are commonly used paediatric reference intervals for water and electrolyte balance appropriate for clinical use?
Authors: Dodd Alan , El-Farhan Nadia , Moat Stuart 
Published: May 2014

Background: Paediatric reference intervals are less well characterized than in adults. An initiative for harmonization of pathology across the United Kingdom has recommended an interval for sodium of 133–146 mmol/L at all ages. Methods: To assess the validity of this, the laboratory database was interrogated for all renal profiles (sodium, potassium, urea and creatinine) for children presenting to primary care over a 13-year period. While the primary interest was in sodium results, sufficient current data were also available for potassium and creatinine and so these were included for study. The electrolyte results were filtered to include only normal renal function and the remaining data were analysed for age-related differences. Results: Sodium concentrations were observed to be lower for infants (1–5 years of age) with a mean of 138 mmol/L, increasing towards adult concentrations (mean 140 mmol/L) by teenage years. A similar pattern was seen for potassium results, and creatinine was seen to increase with age. At all ages, the distributions of sodium concentrations measured in this population were observably tighter than the interval of 133–146 mmol/L recommended by Pathology Harmony. Conclusions: We suggest that this interval is too wide, and more work is needed to establish more appropriate paediatric ranges.