bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of MEK and PI3K/mTOR Suppresses Tumor Growth but Does Not Cause Tumor Regression in Patient-Derived Xenografts of RAS-Mutant Colorectal Carcinomas
Authors: Migliardi Giorgia , Sassi Francesco , Torti Davide , Galimi Francesco , Zanella Eugenia R. , Buscarino Michela , Ribero Dario , Muratore Andrea , Massucco Paolo , Pisacane Alberto , Risio Mauro , Capussotti Lorenzo , Marsoni Silvia , Di Nicolantonio Federica , Bardelli Alberto , Comoglio Paolo M. , Trusolino Livio , Bertotti Andrea 
Published: March 2012

Abstract
Purpose: Gene mutations along the Ras pathway (KRAS, NRAS, BRAF, PIK3CA) occur in approximately 50% of colorectal cancers (CRC) and correlate with poor response to anti–EGF receptor (EGFR) therapies. We assessed the effects of mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK) and phosphoinositide 3-kinase (PI3K)/mTOR inhibitors, which neutralize the major Ras effectors, in patient-derived xenografts from RAS/RAF/PIK3CA-mutant metastatic CRCs (mCRC).
Experimental Design: Forty mCRC specimens harboring KRAS, NRAS, BRAF, and/or PIK3CA mutations were implanted in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Each xenograft was expanded into four treatment arms: placebo, the MEK inhibitor AZD6244, the PI3K/mTOR inhibitor, BEZ235, or AZD6244 + BEZ235. Cases initially treated with placebo crossed over to AZD6244, BEZ235, and the anti-EGFR monoclonal antibody cetuximab.
Results: At the 3-week evaluation time point, cotreatment of established tumors with AZD6244 + BEZ235 induced disease stabilization in the majority of cases (70%) but did not lead to overt tumor regression. Monotherapy was less effective, with BEZ235 displaying higher activity than AZD6244 (disease control rates, DCRs: AZD6244, 27.5%; BEZ235, 42.5%). Triple therapy with cetuximab provided further advantage (DCR, 88%). The extent of disease control declined at the 6-week evaluation time point (DCRs: AZD6244, 13.9%; BEZ235, 16.2%; AZD6244 + BEZ235, 34%). Cross-analysis of mice harboring xenografts from the same original tumor and treated with each of the different modalities revealed subgroups with preferential sensitivity to AZD6244 (12.5%), BEZ235 (35%), or AZD6244 + BEZ235 (42.5%); another subgroup (10%) showed equivalent response to any treatment.
Conclusions: The prevalent growth-suppressive effects produced by MEK and PI3K/mTOR inhibition suggest that this strategy may retard disease progression in patients. However, data offer cautionary evidence against the occurrence of durable responses. Clin Cancer Res; 18(9); 2515–25. ©2012 AACR.
Whole Blood Stem Cell Reinfusion and Escalated Dose Melphalan in Castration-Resistant Prostate Cancer: A Phase 1 Study
Authors: Shamash Jonathan , Jacob Jimmy , Agrawal Samir , Powles Thomas , Mutsvangwa Katherine , Wilson Peter , Stebbing Justin 
Published: March 2012

Abstract
Purpose: Nontaxane-based chemotherapeutic options in castrate-resistant prostate cancer (CRPC) are limited despite the long natural history of the disease. We carried out a phase 1 dose-escalation study of the alkylating agent melphalan with autologous stem cell transplantation, comparing rapid changes in circulating tumor cells (CTC) and prostate-specific antigen (PSA) as a measure of response.
Experimental Design: Cohorts of individuals with advanced CRPC received high-dose intravenous melphalan, and autologous blood was returned to patients during treatment. The efficacy endpoints were the PSA reduction rate, CTC response, survival parameters, toxicity and whether reinduction of endocrine sensitivity occurred.
Results: Twenty-four patients were recruited. Dose escalation was feasible with the highest dose cohort being reached. Of 23 individuals evaluable for response, 16 had a PSA response of more than 30%; of 11 patients with soft tissue disease, 4 achieved a partial response and 7 had stable disease. Patients with CTC counts that decreased to less than 5 within 2 weeks from the start of therapy had a longer overall survival (30.6 months vs. 15.3 months, P = 0.03) Treatment was associated with myelosuppression and frequent hospitalizations. In 20 patients after the study, hormone therapy was reintroduced when PSA increased again; response rates were high.
Conclusions: Autologous transplantation following high-dose alkylating agent chemotherapy induces responses but proved toxic, although dose escalation proved possible. The possibility of using CTCs to identify responders at two weeks may be used to justify such an intensive approach. Many individuals went on to further respond to both docetaxel and hormonal therapy. Clin Cancer Res; 18(8); 2352–9. ©2012 AACR.
Rapid High Resolution Electroanatomical Mapping
Authors: Nakagawa Hiroshi , Ikeda Atsushi , Sharma Tushar , Lazzara Ralph , Jackman Warren M. 
Published: March 2012

Background—
A canine right atrial (RA) linear lesion model was used to produce a complex pattern of RA activation to evaluate a novel mapping system for rapid, high resolution (HR) electroanatomical mapping.

Methods and Results—
The mapping system (Rhythmia Medical, Incorporated) uses an 8F deflectable catheter with a minibasket (1.8 cm diameter), containing 8 splines of 8 electrodes (total 64 electrodes, 2.5 mm spacing). The system automatically acquires electrograms and location information based on electrogram stability and respiration phase. In 10 anesthetized dogs, HR-RA map was obtained by maneuvering the minibasket catheter during sinus rhythm and coronary sinus pacing. A right thoracotomy was performed, and either 1 or 2 (to create a gap) epicardial linear lesions were created on the RA free wall (surgical incision or epicardial radiofrequency lesions). RA maps during RA pacing close to the linear lesions were obtained. A total of 73 maps were created, with 44 to 729 (median 237) beats and 833 to 12 412 (median 3589) electrograms (≤2 to ≤5 mm from surface geometry), resolution 1.8 to 5.3 (median 2.7) mm, and 2.6 to 26.3 (median 7.3) minutes mapping time. Without manual annotation, the system accurately created RA geometry and demonstrated RA activation, identifying the location of lines of block and presence or absence of a gap in all 10 dogs. Endocardial radiofrequency catheter ablation of a gap (guided by activation map) produced complete block across the gap in all 3 dogs tested.

Conclusions—
The new HR mapping system accurately and quickly identifies geometry and complex patterns of activation in the canine RA, with little or no manual annotation of activation time.
The Possibility of Theomusicology: William Bradbury’s Esther, the Beautiful Queen
Authors: Karpf Juanita 
Published: March 2012

AbstractAfrican-American scholar, theologian, and musician Jon Michael Spencer issued his initial publications on his theory of theomusicology in 1986. As an alternative to more traditional musicologies, Spencer specifies theomusicology as a theoretical model of theologically, biblically, and spiritually-informed historical and analytical studies in music, of particular appropriateness to African-American music making. Theomusicology redirects the analytical and critical objectivity of musicologies to facilitate concentration on iterations of ethical, religious, and mythological beliefs, regardless of their medium, location, and cultural function. It seeks ways to describe the synthesis of the sacred and profane—the meshing of seeming opposites. This article explores the application of theomusicology to African-American performances of a popular large-scale vocal work entitled,Esther, the Beautiful Queen, written in 1856 by U.S. composer William Bradbury.
An EU Immigration Code: Towards a Common Immigration Policy
Authors: Peers Steve 
Published: March 2012

Abstract
The Commission is planning to propose an EU immigration code in 2013. This will be an opportunity to revise the existing EU legislation in order to enhance standards and procedural rights for migrants, as well as to improve its clarity and coherence. This article discusses the key issues which the Code should address, and suggests a list of amendments which it should adopt. It is accompanied by a complete proposal for a text of the Code, published online.
Does an Extension of Time Clause Prevent a Construction Contract Being Infected by Gharar?
Authors: Crawley Shaun 
Published: March 2012

Abstract
This article examines how gharar can infect a construction contract and if and how the extension of time and additional payment clauses can operate to negate the effect of gharar, and whether such provisions are compliant with the relevant articles of Law No. 1, 1987. This is done by identifying how gharar can infect a construction contract, reviewing the applicable laws that apply with respect to a construction contract and then the relevant provisions of FIDIC, Employer’s design forms of Contract.
The Constitutionality of the Jordanian Law of Election to the House of Deputies of 2010
Authors: Nasrawin Laith K. 
Published: March 2012

Abstract
This article examines the constitutionality of the Law of Election to the Jordanian House of Deputies No. (9) for 2010. This law was introduced as a Provisional Law by the Executive, owing to the absence of legislative authority. The power of the Executive to decree provisional laws is constitutionally recognised; nevertheless, specific conditions in Article 94 of the Jordanian Constitution still apply. The Provisional Law of Election raises concerns regarding its adherence to the provision of Article 94, which makes its compliance with the Constitution questionable. Therefore, this article examines to what extent the conditions of Article 94 apply to the new Law of Election so that, in the event that one or more of the conditions are missing, the law should be deemed unconstitutional. This article concludes that the condition of ‘a state of necessity’ is not applicable, and, as such, the new Law of Election could be classified as unconstitutional.
The Force Majeure ‘Excuse’
Authors: Azfar Fareya 
Published: March 2012

Abstract
This article elucidates the general meaning, concept, and scope of the legal doctrine of ‘force majeure’. It deals briefly with the concept and application of force majeure in the United Arab Emirates and addresses specifically whether, and if so, and when economic recession can amount to a force majeure excuse. Furthermore, the article also explains the application and impact of the ‘catch-all’ phrases that are used to define force majeure in many prevailing agreements, which are the subject matter of disputes today.
Rights of a Wife in the Case of Conversion to Islam under Family Law in Malaysia
Authors: Hak Nora Abdul 
Published: March 2012

Abstract
This article focuses on the issues of conversion to Islam of one party to a non-Muslim marriage. In Malaysia, some legal problems need to be addressed, particularly concerning the rights of a wife to the ancillary claims after dissolution of the marriage such as maintenance, matrimonial property and custody. These issues have been discussed by the Malaysian courts in their judgments when they preside over cases involving conversion to Islam. Among the issues that have been raised is whether a non-Muslim wife is entitled to maintenance after her husband has converted to Islam and, if she is still entitled, for how long. Other problems concern which party shall be entitled to custody of any children as well as the legal status of the marriage. All these issues need to be discussed further as to whether amendment of the existing relevant law is necessary. This article analyses the legal provisions and the cases that have been decided by the Malaysian courts on conversion to Islam.
Building a South African Human Rights Culture in the Face of Cultural Diversity: Context and Conflict
Authors: Mubangizi John Cantius 
Published: March 2012

Abstract
South Africa has faced enormous challenges since the advent of democracy in 1994. One of the difficulties in the post-apartheid era has been the building of a human rights culture in the context of substantial cultural diversity. In this paper, the constitutional, judicial and institutional contexts – which have consolidated and supported the expression of human rights in the face of cultural diversity – are reviewed. The focus on cultural rights in the constitution is discussed, and the relevance of several constitutional institutions in terms of ensuring human rights, is mentioned. With a clear understanding of the constitutional, judicial and institutional contexts in place, the paper discusses the potentially inherent conflict between human rights and cultural rights, using gender-related issues as a proxy. Several examples of this potential conflict are discussed, including female circumcision, virginity testing and polygamy. The importance of human rights education for informing the debate about cultural and human rights in South Africa is emphasized. The answers to the challenges associated with the clash between cultural rights and human rights are not simple, although pragmatically – in addition to the role of the available constitutional, judicial and institutional structures – they could reside in a cross-cultural debate.
Comparison of Objective Supercell Identification Techniques Using an Idealized Cloud Model
Authors: Naylor Jason , Gilmore Matthew S. , Thompson Richard L. , Edwards Roger , Wilhelmson Robert B. 
Published: March 2012

AbstractThe accuracy, reliability, and skill of several objective supercell identification methods are evaluated using 113 simulations from an idealized cloud model with 1-km horizontal grid spacing. Horizontal cross sections of vorticity and radar reflectivity at both mid- and low levels were analyzed for the presence of a supercell, every 5 min of simulation time, to develop a “truth” database. Supercells were identified using well-known characteristics such as hook echoes, inflow notches, bounded weak-echo regions (BWERs), and the presence of significant vertical vorticity.The three objective supercell identification techniques compared were the Pearson correlation (PC) using an analysis window centered on the midlevel storm updraft; a modified Pearson correlation (MPC), which calculates the PC at every point in the horizontal using a small 3 km × 3 km analysis window; and updraft helicity (UH). Results show that the UH method integrated from 2 to 5 km AGL, and using a threshold value of 180 m2 s−2, was equally as accurate as the MPC technique—averaged from 2 to 5 km AGL and using a minimum updraft threshold of 7 m s−1 with a detection threshold of 0.3—in discriminating between supercells and nonsupercells for 1-km horizontal grid spacing simulations. At courser resolutions, the UH technique performed best, while the MPC technique produced the largest threat scores for higher-resolution simulations. In addition, requiring that the supercell detection thresholds last at least 20 min reduced the number of false alarms.
Lightning in the Anvils of Supercell Thunderstorms
Authors: Weiss Stephanie A. , MacGorman Donald R. , Calhoun Kristin M. 
Published: March 2012

AbstractThis study uses data from the Oklahoma Lightning Mapping Array (OK-LMA), the National Lightning Detection Network, and the Norman, Oklahoma (KOUN), prototype Weather Surveillance Radar-1988 Doppler (WSR-88D) radar to examine the evolution and structure of lightning in the anvils of supercell storms as they relate to storm dynamics and microphysics. Several supercell storms within the domain of the OK-LMA were examined to determine whether they had lightning in the anvil region, and if so, the time and location of the initiation of the anvil flashes were determined. Every warm-season supercell storm had some flashes that were initiated in or near the stronger reflectivities of the parent storm and propagated 40–70 km downstream to penetrate well into the anvil. Some supercell storms also had flashes that were initiated within the anvil itself, 40–100 km beyond the closest 30-dBZ contour of the storm. These flashes were typically initiated in one of three locations: 1) coincident with a local reflectivity maximum, 2) between the uppermost storm charge and a screening-layer charge of opposite polarity near the cloud boundary, or 3) in a region in which the anvils from two adjoining storms intersected. In some storms, anvil flashes struck ground beneath a reflectivity maximum in which reflectivity ≥20 dBZ had extended below the 0°C isotherm, possibly leading to the formation of embedded convection. This relationship may be useful for identifying regions in which there is a heightened risk for cloud-to-ground strikes beneath anvil clouds. In one storm, however, anvil lightning struck ground even though this reflectivity signature was absent.
Synoptic Composites of Tornadic and Nontornadic Outbreaks
Authors: Mercer Andrew E. , Shafer Chad M. , Doswell Charles A. , Leslie Lance M. , Richman Michael B. 
Published: March 2012

Abstract
Tornadic and nontornadic outbreaks occur within the United States and elsewhere around the world each year with devastating effect. However, few studies have considered the physical differences between these two outbreak types. To address this issue, synoptic-scale pattern composites of tornadic and nontornadic outbreaks are formulated over North America using a rotated principal component analysis (RPCA). A cluster analysis of the RPC loadings group similar outbreak events, and the resulting map types represent an idealized composite of the constituent cases in each cluster. These composites are used to initialize a Weather Research and Forecasting Model (WRF) simulation of each hypothetical composite outbreak type in an effort to determine the WRF’s capability to distinguish the outbreak type each composite represents.
Synoptic-scale pattern analyses of the composites reveal strikingly different characteristics within each outbreak type, particularly in the wind fields. The tornado outbreak composites reveal a strong low- and midlevel cyclone over the eastern Rockies, which is likely responsible for the observed surface low pressure system in the plains. Composite soundings from the hypothetical outbreak centroids reveal significantly greater bulk shear and storm-relative environmental helicity values in the tornado outbreak environment, whereas instability fields are similar between the two outbreak types. The WRF simulations of the map types confirm results observed in the composite soundings.
‘Something to Smile About’: An evaluation of a capacity-building oral health intervention for staff working with homeless people
Authors: Coles Emma , Watt Celia , Freeman Ruth 
Published: March 2012

Objective: To use a qualitative exploration to evaluate whether ‘Something to Smile About’ (STSA), an oral health intervention, had increased the oral health capacity of staff working with homeless people. Setting: A National Health Service board area in Scotland. Method: A purposive sample of 14 staff members from STSA-participating organizations took part in the evaluation. Three focus groups were held and the participants were encouraged to speak freely about their views on the intervention. The qualitative data was analyzed using content analysis. Results: The majority of participants stated they were able to use their newly-acquired oral health knowledge and pass it to their homeless clients. STSA appeared to be less successful with regard to assisting clients to change their oral health behaviours. Staff felt that oral health considerations were a low priority compared to the need for shelter, food, clothing and money. In addition, they stated that the level of success with clients was influenced by the homeless person’s specific and complex needs. Conclusion: STSA was successful in building staff oral health capacity; however, for STSA to be successful with clients, and for clients to achieve adherence with oral health messages, the complex needs and current life circumstances of homeless client groups must be incorporated into STSA.
The use of outpatient mental health care services of migrants vis-à-vis Dutch natives: Equal access?
Authors: Koopmans GT , Uiters E , Devillé W , Foets M 
Published: March 2012

Background: Although the use of outpatient mental health care services by migrants in the Netherlands has increased in recent years, whether it aligns with the need for care is unclear. Aims: To investigate ethnic-related differences in utilization in outpatient mental health care, taking need into account, and to examine whether socio-economic or cultural barriers explain such differences. Methods: Data for the native population was taken from the second Dutch National Survey of General Practice ( N = 7,772). An additional random sample was drawn ( N = 1,305) from four migrant groups (Surinamese, Dutch Antilleans, Moroccans and Turks) living in the Netherlands. Participants were surveyed on mental health care utilization, indicators of need, educational level, proficiency in Dutch and acculturation. Results: Use of outpatient mental health care was about 5% for the indigenous population. Among migrants, percentages of use ranged from 6.5% (Moroccans) to 9.0% (Turks). Corrected for need, however, all non-Dutch groups had a lower chance of service utilization than the native group. Acculturation predicted utilization but did not explain all ethnic-related differences; proficiency in Dutch and health beliefs were not explanatory factors. Conclusions: In non-Dutch-speaking migrant groups, utilization is about half the level of the native Dutch, suggesting that a substantial gap exists. Our study found that acculturation only partially explains the differences.