bluuebunny/crossref_metadata_2025_split huggingface dataset:
Amplification of CRKL Induces Transformation and Epidermal Growth Factor Receptor Inhibitor Resistance in Human Non–Small Cell Lung Cancers
Authors: Cheung Hiu Wing , Du Jinyan , Boehm Jesse S. , He Frank , Weir Barbara A. , Wang Xiaoxing , Butaney Mohit , Sequist Lecia V. , Luo Biao , Engelman Jeffrey A. , Root David E. , Meyerson Matthew , Golub Todd R. , Jänne Pasi A. , Hahn William C. 
Published: October 2011

Abstract
We previously identified a region of recurrent amplification on chromosome 22q11.21 in a subset of primary lung adenocarcinomas. Here we show that CRKL, encoding for an adaptor protein, is amplified and overexpressed in non–small cell lung cancer (NSCLC) cells that harbor 22q11.21 amplifications. Overexpression of CRKL in immortalized human airway epithelial cells promoted anchorage-independent growth and tumorigenicity. Oncogenic CRKL activates the SOS1-RAS-RAF-ERK and SRC-C3G-RAP1 pathways. Suppression of CRKL in NSCLC cells that harbor CRKL amplifications induced cell death. Overexpression of CRKL in epidermal growth factor receptor (EGFR)-mutant cells induces resistance to gefitinib by activating extracellular signal–regulated kinase and AKT signaling. We identified CRKL amplification in an EGFR inhibitor–treated lung adenocarcinoma that was not present before treatment. These observations demonstrate that CRKL overexpression induces cell transformation, credential CRKL as a therapeutic target for a subset of NSCLC that harbor CRKL amplifications, and implicate CRKL as an additional mechanism of resistance to EGFR-directed therapy.
Significance: These studies credential CRKL as an oncogene in a subset of NSCLC. Overexpression of CRKL induces cell transformation and resistance to epidermal growth factor receptor inhibitor treatment and suggest that therapeutic interventions targeting CRKL may confer a clinical benefit in a defined subset of NSCLCs. Cancer Discovery; 1(7); 608–25. ©2011 AACR.
Read the Commentary on this article by Ladanyi, p. 560
This article is highlighted in the In This Issue feature, p. 539
Monocyte Chemotactic Protein-1 Promotes Inflammatory Vascular Repair of Murine Carotid Aneurysms via a Macrophage Inflammatory Protein-1α and Macrophage Inflammatory Protein-2–Dependent Pathway
Authors: Hoh Brian L. , Hosaka Koji , Downes Daniel P. , Nowicki Kamil W. , Fernandez Cristina E. , Batich Christopher D. , Scott Edward W. 
Published: October 2011

Background—
Up to 5% of the population may have a brain aneurysm. If the brain aneurysm ruptures, there is >50% mortality, and more than one third of survivors are dependent. Brain aneurysms detected before rupture can be treated to prevent rupture, or ruptured aneurysms can be treated to prevent rerupture. Endovascular coiling of brain aneurysms is the treatment of choice for some aneurysms; however, up to one quarter of aneurysms may recur. The coiled aneurysms that do not recur are characterized by inflammatory intra-aneurysmal tissue healing; therefore, we studied the biology of this process, specifically the role of monocyte chemotactic protein-1 (MCP-1), a cytokine known for tissue healing.

Methods and Results—

We created coils with a 50:50 poly-
dl
-lactic glycolic acid (PLGA) coating that released MCP-1 at 3 different doses (100 μg/mL, 1 mg/mL, and 10 mg/mL) and performed a dose-response study for effect on intra-aneurysmal tissue healing in a murine carotid aneurysm model. We then demonstrated that MCP-1 (100 μg/mL)–releasing coils promote significantly greater aneurysm tissue in-growth than bare platinum or PLGA-only coils. We show that MCP-1 recruits the migration of fibroblasts, macrophages, smooth muscle cells, and endothelial cells in vitro in cell migration assays and in vivo in murine carotid aneurysms. Using
gfp
+
bone marrow-transplant chimeric mice, we demonstrate that the MCP-1–recruited fibroblasts and macrophages are derived from the bone marrow. We demonstrate that this MCP-1–mediated vascular inflammatory repair occurs via a macrophage inflammatory protein (MIP)-1α– and MIP-2–dependent pathway. MCP-1 released from coiled murine aneurysms causes significant upregulation of MIP-1α and MIP-2 expression by cytokine array assay. Blocking MIP-1α and MIP-2 with antagonist antibody causes a significant decrease in MCP-1–mediated intra-aneurysmal tissue healing.

Conclusion—
Our findings suggest that MCP-1 has a critical role in promoting inflammatory intra-aneurysmal tissue healing in an MIP-1α– and MIP-2–dependent pathway.
Improved Cardiac Risk Assessment With Noninvasive Measures of Coronary Flow Reserve
Authors: Murthy Venkatesh L. , Naya Masanao , Foster Courtney R. , Hainer Jon , Gaber Mariya , Di Carli Gilda , Blankstein Ron , Dorbala Sharmila , Sitek Arkadiusz , Pencina Michael J. , Di Carli Marcelo F. 
Published: October 2011

Background—
Impaired vasodilator function is an early manifestation of coronary artery disease and may precede angiographic stenosis. It is unknown whether noninvasive assessment of coronary vasodilator function in patients with suspected or known coronary artery disease carries incremental prognostic significance.

Methods and Results—

A total of 2783 consecutive patients referred for rest/stress positron emission tomography were followed up for a median of 1.4 years (interquartile range, 0.7–3.2 years). The extent and severity of perfusion abnormalities were quantified by visual evaluation of myocardial perfusion images. Rest and stress myocardial blood flows were calculated with factor analysis and a 2-compartment kinetic model and were used to compute coronary flow reserve (coronary flow reserve equals stress divided by rest myocardial blood flow). The primary end point was cardiac death. Overall 3-year cardiac mortality was 8.0%. The lowest tertile of coronary flow reserve (<1.5) was associated with a 5.6-fold increase in the risk of cardiac death (95% confidence interval, 2.5–12.4;
P
<0.0001) compared with the highest tertile. Incorporation of coronary flow reserve into cardiac death risk assessment models resulted in an increase in the c index from 0.82 (95% confidence interval, 0.78–0.86) to 0.84 (95% confidence interval, 0.80–0.87;
P
=0.02) and in a net reclassification improvement of 0.098 (95% confidence interval, 0.025–0.180). Addition of coronary flow reserve resulted in correct reclassification of 34.8% of intermediate-risk patients (net reclassification improvement=0.487; 95% confidence interval, 0.262–0.731). Corresponding improvements in risk assessment for mortality from any cause were also demonstrated.

Conclusion—
Noninvasive quantitative assessment of coronary vasodilator function with positron emission tomography is a powerful, independent predictor of cardiac mortality in patients with known or suspected coronary artery disease and provides meaningful incremental risk stratification over clinical and gated myocardial perfusion imaging variables.
Regulating Germ-Line Gene Therapy to avoid Sliding down the Slippery Slope
Authors: Pattinson Shaun D. 
Published: October 2011

Many arguments can be made for or against various regulatory approaches towards germ-line gene therapy and its associated research. A popular conclusion is that it ought to be prohibited, and this is commonly defended by use of a slippery slope argument. This paper will begin by outlining the regulatory approaches adopted towards germ-line gene therapy in EU countries, demonstrating the popularity of the restrictive approach. The slippery slope argument will then be examined. A number of variants of the slippery slope argument will be distinguished, highlighting the conceptually different claims made by each. Finally, examples of slippery slope arguments often invoked to support the prohibition of germ-line gene therapy will be examined with regard to the conditions that each must satisfy to form a theoretically sound argument. I will argue that these conditions are rarely given sufficient consideration. For the purposes of this paper, “germ-line gene therapy” is defined as the deliberate genetic modification of germ cells (sperm or oocytes), their precursors, or the cells of early embryos where the germ-line1 has yet to be segregated.
Vaccination and other Altruistic Medical Treatments: Should Autonomy or Communitarianism Prevail?
Authors: Pywell Stephanie 
Published: October 2011

The publication of a report into a case where an organ donor's constraints on the race of potential recipients raises questions about whether respect for autonomy or communitarianism should prevail in altruistic medical procedures. This article briefly reviews how autonomy and communitarianism are balanced in cadaveric and live organ donation, bone marrow donation, gamete donation, blood donation and vaccination. It criticises vaccination policy for ostensibly respecting patient autonomy yet in practice compromising that autonomy in various ways. Vaccination is properly viewed as an altruistic medical procedure because some vaccines are of more good to society than to the vaccinee, who runs associated health risks. The conclusion is that there is a spectrum of attitudes to the value of autonomy, depending principally upon the invasiveness of the procedure. In most cases the autonomy-communitarianism balance is satisfactory, but this is not so in respect of cadaveric organ donation and vaccination. The article proposes that cadaveric organ donation should be governed by the communitarian law of well-publicised presumed consent. It proposes two alternatives for vaccination: that vaccination should be compulsory or, preferably, that procedures be modified so that parents have real autonomy in their decisions whether to vaccinate their children.
Expert Witnesses in Child Sexual Abuse Cases
Authors: Keenan Caroline , Williams Catherine 
Published: October 2011

This paper aims to look at the relationship between the courts and the witnesses, who, as experts in their particular discipline, give evidence to the court. It focuses particularly on civil cases relating to child sexual abuse. It asks what the court considers an expert to be and what is expected of an expert in court proceedings. It then goes on to look at the problems within that relationship and their possible solutions. “If matters arise in our law which concern other sciences or faculties, we commonly apply for the aid of that science or faculty which it concerns. This is a commendable thing in our law. For thereby it appears that we do not dismiss all other sciences but our own, but we approve of them and encourage them as things worthy of commendation”. 1
The Role of the Human Fertilisation and Embryology Authority
Authors: Hagger Lynn 
Published: October 2011

The recent publicity surrounding Diane Blood and the theoretical possibility of cloning human beings has highlighted yet again the important role of the Human Fertilisation and Embryology Authority (HFEA). It will be remembered that Mrs Blood sought to establish a right to be inseminated with her dead husband's sperm without his written consent. The HFEA, following the strict letter of the Human Fertilisation and Embryology Act 1990, withheld its permission for the procedure. Following a Court of Appeal decision to allow Mrs Blood access to treatment abroad the Department of Health commissioned an independent ethicist to address the relevant issues. The use of such an expert which avoids any potential conflicts of interest, when the body has many members with the relevant expertise, is another example of how important the HFEA's integrity is viewed. It strives to act in an exemplary manner in the often hostile environment of uninformed public concern and against a backdrop of a statutory framework that is generally thought to suffer from a democratic deficit. This article will provide an outline of the HFEA's background, structure and manner of operation in an attempt to demonstrate that it offers a model of regulation for the new reproductive technologies despite the constraints it faces.
Article commentary: Case Commentary Anonymisation is Not Exoneration
Authors: Beyleveld Deryck , Histed Elise 
Published: October 2011

This case commentary analyses a ruling that any use of information given in confidence for unconsented purposes is a breach of confidence capable of supporting a legal action (even if the information has previously been anonymised and aggregated). The ruling is being appealed. It is argued that, while it is reasonable to delineate a narrower duty of confidentiality (not to disclose personal information, against breach of which anonymisation protects), this must be within a broad duty of confidence (not to use private information, which using anonymous information can still breach). Thus, the ruling is fundamentally correct in holding that anonymisation does not permit information obtained in confidence to be used for unconsented purposes. This, however, implies that information obtained for a patient's treatment may not be used lawfully for medical research or NHS management purposes without consent, even if it is anonymised. Such a consequence is unacceptable as a matter of public policy. However, it is equally unacceptable to seek an exemption through the idea that patients give “implied consent” for medical research and NHS management purposes. It is also unacceptable to maintain that the public interest in medical research ( regardless of its aims) justifies unconsented use of information obtained in confidence, even if the information is anonymised. The way in which Section 33 of the Data Protection Act 1998 creates an exemption to its Second Data Protection Principle provides a ready-made model for a public interest based exemption for medical research and statistical NHS purposes.
Entrenching Equality by Countering Racism in South Africa: A Legislative Brief
Authors: February Judith , Abrahams Lynne 
Published: October 2011

The Constitutional prohibition on unfair discrimination seeks to place equality and the preservation of fundamental human dignity at the heart of South Africa's nascent democracy. The Constitutional ideal is that all South Africans are regarded as equal and deserving of respect. More than that, however, the Constitution also allows for measures to redress the inequalities which resulted from the previous system of racial oppression. By becoming a signatory to the International Convention on the Elimination of all Forms of Racial Discrimination on 10 December 1998 South Africa took upon ‘itself certain obligations, namely, to promote equality and prohibit unfair discrimination. South Africa has shown itself to be committed to reconciling its racially diverse population, although, predictably perhaps, the attempts at nation-building over the past seven years have not been without difficulty. This brief attempts to examine the current legislation that exists to combat racism in South Africa; The Constitution, the Employment Equity Act, the Promotion of Equality and Prevention of Discrimination Act and ancillary legislation such as the Labour Relations Act. It will ask whether there are any obstacles to the implementation of such legislation. Lastly it will examine the body of law which the judiciary has developed on equality and racial equality in particular.
Sexual Harassment in the Workplace: A United States Perspective
Authors: Kelly Joseph M. , Kadue David D. , Mignin Robert J. 
Published: October 2011

Sexual harassment litigation has increased significantly within the United States. It is a cause of action that was created by the judiciary to enable an employee to work in an atmosphere free from a sexually hostile environment. Some parameters of U.S. sexual harassment law are still unclear, but the law now applies to men and women, and the burden of proof has gradually been eased. Under judge-made law, an employer will always be liable when harassment culminates in a tangible employment detriment. The employer is also automatically liable when a supervisor creates a hostile environment, unless the employer can prove that it has taken reasonable steps to prevent or correct harassment and that the employee unreasonably failed to use the employer's anti-harassment procedures. Employers are also liable for harassment perpetrated by supervisors, co-workers and non-employees if the employer is negligent in failing to prevent or correct harassment. Employers are thus well advised to formulate and enforce an anti-harassment workplace policy that allows a complainant to have a thorough, impartial and prompt investigation of any allegation of harassment. Complainants can elect to use federal-law and state-law remedies for sexual harassment/discrimination. The state law, unlike the federal, may allow unlimited tort-like damages. A complainant may also allege common law causes of action such as infliction of emotional distress.
Sexual Harassment: The South African Perspective
Authors: Govender Sandra 
Published: October 2011

Sexual harassment is not a new phenomenon in South Africa but until recently nothing significant was done to address it. The problem is currently being addressed through legislation aimed at prevention and eradication. Sexual harassment in the employment environment is an area of great concern. With the advent of new legislation a positive duty has been placed on employers to take steps to combat the problem. Cases have already been brought before the South African courts in terms of the new legislation and the courts have shown no hesitation in implementing the law. Recent decisions have spelt victory for victims of sexual harassment whilst sending out a clear message to perpetrators and employers. The approach adopted by the courts is a laudable one. The scene has been set in South Africa for the eradication of sexual harassment. The last step is the creation of a culture of non-victimisation. Employers have a crucial role to play as far as their employees are concerned. New legislation does address this issue but awareness is necessary to enable individuals to exercise their rights without fear of victimisation. This is of paramount importance if the various pieces of legislation are to achieve their objectives.
Discrimination and Freedom of Contract
Authors: Besson Samantha A. 
Published: October 2011

The aim of this article is to clarify the apparent antithesis between the fundamental private autonomy of the contractual parties and the right of a party not to be discriminated against and found anti-discrimination law’s legitimacy in philosophy and economics. The purpose of reviving this controversy derives from a recent attack from some of the scholars of the ‘law and economics’ movement on anti-discrimination law, and from Richard Epstein’s Forbidden Grounds in particular. Within the efficiency rationale discourse it is in reality the freedom of contract principle which is reassessed as being fundamentally violated by anti-discrimination law. The study tackles the problem by, first, analyzing potential philosophical foundations, denying any plausibility to Epstein’s derived libertarianism and supporting Gardner’s autonomy-based perfectionism, and, secondly, presenting efficiency-based foundations of anti-discrimination law, leading to the conclusion that anti-discrimination law may lead to efficient results by speeding-up the market process. The final aim of the study is to reconcile anti-discrimination policy and freedom of contract within both a market- and a social-sensitive contract theory, such as the ‘Social Market’ Theory that conceives of freedom of contract as autonomy-based and thus conditioned upon the respect of the prohibition of discrimination.
End-stage dementia: Aminoff suffering syndrome and decubitus ulcers
Authors: Zvi Aminoff Bechor 
Published: October 2011

Objective: to study possible interrelations between decubitus ulcers and Aminoff suffering syndrome in end-stage dementia (ESD). Subjects: a cohort study of 200 ESD patients with a six-month follow-up period. Methods: interrelations between decubitus ulcers and Mini-Suffering State Examination scores on admission were studied. Results: on the day of admission to the Geriatric Department, 40% of ESD patients, of whom 63.8% (51/80) were male, suffered from decubitus ulcers (80/200). Patients with decubitus ulcers had a higher Mini-Suffering State Examination score (5.49 + 2.17) than those without bedsores (3.48 ± 2.22), with a significant difference ( P < 0.0001). During a six-month follow-up period, 71.2% (57/80) of end-stage patients with decubitus ulcers were diagnosed as having Aminoff suffering syndrome and subsequently died, versus 45.8% (55/120) ESD patients who had not bedsores ( P < 0.0001). Conclusions: Decubitus ulcers contribute to the development of Aminoff suffering syndrome in ESD.
Dietary antioxidants and forced expiratory volume in 1 s decline: the Health, Aging and Body Composition study
Authors: Bentley A.R. , Kritchevsky S.B. , Harris T.B. , Holvoet P. , Jensen R.L. , Newman A.B. , Lee J.S. , Yende S. , Bauer D. , Cassano P.A. 
Published: October 2011

Increased antioxidant defences are hypothesised to decrease age- and smoking-related decline in lung function.The relationship between dietary antioxidants, smoking and forced expiratory volume in 1 s (FEV1) was investigated in community-dwelling older adults in the Health, Aging and Body Composition study. 1,443 participants completed a food frequency questionnaire, self-reported smoking history and had measurements taken of FEV1at both baseline and after 4 yrs of follow-up. The association of dietary intake of nutrients and foods with antioxidant properties and rate of FEV1decline was investigated using hierarchical linear regression models.In continuing smokers (current smokers at both time-points), higher vitamin C intake and higher intake of fruit and vegetables were associated with an 18 and 24 mL·yr−1slower rate of FEV1decline compared with a lower intake (p<0.0001 and p=0.003, respectively). In quitters (a current smoker at study baseline who had quit during follow-up), higher intake was associated with an attenuated rate of decline for each nutrient studied (p≤0.003 for all models). In nonsmoking participants, there was little or no association of diet and rate of decline in FEV1.The intake of nutrients with antioxidant properties may modulate lung function decline in older adults exposed to cigarette smoke.