bluuebunny/crossref_metadata_2025 huggingface dataset:
Medical students’ attitudes towards abortion: a UK study
Authors: Gleeson R , Forde E , Bates E , Powell S , Eadon-Jones E , Draper H
Published: October 2008

Background:

There is little research into medical students’ or doctors’ attitudes to abortion, yet knowing this is important, as policy makers should be aware of the views held by professionals directly involved in abortion provision and changing views may have practical implications for the provision of abortion in the future.

Methods:

We surveyed 300 medical students about their views on abortion, their beliefs about the status of the fetus and the rights of the mother, their attitude towards UK law and their willingness to be involved in abortion provision as qualified doctors.

Results:

62% of medical students were pro-choice, 33% pro-life and 7% undecided. Students’ views correlated with gender, year of study and holding a religious belief. Their beliefs about abortion, the status of the fetus and the rights of women significantly correlated with their attitudes towards the UK law and their willingness to be involved in abortion provision. Students’ willingness to be involved in abortion provision was related to their views on abortion, the extent of participation required, the circumstances of the pregnancy and the stage of pregnancy.

Conclusions:

The percentage of pro-choice students was lower than that found in research on general practitioners’ attitudes to abortion. It is unclear whether this is because students become more pro-choice as they progress through their medical career or because there is genuinely a change in attitudes to abortion.
Ethical rhetoric: genomics and the moral content of UNESCO’s “universal” declarations
Authors: Harmon S H E
Published: October 2008

Genomic research is an expanding and subversive field, leaking into various others, from environmental protection to food production to healthcare delivery, and in doing so, it is reshaping our relationship with them. The international community has issued various declaratory instruments aimed at the human genome and genomic research. These soft law instruments stress the special nature of genomics and our genetic heritage, and attempt to set limits on our activities with respect to same, as informed by the human rights paradigm. This paper examines the primary thrust and, more importantly, the joint value position of the Universal Declaration on the Human Genome and Human Rights and the Universal Declaration on Bioethics and Human Rights, concluding that, though important legal instruments from the human rights paradigm, these instruments, or rather the values contained therein, must find a more influential hard law voice and a broader policy environment.
Our right to in vitro fertilisation—its scope and limits
Authors: Tännsjö T
Published: October 2008

There exists a derived negative right to procreative freedom, including a right to in vitro fertilisation (IVF) and to the exercise of selective techniques such as preimplantation genetic diagnosis. This is an extensive freedom, including not only the right to the exercise of a responsible parenthood, but also, in rare cases, to wrong decisions. It includes also a right for less than perfect parents to the use of IVF, and for IVF doctors to assist them, if they want and can agree about the terms.
A novel boundary issue: should a patient be an organ donor for their physician?
Authors: Steinberg D , Pomfret E A
Published: October 2008

It is argued that organ donation from a patient to the patient's physician is ethically dubious because donation decisions will be inappropriately influenced and the negative public perceptions will result in more harm than good. It is suggested that to protect the perception of the physician–patient relationship, avoid cynicism about medicine’s attitude to patient welfare and maintain trust in the medical profession, a new professional boundary should be established to prevent physicians from receiving organs for transplantation donated by their patients.
Fearing a non-existing Minotaur? The ethical challenges of research on cytoplasmic hybrid embryos
Authors: Camporesi S , Boniolo G
Published: October 2008

In this paper we address the ethical challenges of research on cytoplasmic hybrid embryos, or “cybrids”. The controversial pronouncement of the UK’s Human Embryology and Fertilisation Authority of September 2007 on the permissibility of this area of research is the starting point of our discussion, and we argue in its favour. By a rigorous definition of the entities at issue, we show how the terms “chimera” and “hybrid” are improper in the case of cybrids, and how their use can bias the debate creating moral prejudices. After analysing the scientific aspects of cybrids research and sketching out current alternatives, we enter the ethical debate, starting from the premise that research on early human embryos is ethically permissible under some circumstances. We emphasise how research on cybrids has positive consequences in terms of scientific and therapeutic applications, since it allows the derivation of human embryonic stem cells genetically tailored to the somatic cell donor. Such cell lines offer a unique in vitro model both for studies of human pathogenesis and for drug screening and discovery. Research on cybrids also circumvents the problem of the scarcity of human oocytes and their ethically dubious donation. Finally, we object to the most common arguments against cybrids research, that is, moral repugnance, the slippery slope argument, the appeal to “nature”, and the unfair distribution of economical resources.
SELF-ORGANIZED CRITICAL BEHAVIOR: THE EVOLUTION OF FROZEN SPIN NETWORKS MODEL IN QUANTUM GRAVITY
Authors: CHEN JIAN-ZHEN , ZHU JIAN-YANG
Published: October 2008

In quantum gravity, we study the evolution of a two-dimensional planar open frozen spin network, in which the color (i.e. the twice spin of an edge) labeling edge changes but the underlying graph remains fixed. The mainly considered evolution rule, the random edge model, is depending on choosing an edge randomly and changing the color of it by an even integer. Since the change of color generally violate the gauge invariance conditions imposed on the system, detailed propagation rule is needed and it can be defined in many ways. Here, we provided one new propagation rule, in which the involved even integer is not a constant one as in previous works, but changeable with certain probability. In random edge model, we do find the evolution of the system under the propagation rule exhibits power-law behavior, which is suggestive of the self-organized criticality (SOC), and it is the first time to verify the SOC behavior in such evolution model for the frozen spin network. Furthermore, the increase of the average color of the spin network in time can show the nature of inflation for the universe.
Communicating environmental geoscience: introduction
Authors: Liverman Dave , Pereira Christopher P. G. , Marker Brian
Published: October 2008

This collection of papers is aimed primarily at the environmental geoscientist faced with the challenges of communicating important scientific results to those who might benefit from them, whether they are politicians, policy-makers, potential victims of geological disasters, fellow scientists or other members of the public. Environmental geoscience has grown to become one of the most important disciplines of geoscience as a whole, and scientific methods of investigation have become sophisticated and effective at addressing numerous problems that directly affect health and safety. The audience for such research thus is wide, and for such research to be used in the most effective manner requires well-developed communication skills to reach an audience that varies greatly in education and ability to comprehend scientific concepts. The implications of failing to communicate effectively may be severe: geological disasters have had a massive economic and social impact, with major loss of life.
The modelling and visualization of digital geoscientific data as a communication aid to land-use planning in the urban environment: an example from the Thames Gateway
Authors: Royse K. R. , Reeves H. J. , Gibson A. R.
Published: October 2008

The Thames Gateway Development Zone is the biggest urban development project in the UK for over 50 years. Developers and planners need to understand the implications of such large-scale urbanization on the environment. Requirements for sustainable growth within the Thames Gateway region mean that developers are being required to demonstrate that proposals are based on sound scientific information. This has resulted in a growing demand for geo-environmental information to be provided in more accessible, relevant and understandable forms. Advances in the use of geographic information systems (GIS) and 3D modelling software mean that there is now far greater opportunity to develop geo-environmental information products for urban development. New and innovative ways of visualizing and communicating geoscience information have been developed. Using this new technology it is possible to predict not only the types of rocks beneath a site, but also the engineering properties (such as rock strength, shrink–swell characteristics or compressibility), hydrogeological properties (such as permeability, porosity and thickness of the unsaturated zone) and geohazard potential. Geoscientific information can then be imported into standard GIS packages and queried along with other complementary ground investigation data, resulting in the creation of a powerful tool to assist in strategic planning and sustainable development.
Hazard and vulnerability assessment and adaptive planning: mutual and multilateral community–researcher communication, Arctic Canada
Authors: Catto Norm R. , Parewick Kathleen
Published: October 2008

Communities in Arctic Canada are faced with natural geological and environmental hazards. Successful adaptation requires assessment of hazards from a physical science perspective, and appropriate communication with the communities. Transforming a hazard assessment exercise into an effective plan for adaptation requires an intimate cultural understanding. Hazard assessment involving substantial input from all research, administrative, socio-economic and cultural communities will lead to more appropriate and valuable analyses of risk, sensitivity and vulnerability. Residents and communities can contribute greatly to the identification and assessment of natural hazards. Community-driven communication is essential for meaningful risk analysis, adaptive planning and vulnerability assessment. Developing relationships with local media can be extremely beneficial. Using the practices of participatory community planning allows local environmental changes to be assessed and responded to by the people affected. Establishing effective working partnerships is essential for a true vulnerability assessment. The particularly sensitive nature of hazard assessments indicating increasing risk and vulnerability, and the continuing socio-economic changes in some communities, in the work described here, required consideration of the most appropriate methods of communication for each instance. The relationships that have emerged through the course of work in the communities have differed markedly from those originally envisioned, and also exhibit significant differences between communities.
Communicating geoscience to indigenous people: examples from the Solomon Islands
Authors: Petterson M. G. , Tolia D. , Cronin S. J. , Addison R.
Published: October 2008

This paper examines communicating geoscience to indigenous peoples using a communication model that closely follows geological models for pollution issues. Although geoscientists will expend large amounts of energy in understanding a scientific process, relatively little energy is often expended in the analogous communication model. Reasons for this include a narrow focus on pure science, lack of confidence in engaging in communication and negative perceptions of communication ideas. Indigenous peoples are defined as ‘first occupiers’ of regions or nations relatively untouched by the predominant ‘Western–Asian’ technological-oriented culture. Few indigenous peoples are totally ‘untouched’ by the dominant world culture. Four cases studies from the Solomon Islands explore communication strategies relating to land access, a live volcanic event, the setting up of a gold mine, and raising awareness of volcanic hazards. Generic best practice advice offered includes the following: understanding of indigenous culture, customs, values, taboos and political–governance structures; involvement of indigenous people at every level of the communication process; identifying and including all stakeholders; a clear message, method and outcome focus; usage wherever possible of face-to-face communication and pictures as well as words; involvement of the community in practical exercises; a thorough follow-up and evaluation process; and sufficient time to allow the process to be effective.
Framing volcanic risk communication within disaster risk reduction: finding ways for the social and physical sciences to work together
Authors: Barclay Jenni , Haynes Katharine , Mitchell Tom , Solana Carmen , Teeuw Richard , Darnell Amii , Crosweller H. Sian , Cole Paul , Pyle David , Lowe Catherine , Fearnley Carina , Kelman Ilan
Published: October 2008

Sixteen years have passed since the last global volcanic event and more than 25 since a volcanic catastrophe that killed tens of thousands. In this time, volcanology has seen major advances in understanding, modelling and predicting volcanic hazards and, recently, an interest in techniques for reducing and mitigating volcanic risk. This paper provides a synthesis of literature relating to this last aspect, specifically the communication of volcanic risk, with a view to highlighting areas of future research into encouraging risk-reducing behaviour. Evidence suggests that the current ‘multidisciplinary’ approach within physical science needs a broader scope to include sociological knowledge and techniques. Key areas where this approach might be applied are: (1) the understanding of the incentives that make governments and communities act to reduce volcanic risk; (2) improving the communication of volcanic uncertainties in volcanic emergency management and long-term planning and development. To be successful, volcanic risk reduction programmes will need to be placed within the context of other other risk-related phenomena (e.g. other natural hazards, climate change) and aim to develop an all-risks reduction culture. We suggest that the greatest potential for achieving these two aims comes from deliberative inclusive processes and geographic information systems.
Communication of geoscience information in public administration: UK experiences
Authors: Marker OBE Brian
Published: October 2008

This paper is intended to provoke thought and discussion rather than to set out any ‘right way’ to communicate geoscience information. Public administration is complex, operating at several levels. It involves a wide variety of people, many of whom have little or no geoscience knowledge. It is important for geoscientists to understand administrative procedures so that results can be provided in the right form at the optimum time. There should also be a good understanding of the views, requirements and capacities of each potential target audience. This is best achieved through direct consultation and discussion. Consultation also helps to build trust and to guide the design of specific products. Results need to be presented logically, clearly and in straightforward language supported by good illustrations. These need to be tailored to fit the needs of each target audience; a single output will seldom meet the specific needs of all. The focus should be on the matters that are of importance to each audience, rather than on the research as such. Good dissemination of results is crucial and may require continuing efforts rather than just taking place at the end of the study. Consultation, presentation for non-specialists, and dissemination are time consuming. There needs to be adequate provision of staff time and money to support these. This may require a change in attitudes of some funding organizations. It is wise to plan consultation, presentation and dissemination from the commencement of work, revising plans as a fuller understanding of systems and audience requirements is gained.
Media and scientific communication: a case of climate change
Authors: Boykoff Maxwell T.
Published: October 2008

This paper explores how media representational practices shape and affect current international science and policy or practice communications, through a focus on climate change. Many complex factors contribute to these interactions. The norms and pressures that guide journalistic decision-making and shape mass-media coverage of anthropogenic climate science critically shape current discourses at the highly politicized climate science–policy interface. This paper investigates the multifarious journalistic, political, cultural and economic norms that dynamically influence media coverage of climate science. It explores the case-study of climate change to also work through factors shaping the translation of uncertainty in climate science. This project demonstrates that mass-media coverage of climate change is not simply a random amalgam of articles and segments; rather, it is a social relationship between scientists, policy actors and the public that is mediated by such news packages. Moreover, this research shows how mass media play a significant role in shaping the construction and maintenance of discourse on climate change at the interface of science and policy.
Good and bad practice in the communication of uncertainties associated with the relationship between climate change and weather-related natural disasters
Authors: Ward Robert E. T.
Published: October 2008

There is evidence that climate change is affecting the frequency, intensity and geographical distribution of weather-related natural disasters. However, the exact details of this relationship are subject to varying degrees of uncertainty. Scientists, policy-makers and others have recognized how this connection could influence public support for decisions and policies around climate change, such as measures to reduce greenhouse gas emissions. This has led to a number of cases in which stakeholders in the public policy debate about climate change have overstated or understated uncertainties, relative to the scientific assessments of the Intergovernmental Panel on Climate Change. Although such distortions in the expression of uncertainties are motivated by a desire to justify particular policy positions, they could instead undermine the credibility of, and trust in, information sources and diminish public support.
Community participation in natural risk prevention: case histories from Colombia
Authors: Hermelin M. , Bedoya G.
Published: October 2008

More than 75% of Colombia's 42 million people live in urban areas located in the mountains and are exposed to numerous natural hazards: floods, flash floods, landslides, earthquakes and volcanism. The Armero disaster of 1985 triggered the creation of the National System for Disaster Prevention and Relief. National, regional and local committees started to operate across the country, accompanied by education commissions that produced diverse audiovisual materials to help educate people living in these areas. The experiences of working with local committees gained during the last two decades are presented here. Case histories are from cities such as Pereira, Manizales and Medellín, where the local committees are run by people with little or no formal education but who understand that they must participate as a group to prevent or mitigate the effects of natural disasters. The co-operation between technical experts and trained residents represents an outstanding example of good communication and co-operation for urban populations living in dangerous areas. Although many problems have yet to be resolved, these case histories show that this type of organization seems to be more effective than direct intervention from national government agencies. The models of community participation and communication developed and refined here may have application to similar social environments in other countries.
Lead contamination, the media and risk communication: a case study from the Ribeira Valley, Brazil
Authors: Giulio Gabriela Marques Di , Pereira Newton Müller , Figueiredo Bernardino Ribeiro de
Published: October 2008

This paper discusses the importance of risk communication in studies of public health issues, and analyses the roles of scientists and the media in communicating scientific data, and their influence on risk perception. The findings are based on a case study from Adrianópolis in the Ribeira Valley (Brazil), conducted between 2005 and 2006, where residents were exposed to lead contamination that originated from a smelter and a sulphide mine. This study had two goals: (1) to understand the impact of information regarding lead contamination on the daily lives of the local inhabitants; (2) to understand and analyse the consequences of an absence of a strategy for risk communication by the researchers involved in the study. Besides drawing attention to the need for studies concerning passive environmental issues, the Adrianópolis case study showed that there was a lack of adequate planning for dissemination of information to local inhabitants that seriously undermined the relationships between researchers, the community and the media, and this caused damage to the various stakeholders.
Iron feeding induces ferroportin 1 and hephaestin migration and interaction in rat duodenal epithelium
Authors: Yeh Kwo-yih , Yeh Mary , Mims Laura , Glass Jonathan
Published: October 2008

Intestinal iron absorption involves proteins located in the brush border membrane (BBM), cytoplasm, and basolateral membrane (BLM) of duodenal enterocytes. Ferroportin 1 (FPN1) and hephaestin (Heph) are necessary for transport of iron out of enterocytes, but it is not known whether these two proteins interact during iron absorption. We first examined colocalization of the proteins by cotransfection of HEK293 cells with pDsRed-FPN1 with pEmGFP-Heph or with the COOH-terminal truncated pEmGFP-HephΔ43 or -HephΔ685 and found that FPN1 and Heph with or without the COOH terminus colocalized. In rat duodenal enterocytes, within 1 h of iron feeding prominent migration of FPN1 from the apical subterminal zone to the basal subnuclear zone of the BLM occurred and increased to at least 4 h after feeding. Heph exhibited a similar though less prominent migration after iron ingestion. Analysis using rat duodenal epithelial cell sheets demonstrated that 1) by velocity sedimentation ultracentrifugation, FPN1 and Heph occupied vesicles of different sizes prior to iron feeding and migrated to similar fractions 1 h after iron feeding; 2) by blue native/SDS-PAGE, FPN1, and Heph interacted to form two complexes, one containing dimeric FPN1 and intact Heph and the other consisting of monomeric FPN1 and a Heph fragment; and 3) by immunoprecipitation, anti-Heph or anti-FPN1 antiserum coimmunoprecipitated FPN1 and Heph. Thus the data indicate that FPN1 and Heph migrate and interact during iron feeding and suggest that dimeric FPN1 is associated with intact Heph.
Effect of high-fat diet during gestation, lactation, or postweaning on physiological and behavioral indexes in borderline hypertensive rats
Authors: Mitra Anaya , Alvers Kristin M. , Crump Erica M. , Rowland Neil E.
Published: October 2008

Maternal obesity is becoming more prevalent. We used borderline hypertensive rats (BHR) to investigate whether a high-fat diet at different stages of development has adverse programming consequences on metabolic parameters and blood pressure. Wistar dams were fed a high- or low-fat diet for 6 wk before mating with spontaneously hypertensive males and during the ensuing pregnancy. At birth, litters were fostered to a dam from the same diet group as during gestation or to the alternate diet condition. Female offspring were weaned on either control or “junk food” diets until about 6 mo of age. Rats fed the high-fat junk food diet were hyperphagic relative to their chow-fed controls. The junk food-fed rats were significantly heavier and had greater fat pad mass than those rats maintained on chow alone. Importantly, those rats suckled by high-fat dams had heavier fat pads than those suckled by control diet dams. Fasting serum leptin and insulin levels differed as a function of the gestational, lactational, and postweaning diet histories. Rats gestated in, or suckled by high-fat dams, or maintained on the junk food diet were hyperleptinemic compared with their respective controls. Indirect blood pressure did not differ as a function of postweaning diet, but rats gestated in the high-fat dams had lower mean arterial blood pressures than those gestated in the control diet dams. The postweaning dietary history affected food-motivated behavior; junk food-fed rats earned less food pellets on fixed (FR) and progressive (PR) ratio cost schedules than chow-fed controls. In conclusion, the effects of maternal high-fat diet during gestation or lactation were mostly small and transient. The postweaning effects of junk food diet were evident on the majority of the parameters measured, including body weight, fat pad mass, serum leptin and insulin levels, and operant performance.
Regional decreases in renal oxygenation during graded acute renal arterial stenosis: a case for renal ischemia
Authors: Warner Lizette , Gomez Sabas I. , Bolterman Rodney , Haas John A. , Bentley Michael D. , Lerman Lilach O. , Romero Juan C.
Published: October 2008

Ischemic nephropathy describes progressive renal failure, defined by significantly reduced glomerular filtration rate, and may be due to renal artery stenosis (RAS), a narrowing of the renal artery. It is unclear whether ischemia is present during RAS since a decrease in renal blood flow (RBF), O2delivery, and O2consumption occurs. The present study tests the hypothesis that despite proportional changes in whole kidney O2delivery and consumption, acute progressive RAS leads to decreases in regional renal tissue O2. Unilateral acute RAS was induced in eight pigs with an extravascular cuff. RBF was measured with an ultrasound flow probe. Cortical and medullary tissue oxygen [Formula: see text] of the stenotic kidney was measured continuously with sensors during baseline, three sequentially graded decreases in RBF, and recovery. O2consumption decreased proportionally to O2delivery during the graded stenosis (19 ± 10.8, 48.2 ± 9.1, 58.9 ± 4.7 vs. 15.1 ± 5, 35.4 ± 3.5, 57 ± 2.3%, respectively) while arterial venous O2differences were unchanged. Acute RAS produced a sharp reduction in O2efficiency for sodium reabsorption ( P < 0.01). Cortical [Formula: see text] decreases are exceeded by medullary decreases during stenosis (34.8 ± 1.3%). Decreases in tissue oxygenation, more pronounced in the medulla than the cortex, occur despite proportional reductions in O2delivery and consumption. This demonstrates for the first time that hypoxia is present in the early stages of RAS and suggests a role for hypoxia in the pathophysiology of this disease. Furthermore, the notion that arteriovenous shunting and increased stoichiometric energy requirements are potential contributors toward ensuing hypoxia with graded and progressive acute RAS cannot be excluded.
Salubrinal, an inhibitor of protein synthesis, promotes deep slow wave sleep
Authors: Methippara Melvi M. , Bashir Tariq , Kumar Sunil , Alam Noor , Szymusiak Ronald , McGinty Dennis
Published: October 2008

Previous work showed that sleep is associated with increased brain protein synthesis and that arrest of protein synthesis facilitates sleep. Arrest of protein synthesis is induced during the endoplasmic reticulum (ER) stress response, through phosphorylation of eukaryotic initiation factor 2α (p-eIF2α). We tested a hypothesis that elevation of p-eIF2α would facilitate sleep. We studied the effects of intracerebroventricular infusion of salubrinal (Salub), which increases p-eIF2α by inhibiting its dephosphorylation. Salub increased deep slow wave sleep by 255%, while reducing active waking by 49%. Delta power within non-rapid eye movement (NREM) sleep was increased, while power in the sigma, beta, and gamma bands during NREM was reduced. We found that Salub increased expression of p-eIF2α in the basal forebrain (BF) area, a sleep-wake regulatory brain region. Therefore, we quantified the p-eIF2α-immunolabeled neurons in the BF area; Salub administration increased the number of p-eIF2α-expressing noncholinergic neurons in the caudal BF. In addition, Salub also increased the intensity of p-eIF2α expression in both cholinergic and noncholinergic neurons, but this was more widespread among the noncholinergic neurons. Our findings support a hypothesis that sleep is facilitated by signals associated with the ER stress response.
Angiostatin overexpression is associated with an improvement in chronic kidney injury by an anti-inflammatory mechanism
Authors: Mu Wei , Long David A. , Ouyang Xiaosen , Agarwal Anupam , Cruz Pedro E. , Roncal Carlos A. , Nakagawa Takahiko , Yu XueQing , Hauswirth William W. , Johnson Richard J.
Published: October 2008

Angiostatin, a proteolytic fragment of plasminogen, is a potent anti-angiogenic factor recently shown also to have an inhibitory effect on leukocyte recruitment and macrophage migration. Because both angiogenesis and inflammation play key roles in the progression of chronic kidney disease, we evaluated the effect of angiostatin treatment in the rat remnant kidney model. Rats were pretreated for 4 wk with recombinant adeno-associated viruses expressing either angiostatin or green fluorescence protein. Chronic renal disease was then induced by a subtotal nephrectomy, and rats were killed 8 wk later for analysis. Angiostatin treatment was associated with significantly less proteinuria but no alterations in serum creatinine, creatinine clearance, and blood urea nitrogen levels. Treatment with angiostatin reduced renal peritubular capillary number and decreased urinary nitric oxide levels. Despite reducing capillary density, angiostatin diminished interstitial fibrosis in association with reduced macrophage and T-cell infiltration and renal monocyte chemoattractant protein-1 mRNA levels. In conclusion, angiostatin overexpression was associated with attenuated renal disease progression in a model of chronic kidney injury, likely because of its anti-inflammatory actions. However, its anti-angiogenic actions suggest countering effects that could partially offset its benefit in chronic kidney diseases.
Meprin A metalloproteases enhance renal damage and bladder inflammation after LPS challenge
Authors: Yura Renee E. , Bradley S. Gaylen , Ramesh Ganesan , Reeves W. Brian , Bond Judith S.
Published: October 2008

Meprin metalloproteases, composed of α and/or β subunits, consist of membrane-bound and secreted forms that are abundantly expressed in proximal tubules of the kidney as well as secreted into the urinary tract. Previous studies indicated that meprin metalloproteases play a role in pathological conditions such as ischemic acute renal failure and urinary tract infection. The aim of this work was to examine the role of meprins in endotoxemic acute renal failure using meprin α knockout (αKO), meprin β knockout (βKO), and wild-type (WT) mice. Differences among the responses of the genotypes were observed as early as 1 h after challenge with 2.5 mg/kg ip Escherichia coli LPS, establishing roles for meprins in the endotoxemic response. Meprin αKO mice displayed lower blood urea nitrogen levels and decreased nitric oxide levels, indicative of a decreased systemic response to LPS compared with WT and meprin βKO mice. Serum cytokine profiles showed lower levels of IL-1β and TNF–α in the meprin αKO mice within 3 h after LPS challenge and confirmed a role for meprins in the early phases of the host response. Meprin αKO mice were also hyporesponsive to LPS administered to the bladder, exhibiting significantly less bladder edema, leukocyte infiltration, and bladder permeability than WT mice. These data indicate that meprin A contributes to the renal and urogenital pathogenesis of endotoxicity.
Diminished NO generation by injured endothelium and loss of macula densa nNOS may contribute to sustained acute kidney injury after ischemia-reperfusion
Authors: Kwon Osun , Hong Seok-Min , Ramesh Ganesan
Published: October 2008

In postischemic acute kidney injury (AKI) or acute renal failure, a dissipation of glomerular filtration pressure is associated with an altered renal vascular tone and reactivity, as well as a loss of vascular autoregulation. To test the hypothesis that renal nitric oxide (NO) generation reflects endothelial damage in the kidney after ischemia-reperfusion, we quantified the urinary NO levels and identified the site of its generation in postischemic AKI. Subjects were 50 recipients of cadaveric renal allografts: 15 with sustained AKI and 35 with recovering renal function. Urine and blood samples were obtained after transplant, and intraoperative allograft biopsies were performed to examine NO synthases (NOSs) in the kidney. In the sustained AKI group, urinary nitrite and nitrate excretion (in μmol/g urine creatinine) was lower (12.3 ± 1.8 and 10.0 ± 1.4 on postoperative days 0 and 3) than in the recovery group [20.0 ± 3.6 and 35.1 ± 5.3 ( P < 0.005 vs. sustained AKI on days 0 and 3) on postoperative days 0 and 3]. Endothelial NOS expression diminished from the peritubular capillaries of 6 of 7 subjects in the sustained AKI group but from only 6 of 16 subjects in the recovery group. No differences were observed in the inducible NOS staining pattern between the two groups. Neuronal NOS staining was rarely observed in the macula densae of subjects but was prominent in control tissues. These findings suggest that a diminished NO generation by injured endothelium and loss of macula densa neuronal NOS could impair the vasodilatory ability of the renal vasculature and contribute to the reduction in the glomerular filtration rate in postischemic AKI.
Cytokines derived from cultured skeletal muscle cells after mechanical strain promote neutrophil chemotaxis in vitro
Authors: Peterson Jennifer M. , Pizza Francis X.
Published: October 2008

We tested the hypothesis that cytokines derived from differentiated skeletal muscle cells in culture induce neutrophil chemotaxis after mechanical strain. Flexible-bottom plates with cultured human muscle cells attached were exposed to mechanical strain regimens (ST) of 0, 10, 30, 50, or 70 kPa of negative pressure. Conditioned media were tested for the ability to induce chemotaxis of human blood neutrophils in vitro and for a marker of muscle cell injury (lactate dehydrogenase). Conditioned media promoted neutrophil chemotaxis in a manner that was related both to the degree of strain and to the magnitude of muscle cell injury (ST 70 > ST 50 > ST 30). Protein profiling using a multiplex cytokine assay revealed that mechanical strain increased the presence of IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor, monocyte chemotactic protein (MCP)-1, and IL-6 in conditioned media. We also detected 14 other cytokines in conditioned media from control cultures that did not respond to mechanical strain. Neutralization of IL-8 and GM-CSF completely inhibited the chemotactic response for ST 30 and ST 50 and reduced the chemotactic response for ST 70 by 40% and 47%, respectively. Neutralization of MCP-1 or IL-6 did not reduce chemotaxis after ST 70. This study enhances our understanding of the immunobiology of skeletal muscle by revealing that skeletal muscle cell-derived IL-8 and GM-CSF promote neutrophil chemotaxis after injurious mechanical strain.
DNA Hypomethylation Arises Later in Prostate Cancer Progression than CpG Island Hypermethylation and Contributes to Metastatic Tumor Heterogeneity
Authors: Yegnasubramanian Srinivasan , Haffner Michael C. , Zhang Yonggang , Gurel Bora , Cornish Toby C. , Wu Zhijin , Irizarry Rafael A. , Morgan James , Hicks Jessica , DeWeese Theodore L. , Isaacs William B. , Bova G. Steven , De Marzo Angelo M. , Nelson William G.
Published: October 2008

Hypomethylation of CpG dinucleotides in genomic DNA was one of the first somatic epigenetic alterations discovered in human cancers. DNA hypomethylation is postulated to occur very early in almost all human cancers, perhaps facilitating genetic instability and cancer initiation and progression. We therefore examined the nature, extent, and timing of DNA hypomethylation changes in human prostate cancer. Contrary to the prevailing view that global DNA hypomethylation changes occur extremely early in all human cancers, we show that reductions in 5meC content in the genome occur very late in prostate cancer progression, appearing at a significant extent only at the stage of metastatic disease. Furthermore, we found that, whereas some LINE1 promoter hypomethylation does occur in primary prostate cancers compared with normal tissues, this LINE1 hypomethylation is significantly more pronounced in metastatic prostate cancer. Next, we carried out a tiered gene expression microarray and bisulfite genomic sequencing–based approach to identify genes that are silenced by CpG island methylation in normal prostate cells but become overexpressed in prostate cancer cells as a result of CpG island hypomethylation. Through this analysis, we show that a class of cancer testis antigen genes undergoes CpG island hypomethylation and overexpression in primary prostate cancers, but more so in metastatic prostate cancers. Finally, we show that DNA hypomethylation patterns are quite heterogeneous across different metastatic sites within the same patients. These findings provide evidence that DNA hypomethylation changes occur later in prostate carcinogenesis than the CpG island hypermethylation changes and occur heterogeneously during prostate cancer progression and metastatic dissemination. [Cancer Res 2008;68(21):8954–67]
Fibroblasts Isolated from Common Sites of Breast Cancer Metastasis Enhance Cancer Cell Growth Rates and Invasiveness in an Interleukin-6–Dependent Manner
Authors: Studebaker Adam W. , Storci Gianluca , Werbeck Jillian L. , Sansone Pasquale , Sasser A. Kate , Tavolari Simona , Huang Tim , Chan Michael W.Y. , Marini Frank C. , Rosol Thomas J. , Bonafé Massimiliano , Hall Brett M.
Published: October 2008

Common sites of breast cancer metastasis include the lung, liver, and bone, and of these secondary metastatic sites, estrogen receptor α (ERα)–positive breast cancer often favors bone. Within secondary organs, cancer cells would predictably encounter tissue-specific fibroblasts or their soluble factors, yet our understanding of how tissue-specific fibroblasts directly affect cancer cell growth rates and survival remains largely unknown. Therefore, we tested the hypothesis that mesenchymal fibroblasts isolated from common sites of breast cancer metastasis provide a more favorable microenvironment with respect to tumor growth rates. We found a direct correlation between the ability of breast, lung, and bone fibroblasts to enhance ERα-positive breast cancer cell growth and the level of soluble interleukin-6 (IL-6) produced by each organ-specific fibroblast, and fibroblast-mediated growth enhancement was inhibited by the removal or inhibition of IL-6. Interestingly, mice coinjected with MCF-7 breast tumor cells and senescent skin fibroblasts, which secrete IL-6, developed tumors, whereas mice coinjected with presenescent skin fibroblasts that produce little to no IL-6 failed to form xenograft tumors. We subsequently determined that IL-6 promoted growth and invasion of breast cancer cells through signal transducer and activator of transcription 3–dependent up-regulation of Notch-3, Jagged-1, and carbonic anhydrase IX. These data suggest that tissue-specific fibroblasts and the factors they produce can promote breast cancer disease progression and may represent attractive targets for development of new therapeutics. [Cancer Res 2008;68(21):9087–95]
Different Roles of Estrogen Receptors α and β in the Regulation of E-Cadherin Protein Levels in a Mouse Mammary Epithelial Cell Line
Authors: Helguero Luisa A. , Lindberg Karolina , Gardmo Cissi , Schwend Thomas , Gustafsson Jan-Åke , Haldosén Lars-Arne
Published: October 2008

Two estrogen receptors (ERα and ERβ) are found throughout the mammary gland. Evidence indicates that, while ERα transduces proliferation signals, ERβ opposes this effect and is necessary for epithelial differentiation. Using mouse mammary epithelial cells, we have previously shown that activation of ERβ opposes ERα-induced proliferation and increases apoptosis. Furthermore, stable knockdown of ERβ resulted in loss of growth contact inhibition. In this work, we report that loss of ERβ is associated with a decrease of E-cadherin protein levels through different posttranscriptional regulatory mechanisms. Ligand activation of ERα induced E-cadherin extracellular shedding and internalization only in the absence of ERβ, followed by lysosomal degradation. Loss of ERβ also led to an increase of E-cadherin uptake in a ligand-independent manner through mechanisms that required caveolae formation. Proteasome activity was necessary for both mechanisms to operate. Increased E-cadherin internalization correlated with the up-regulation of β-catenin transcriptional activity and impaired morphogenesis on Engelbreth-Holm-Swarm matrix. Taken together, these results emphasize the role of epithelial ERβ in maintaining cell adhesion and a differentiated phenotype and highlight the potential importance of ERβ for the design of specific agonists for use in breast cancer therapy. [Cancer Res 2008;68(21):8695–704]
Reduced Eukaryotic Initiation Factor 2Bε-Subunit Expression Suppresses the Transformed Phenotype of Cells Overexpressing the Protein
Authors: Gallagher James W. , Kubica Neil , Kimball Scot R. , Jefferson Leonard S.
Published: October 2008

Eukaryotic initiation factor 2B (eIF2B), a five-subunit guanine nucleotide exchange factor, plays a key role in the regulation of mRNA translation. Expression of its ε-subunit is specifically up-regulated in certain conditions associated with increased cell growth. Therefore, the purpose of the present study was to examine the effect of repressing eIF2Bε expression on growth rate, protein synthesis, and other characteristics of two tumorigenic cell lines that display up-regulated expression of the ε-subunit. Experiments were designed to compare spontaneously transformed fibroblasts to transformed mouse embryonic fibroblasts infected with a lentivirus containing a short hairpin RNA directed against eIF2Bε. Cells expressing the short hairpin RNA displayed a reduction in eIF2Bε abundance to 30% of the value observed in uninfected transformed mouse embryonic fibroblasts, with no change in the expression of any of the other four subunits. The repression of eIF2Bε expression was accompanied by reductions in guanine nucleotide exchange factor activity and global rates of protein synthesis. Moreover, repressed eIF2Bε expression led to marked reductions in cell growth rate in culture, colony formation in soft agar, and tumor progression in nude mice. Similar results were obtained in MCF-7 human breast cancer cells in which eIF2Bε expression was repressed through transient transfection with a small interfering RNA directed against the ε-subunit. Overall, the results support a role for eIF2Bε in the regulation of cell growth and suggest that it might represent a therapeutic target for the treatment of human cancer. [Cancer Res 2008;68(21):8752–60]
Macrophage-Derived SPARC Bridges Tumor Cell-Extracellular Matrix Interactions toward Metastasis
Authors: Sangaletti Sabina , Di Carlo Emma , Gariboldi Silvia , Miotti Silvia , Cappetti Barbara , Parenza Mariella , Rumio Cristiano , Brekken Rolf A. , Chiodoni Claudia , Colombo Mario P.
Published: October 2008

Other than genetic imprinting and epithelial to mesenchymal transition, cancer cells need interaction with the nearby stroma toward metastasis. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein known to regulate extracellular matrix (ECM) deposition and cell-ECM interaction. Gene expression profiles associate SPARC to malignant progression. Using reciprocal bone marrow chimeras between SPARC knockout and wild-type mice, we show that SPARC produced by inflammatory cells is necessary for spontaneous, but not experimental, i.v. metastasis. Macrophage-derived SPARC induces cancer cell migration and enhances their migration to other ECM proteins at least through αvβ5 integrin. Indeed, RNA interference knockdown of β5 integrin expression reduces cell migration in vitro and metastasis in vivo. Together these results show that macrophage-derived SPARC takes part in metastasis, acting at the step of integrin-mediated migration of invasive cells. [Cancer Res 2008;68(21):9050–9]
Prevalence, Acquisition, and Clearance of Cervical Human Papillomavirus Infection among Women with Normal Cytology: Hawaii Human Papillomavirus Cohort Study
Authors: Goodman Marc T. , Shvetsov Yurii B. , McDuffie Katharine , Wilkens Lynne R. , Zhu Xuemei , Thompson Pamela J. , Ning Lily , Killeen Jeffrey , Kamemoto Lori , Hernandez Brenda Y.
Published: October 2008

Few natural history studies of cervical human papillomavirus (HPV) incidence and duration have been conducted among older women, especially from multiethnic populations. Viral and nonviral determinants of HPV acquisition and clearance were examined among 972 sexually active women, ages 18 to 85 years, recruited from clinics on Oahu, Hawaii, and followed for a mean duration of 15 months (range, 2–56 months). Interviews and cervical cell specimens for cytology and HPV DNA detection by PCR, using the PGMY09/PGMY11 primer system, were obtained at baseline and at 4-month intervals. The prevalence of cervical HPV infection was 25.6% at study entry. A total of 476 incident genotype-specific infections were observed during the follow-up period. The incidence of high-risk (HR) HPV types (9.26 per 1,000 woman-months) was similar to low-risk (LR) HPV types (8.24 per 1,000 woman-months). The most commonly acquired HR-HPV types were HPV-52, HPV-16, and HPV-31; and their incidence was increased significantly with a coexisting cervical HPV infection. Cervical HPV acquisition decreased with age, income, and long-term use of oral contraceptives and increased with number of sexual partners, use of hormonal creams, alcohol drinking, and condom use by a sexual partner. Cohort participants cleared 265 of the 476 incident infections during follow-up. LR-HPV infections cleared more rapidly than did HR-HPV infections (median, 180 days versus 224 days). Clearance times were enhanced among older women and women with multiple infections. Our data suggest several viral and nonviral determinants of cervical HPV acquisition and clearance that might be used in cervical cancer prevention programs. [Cancer Res 2008;68(21):8813–24]