bluuebunny/crossref_metadata_2025 huggingface dataset:
Mcl-1 Down-regulation Potentiates ABT-737 Lethality by Cooperatively Inducing Bak Activation and Bax Translocation
Authors: Chen Shuang , Dai Yun , Harada Hisashi , Dent Paul , Grant Steven
Published: January 2007

The Bcl-2 antagonist ABT-737 targets Bcl-2/Bcl-xL but not Mcl-1, which may confer resistance to this novel agent. Here, we show that Mcl-1 down-regulation by the cyclin-dependent kinase (CDK) inhibitor roscovitine or Mcl-1-shRNA dramatically increases ABT-737 lethality in human leukemia cells. ABT-737 induces Bax conformational change but fails to activate Bak or trigger Bax translocation. Coadministration of roscovitine and ABT-737 untethers Bak from Mcl-1 and Bcl-xL, respectively, triggering Bak activation and Bax translocation. Studies employing Bax and/or Bak knockout mouse embryonic fibroblasts (MEFs) confirm that Bax is required for ABT-737 ± roscovitine lethality, whereas Bak is primarily involved in potentiation of ABT-737–induced apoptosis by Mcl-1 down-regulation. Ectopic Mcl-1 expression attenuates Bak activation and apoptosis by ABT-737 + roscovitine, whereas cells overexpressing Bcl-2 or Bcl-xL remain fully sensitive. Finally, Mcl-1 knockout MEFs are extremely sensitive to Bak conformational change and apoptosis induced by ABT-737, effects that are not potentiated by roscovitine. Collectively, these findings suggest down-regulation of Mcl-1 by either CDK inhibitors or genetic approaches dramatically potentiate ABT-737 lethality through cooperative interactions at two distinct levels: unleashing of Bak from both Bcl-xL and Mcl-1 and simultaneous induction of Bak activation and Bax translocation. These findings provide a mechanistic basis for simultaneously targeting Mcl-1 and Bcl-2/Bcl-xL in leukemia. [Cancer Res 2007;67(2):782–91]
Decision Framing and Support for Concessions in the Israeli–Palestinian Conflict
Authors: Maoz Ifat , Yaniv Ilan , Ivri Naama
Published: January 2007

The purpose of the study is to explore, in the context of the Israeli-Palestinian conflict, the influence of framing a decision task as inclusion or exclusion on Israeli Jewish respondents’ support for the concession of Jewish settlements in the West Bank and Gaza. Respondents received a list of 40 Jewish settlements. Details such as the number of residents and geographical location were provided for each settlement. The respondents were randomly assigned to one of two conditions. In the inclusion condition, 55 respondents were asked to mark the settlements for which they recommended that Israeli sovereignty be conceded. In the exclusion condition, 53 respondents were asked to mark the settlements for which they recommended that Israeli sovereignty not be conceded. The findings confirm the predictions tested and indicate that: (1) Framing the task in terms of inclusion or exclusion affects respondents’ support for territorial compromise, so that respondents in the exclusion condition support the concession of more settlements than respondents in the inclusion condition. (2) Framing the task in terms of inclusion or exclusion has a greater effect on support for conceding options (settlements) that are perceived as ambiguous (less consensual in the climate of opinion) in comparison to options (settlements) that are perceived as more clearcut (more consensual). The theoretical and practical implications of these findings are discussed.
Five Decades of Terrorism in Europe: The TWEED Dataset
Authors: Engene Jan Oskar
Published: January 2007

The article presents a regional dataset on internal terrorism, Terrorism in Western Europe: Event Data (TWEED), covering the period 1950 through 2004 for 18 West European countries. As the dataset covers internal terrorism, the distinction between this form of terrorism and international terrorism is discussed. In demarcating international from internal terrorism, the former is usually taken to mean terrorism involving nationals or territory of more than one state. In TWEED, however, terrorism is regarded as internal when terrorists act within their own political systems. Terrorists originating from outside Western Europe, but committing acts of terrorism inside the region, are excluded from TWEED. Next, the article discusses the selection of sources from which the coding is done. With its combination of continuous coverage and good reporting of Western Europe, Keesing’s was chosen as the source for TWEED. The article discusses problems of source coverage related to relying on a single source. Finally, the article presents the structure of the dataset. The coding unit is the event related to terrorism, whether acts of terrorism or government acts directed against terrorists. A total of 11,245 events are recorded in TWEED, of which 86.5% are actions initiated by terrorist groups or non-state agents. TWEED records activities by 214 named terrorist groups. Events are coded for a range of 52 variables falling into two groups: attributes of the action, including basic information such as date and country of the terrorist attack, the agent (group) responsible and the number of deaths and injuries inflicted; and attributes of the agent, which records their ideological profile, regional context and attitude towards the state.
The Short Path and the Long Road: Explaining the Duration of US Military Operations
Authors: Meernik James , Brown Chelsea
Published: January 2007

US presidents have used military force short of war many times since World War II. While some military operations are finished in a fairly brief period of time, such as the evacuation of US citizens from an unstable foreign capital, other deployments may last much longer, as the US military is charged with accomplishing more ambitious foreign policy goals, such as promoting peace, democracy, or maintaining US influence. What explains why some of these uses of force short of war are fairly brief, while other military operations last much longer? The authors contend that the duration of such missions depends on the military resources available, the president’s political support at home, and crisis-specific factors. Using duration modeling techniques, they find that the availability of military resources and the characteristics of the international crisis matter a great deal, while US political and economic conditions mostly do not explain the duration of US military operations. As research has shown with regard to interstate wars, elected leaders prefer short and ostensibly decisive engagements, owing in no small part to the increased risk of not surviving in office over the course of long wars. Thus, this study broadens our understanding of the preferences of democratic leaders in conflict decisionmaking about a larger and increasingly more important set of events in international relations - the use of force short of war.
Rebellion in Africa: Disaggregating the Effect of Political Regimes
Authors: Carey Sabine C.
Published: January 2007

This article analyzes how the selection process for the executive affects the risk of rebellion and insurgencies in sub-Saharan Africa between 1971 and 1995. Four executive recruitment processes are distinguished that are characteristic for the African context: (1) a process without elections; (2) single-candidate elections; (3) single-party, multiple-candidate elections; and (4) multiparty executive elections. The results suggest that single-candidate elections and multiparty elections substantially reduce the risk of insurgencies compared with systems without any kind of executive elections. They further show that during times of political instability, the risk of large-scale violent dissent increases substantially. The article supports findings of the civil war literature that higher levels of income are associated with a lower risk of intrastate violence, while oil-exporting countries are at a higher risk of rebellion. In short, this article further strengthens the need to use more specific measures of elements of political regimes that also take into account regional particularities, in order to paint a more informative picture of how political structures influence the risk of internal violence.
Rallying Around the Podesta: Testing Diversionary Theory Across Time
Authors: Sobek David
Published: January 2007

Diversionary theory argues that leaders threatened by domestic turmoil manipulate the ‘rally around the flag’ effect by initiating conflict abroad. This conflict mitigates the negative effects of the unrest, saving the leader’s position. Previous analyses of the diversionary impulse have proven inconclusive. This study expands the literature in three ways. First, it broadens the spatial and temporal domain by examining the seven major powers of Renaissance Italy (1250-1494). Since diversionary theory was developed by looking at the actions of states in the modern system, testing it in a different empirical domain is important. Second, it uses a directed-dyadic research design, which can examine directional hypotheses. For instance, does domestic unrest increase the probability that the challenger will initiate conflict, or do targets avoid states experiencing unrest? Last, the analyses simultaneously assess the effects of regime change (the highest form of unrest) and domestic turmoil on the conflict behavior of states. In other words, does unrest severe enough to change the political system create an incentive to rally the public to the new regime, or do these states experience a honeymoon of support? The analyses find modest support for the diversionary hypothesis. Oligarchies are more likely to initiate wars during periods of domestic unrest, while republics tend to initiate wars against city-states that experienced a republican reversal.
Immigration, social cohesion and social capital: A critical review
Authors: Cheong Pauline Hope , Edwards Rosalind , Goulbourne Harry , Solomos John
Published: January 2007

In recent years, there has been an intense public and policy debate about ethnic diversity, community cohesion, and immigration in Britain and other societies worldwide. In addition, there has been a growing preoccupation with the possible dangers to social cohesion represented by growing immigration flows and ethnic diversity. This paper proposes a critical framework for assessing the links between immigration, social cohesion, and social capital. It argues that the concept of social capital is episodic, socially constructed and value-based, depending on the prevailing ideological climate. Considerations of social capital as a public policy tool to achieve social cohesion need to incorporate an appreciation of alternative conceptions of social capital rooted in a textured under-standing of immigrant processes and migration contexts.
When two dark figures collide: Evidence and discourse on drug-related crime
Authors: Stevens Alex
Published: January 2007

This paper explores the socio-political construction of drug-related crime; a concept that has dominated recent developments in UK drug policy. It has been assumed that the perceived overlap between known offenders and drug users is also present among the much larger groups of unknown offenders and drug users. This assumption has led to inflated claims of scale, precision and causality in political discussions of the drug-crime link. The discourse coalition approach is used to analyse how such methodologically suspect knowledge has been translated into policy since 1997. It is argued that the concept of drug-related crime has been influential because it is tactically and structurally useful to powerful groups in discursive struggle.
Policing the housing crisis
Authors: Carr Helen , Cowan Dave , Hunter Caroline
Published: January 2007

In this paper, we argue that the ‘crime control housing crisis’ which has engulfed social housing is qualitatively different from most previous and current understandings of housing crisis (which have been of a quantita tive nature, or been resolved to that). By contrast, the crime control housing crisis is a crisis precisely because it appears insoluble. All hous ing problems and policies now have to be legitimated by reference to this crime control housing crisis. The gaze of this crisis has been upon the ‘social’ sector, but that has also caused reflection on how to placate the crime control housing crisis in the private sector. It is this latter area that is the focus of the case study in the second part of this paper and starkly raises the central, deceptively simple, problematization for government: how to govern the ungovernable without being seen to govern. The case study concerns regulations promulgated by the Northern Ireland Housing Executive regarding the licensing of houses in multiple occupation. We argue that this regulation is symptomatic of a mutated ‘housing crisis’ in which the old questions of the adequacy of provision have been supplanted by new questions of responsibility for deviant behaviour.
Closed policy networks, broken chains of communication and the stories behind an ‘entrepreneurial policy’: The case of NHS Local Improvement Finance Trust (NHS LIFT)
Authors: Aldred Rachel
Published: January 2007

This article draws on original case study research to develop more general conclusions about policy-making processes under New Labour. I discuss the Local Improvement Finance Trust (LIFT) as an exemplar of new trends in contemporary capitalist welfare regimes, and I compare some of the enterprise rhetoric surrounding and justifying LIFT to the experiences of National Health Service managers and clinicians in my case study. I consider why many of the voices that I studied appear to remain unheard outside private interviews and meetings, and conclude that changes in the public sector are helping to create closed networks that are unresponsive to concerns expressed ‘on the ground’. Finally, I consider some implications of my data for the future of neo-liberal welfare policies.
Physical and psychological needs of patients dying from colo-rectal cancer
Authors: Maguire Peter , Walsh Sheila , Jeacock Julie , Kingston Reg
Published: January 2007

Sixty-one patients suffering from terminal colo-rectal cancer were interviewed in depth by trained research nurses. The nurses used a semistructured interview, a concerns checklist and the Psychiatric Assessment Schedule to determine patients' key physical complaints, their main concerns and whether or not an affective disorder was present. The interviewers' estimates of these aspects were then compared with the assessments of 48 carers and 58 general practitioners (GPs). The congruence between patients' and carers' reports was reasonable for appetite loss (77%), nausea and vomiting (75%) and pain (72%), and the rate of false positive reporting was low. However, there was much less congruence for breathlessness (48%) and pyrexia (32%). There was even less congruence between the estimates of patients' physical symptoms and GPs' perceptions. The highest congruence was for pain (42%). The congruence was low for appetite loss (8%) and breathlessness (5%). The congruence between patients' and carers' perceptions of the patients' major concerns was low, being at best 33% for patients' concerns about their physical illness. The rate of false positive reporting by carers was high. The carers' major concerns included the patients' illness (47%), the future (33%) and the emotional demands being put on them (23%). Thirteen (22%) of the 59 patients completing a full interview were suffering from an affective disorder. This had been recognized by the GP in only five cases and six patients who had a normal mood were wrongly diagnosed as being depressed. Of the carers interviewed, 22 (46%) considered symptom control had been inadequate and 23 (48%) felt they had no relief from the burden of caring or had too little help. Sixteen (33%) had recently suffered from a major depressive illness, generalized anxiety disorder or adjustment disorder. It is concluded that it is unreliable to rely on carers' proxy reports of the symptoms experienced by terminally ill patients; more accurate personal assessments are needed where possible. It is likely that this will only be achieved by ensuring that those health professionals involved in palliative care have training in the relevant assessment skills.
The Origins of the Joint University Council and the Background to Public Policy and Administration
Authors: Chapman Richard A.
Published: January 2007

This article is the result of research into public records in The National Archives; the Royal Institute of Public Administration archives in the University of Birmingham; the Joint University Council archives in the University of Warwick; and (with the kind assistance of Adrian Allan, Archivist, University of Liverpool) the papers of Professor Lord Simey of Toxteth. Its main purpose is to contribute to the history of the applied social sciences through tracing the background and development of Public Policy and Administration. Constraints of length and problems associated with the largely uncatalogued archives of the Joint University Council and the incomplete records of the Royal Institute of Public Administration prevent a full and comprehensive history of the topics covered, so it has to be selective (hence ‘an interpretation’), and the intention therefore has been to focus on the prehistory and history of influences contributing to the development of the Joint University Council, its Public Administration Committee and, especially, the journal Public Policy and Administration.
Rethinking ‘The Public’ in Troubled Times
Authors: Newman Janet
Published: January 2007

This article begins with contemporary concerns about the demise of public institutions and public values. New strategies of governance across Europe and beyond make any clear delineation of ‘the public’ and the public sphere highly problematic. The modernization of welfare states involves a shift of powers from state to market, but also a shift of responsibility from public to personal domains. The liberal values associated with the traditional public sphere seem illequipped to address questions of social diversity and deepening inequalities, or to respond to contemporary questions of culture, faith and identity. New spatial flows, bringing cross-national and globalized relationships, are dissolving any simple equivalence between nation, citizenship and the public sphere. How, then, might we better understand the terrain on which struggles around the future of publics and publicness are being played out?
Policy Without Learning
Authors: Jordan Grant
Published: January 2007

This article asserts that the current ‘Double Devolution’ idea in the UK is part of a wider fashion in political architecture that generally sees the emergence of larger units. Simultaneously though there is a political need for gestures to smaller scale units and more deliberative procedures. The article argues that the Double Devolution concept simply ignores a rising volume of evidence that finds problems in operationalizing small-scale and deliberative ideas. Among other problems is the consequence that the resulting increased policy diversity is quickly labelled a ‘postcode lottery’. The article also reviews the deliberative literature to find serious questions raised about new biases that emerge in deliberative settings. Finally, the article adopts Hood’s work on cultural theory and public management to say that in fact evidence-based policy making may not be the norm - but policy selections reflect values and normative preferences.
The Unfinished Business of Devolution
Authors: Jeffery Charlie
Published: January 2007

The UK’s devolution reforms were built on long-standing practices of differentiated territorial administration in the non-English parts of the UK. With devolution those practices became subject to new democratic processes, transforming territorial administration into territorial politics. The reforms were introduced in a piecemeal basis, lacking an overall conception of the impact of devolution on the UK state, and lacking consideration of how the government of the non-devolved unit of England can, through its size and weight within the UK, impact on and constrain devolved government. The combination of piecemeal reform and the ‘English question’ raises a number of open questions about the coherence and stability of the devolution arrangements, especially at the point when governments run by different parties import partisan considerations into territorial politics.
The Art of Prescription
Authors: Evans Mark
Published: January 2007

This article addresses a perennial controversy in the study of public administration - should academic knowledge about public administration be used for its betterment? And, if so, how should academic knowledge about public administration be used for its betterment? It is claimed that the answers to these questions lie in the symbiotic relationship between knowledge and action, theory and practice. In consequence it is argued that it is the responsibility of public administration scholars not only to provide explanations and understandings of administrative and political subjects but also to defend bureaucracy and to seek progress through ‘enlightened’ prescription. With these arguments in mind, first a ‘critical approach’ to public administration for reconciling the world of thought and the world of action is presented in which the prescriptive enterprise is used to integrate theory and practice. Second, a set of principles for ‘enlightened’ prescription is formulated to ensure that the knowledge claims that emerge from this process remain as rigorously conceived as possible. And third, a methodology is developed through the use of a logical framework matrix to provide both a practical device for evaluating the utility of public administration research for public action and to draw attention to putative problems in research in terms of theorization, method, data analysis and synthesis - thus demonstrating the benefit of ‘enlightened’ prescription to both the study of public administration and its practice.
Disciplining Bodies, Desires and Subjectivities: Sexuality and HIV-Positive Women
Authors: Gurevich Maria , Mathieson Cynthia M. , Bower Jo , Dhayanandhan Bramilee
Published: January 2007

Very little is known about the sexuality of women who are living with HIV, outside the context of risk prevention and education. Available research in the first-world context shows that, although most women continue to be sexually active following diagnosis, decreased sexual functioning is very common and more prevalent than among HIV-positive men. The present multi-site Canadian study is concerned with the ways in which women’s sexuality is transformed by the experience of living with HIV. Semi-structured interviews with 20 women were analysed using thematic decomposition, an analytic technique that combines discursive approaches with thematic analysis. The women in this study construct HIV as inhibiting in relation to sexuality. A predominant discourse of disciplining bodies, desires and subjectivities emerges, which centers on the restrictions imposed by an HIV-positive diagnosis. The following discursive constructions, in particular, emerge from the women’s accounts: diminished spontaneity, foreclosed (provisional) sexual freedom, foreclosed power, foreclosed flirtation, inciting violence, (un)natural sex, responsibility imperatives, muted/mutated sexuality, and diminished intimacy. The women’s predominant positioning within AIDS discourses as conduits of transmission, the relative neglect of women’s psychological and sexual health concerns in both research and public health agendas, and women’s relatively anomalous standing in AIDS communities imposes limits on bodies, lives, and subjectivities. These are reflected in these women’s accounts, wherein a focus on protecting others frequently impedes access to fulfilling (and safe) sexual and emotional relationships.
Midwifery, Informed Choice, and Reproductive Autonomy: A Relational Approach
Authors: Thachuk Angela
Published: January 2007

This article examines the parallels between the Canadian midwifery model of care and feminist reconfigurations of autonomy and choice. A critical survey of the medical model of informed consent and traditional notions of autonomy brings to light shortcomings of bioethical theories and decision-making practices that maintain a narrow ideology of autonomy and a limited perception of human characteristics. In contrast, relational models emphasize the social situatedness of the individual, and the relationship between self-trust and autonomous decision making. Shifting beyond the consent paradigm of the medical model, the midwifery model of care and the process of informed choice demonstrate an applied form of relational autonomy. It is my contention that Canadian midwifery’s avowed emphasis on empowerment and informed choice offers an exemplary standard of practice that maximizes women’s reproductive autonomy, thus demonstrating the merits of integrating relational approaches within bioethical theory and the health care context at large.
Lesbian Mothers Living Well in the Context of Heterosexism and Discrimination: Resources, Strategies and Legislative Change
Authors: Short Liz
Published: January 2007

Although the heterosexism and discrimination encountered by lesbian women who are mothers can have negative practical, financial, social and psychological consequences, lesbian women and their families frequently thrive. Based on in-depth interviews from the Australian Conceiving the Family: Lesbian Mothers’ Decisions, Experiences and Well-being, and the Current Legal, Public Policy, and Discursive Context project, this article identifies the importance of legislative change in promoting the well-being of lesbian women who are mothers, and presents resources and strategies that some use to live well, resist heterosexism and discrimination and minimise its effects.
‘Spontaneous’ Sexual Consent: An Analysis of Sexual Consent Literature
Authors: Beres Melanie A.
Published: January 2007

Sexual consent is an understudied and undertheorized concept despite its importance to feminist researchers and activists interested in sexual violence. Literature on consent, although sparse, has been produced from a variety of disciplines, including law, psychology, and sociology. This article is a critical review of current literature and current understandings of sexual consent. Different conceptualizations of consent are analysed including implicit and explicit definitions from legal theorists and sexual violence and consent researchers. Alternatives, including communicative sexuality, are discussed and feminist understandings of the social context of consent and the social forces that produce understandings of consent are examined. Directions for future research are suggested.
Shared as well as distinct roles of EHD proteins revealed by biochemical and functional comparisons in mammalian cells and C. elegans
Authors: George Manju , Ying GuoGuang , Rainey Mark A , Solomon Aharon , Parikh Pankit T , Gao Qingshen , Band Vimla , Band Hamid
Published: January 2007

Background

The four highly homologous human EHD proteins (EHD1-4) form a distinct subfamily of the Eps15 homology domain-containing protein family and are thought to regulate endocytic recycling. Certain members of this family have been studied in different cellular contexts; however, a lack of concurrent analyses of all four proteins has impeded an appreciation of their redundant versus distinct functions.

Results

Here, we analyzed the four EHD proteins both in mammalian cells and in a cross-species complementation assay using a C. elegans mutant lacking the EHD ortholog RME-1. We show that all human EHD proteins rescue the vacuolated intestinal phenotype of C. elegans rme-1 mutant, are simultaneously expressed in a panel of mammalian cell lines and tissues tested, and variably homo- and hetero-oligomerize and colocalize with each other and Rab11, a recycling endosome marker. Small interfering RNA (siRNA) knock-down of EHD1, 2 and 4, and expression of dominant-negative EH domain deletion mutants showed that loss of EHD1 and 3 (and to a lesser extent EHD4) but not EHD2 function retarded transferrin exit from the endocytic recycling compartment. EH domain deletion mutants of EHD1 and 3 but not 2 or 4, induced a striking perinuclear clustering of co-transfected Rab11. Knock-down analyses indicated that EHD1 and 2 regulate the exit of cargo from the recycling endosome while EHD4, similar to that reported for EHD3 (Naslavsky et al. (2006) Mol. Biol. Cell 17, 163), regulates transport from the early endosome to the recycling endosome.

Conclusion

Altogether, our studies suggest that concurrently expressed human EHD proteins perform shared as well as discrete functions in the endocytic recycling pathway and lay a foundation for future studies to identify and characterize the molecular pathways involved.
Conserved alternative and antisense transcripts at the programmed cell death 2 locus
Authors: Mihola Ondrej , Forejt Jiri , Trachtulec Zdenek
Published: January 2007

Background

The programmed cell death 2 (Pdcd2) gene on mouse chromosome 17 was evaluated as a member of a highly conserved synteny, a candidate for an imprinted locus, and a candidate for the Hybrid sterility 1 (Hst1) gene.

Results

New mouse transcripts were identified at this locus: an alternative Pdcd2 mRNA skipping the last two coding exons and two classes of antisense RNAs. One class of the antisense RNA overlaps the alternative exon and the other the entire Pdcd2 gene. The antisense RNAs are alternative transcripts of the neighboring TATA-binding protein gene (Tbp) that are located mainly in the cell nucleus. Analogous alternative PDCD2 forms truncating the C-terminal domain were also detected in human and chicken. Alternative transcripts of the chicken PDCD2 and TBP genes also overlap. No correlation in the transcription of the alternative and overlapping mRNAs was detected. Allelic sequencing and transcription studies did not reveal any support for the candidacy of Pdcd2 for Hst1. No correlated expression of Pdcd2 with the other two genes of the highly conserved synteny was observed. Pdcd2, Chd1, and four other genes from this region were not imprinted in the embryo.

Conclusion

The conservation of alternative transcription of the Pdcd2 gene in mouse, human and chicken suggests the biological importance of such truncated protein. The biological function of the alternative PDCD2 is likely to be opposite to that of the constitutive form. The ratio of the constitutive and alternative Pdcd2 mRNAs differs in the tissues, suggesting a developmental role.

The identified Tbp- alternative Pdcd2-antisense transcripts may interfere with the transcription of the Pdcd2 gene, as they are transcribed at a comparable level. The conservation of the Pdcd2/Tbp sense-antisense overlap in the mouse and chicken points out its biological relevance. Our results also suggest that some cDNAs in databases labeled as noncoding are incomplete alternative cDNAs of neighboring protein-coding genes.
Systematic analysis of the regulation of type three secreted effectors in Salmonella enterica serovar Typhimurium
Authors: Dieye Yakhya , Dyszel Jessica L , Kader Rebin , Ahmer Brian MM
Published: January 2007

Background

The type III secretion system (TTSS) is an important virulence determinant of Gram-negative bacterial pathogens. It enables the injection of effector proteins into the cytosol of eukaryotic cells. These effectors ultimately manipulate the cellular functions of the infected organism. Salmonella enterica serovar Typhimurium encodes two virulence associated TTSSs encoded by the Salmonella Pathogenicity Islands (SPI) 1 and 2 that are required for the intestinal and systemic phases of the infection, respectively. However, recent studies suggest that the roles of these TTSSs are not restricted to these compartments. The regulation of TTSSs in Salmonella is very complex with several regulators operating to activate or to repress expression depending on the environmental conditions.

Results

We performed a systematic analysis of the regulation of type III effectors during growth in vitro. We have tested the ability of seven regulatory genes to regulate ten effector genes. Each regulator was expressed in the absence of the other six to avoid cascade effects. Our results confirm and extend the previously reported regulation of TTSS1 and TTSS2 effectors by InvF-SicA and SsrB respectively.

Conclusion

The set of strains constructed for this study can be used to quickly and systematically study the regulation of newly identified effector genes of Salmonella enterica. The approach we have used can also be applied to study complex regulatory cascades in other bacterial species.
A long-term "memory" of HIF induction in response to chronic mild decreased oxygen after oxygen normalization
Authors: Kamat Chandrashekhar D , Thorpe Jessica E , Shenoy Satyendra S , Ceriello Antonio , Green Dixy E , Warnke Linda A , Ihnat Michael A
Published: January 2007

Background

Endothelial dysfunction (ED) is functionally characterized by decreased vasorelaxation, increased thrombosis, increased inflammation, and altered angiogenic potential, has been intimately associated with the progression and severity of cardiovascular disease. Patients with compromised cardiac function oftentimes have a state of chronic mild decreased oxygen at the level of the vasculature and organs, which has been shown to exacerbate ED. Hypoxia inducible factor (HIF) is a transcription factor complex shown to be the master regulator of the cellular response to decreased oxygen levels and many HIF target genes have been shown to be associated with ED.

Methods

Human endothelial and aortic smooth muscle cells were exposed either to A) normoxia (21% O2) for three weeks, or to B) mild decreased oxygen (15% O2) for three weeks to mimic blood oxygen levels in patients with heart failure, or to C) mild decreased oxygen for two weeks followed by one week of normoxia ("memory" treatment). Levels of HIF signaling genes (HIF-1α, HIF-2α, VEGF, BNIP3, GLUT-1, PAI-1 and iNOS) were measured both at the protein and mRNA levels.

Results

It was found that chronic exposure to mild decreased oxygen resulted in significantly increased HIF signaling. There was also a "memory" of HIF-1α and HIF target gene induction when oxygen levels were normalized for one week, and this "memory" could be interrupted by adding a small molecule HIF inhibitor to the last week of normalized oxygen. Finally, levels of ubiquitylated HIF-1α were reduced in response to chronic mild decreased oxygen and were not full restored after oxygen normalization.

Conclusion

These data suggest that HIF signaling may be contributing to the pathogenesis of endothelial dysfunction and that normalization of oxygen levels may not be enough to reduce vascular stress.
Construction and characterization of new piggyBac vectors for constitutive or inducible expression of heterologous gene pairs and the identification of a previously unrecognized activator sequence in piggyBac
Authors: Shi Xianzong , Harrison Robert L , Hollister Jason R , Mohammed Ahmed , Fraser Malcolm J , Jarvis Donald L
Published: January 2007

Background

We constructed and characterized several newpiggyBacvectors to provide transposition of constitutively- or inducibly-expressible heterologous gene pairs. The dual constitutive control element consists of back-to-back copies of a baculovirus immediate early (ie1) promoter separated by a baculovirus enhancer (hr5). The dual inducible control element consists of back-to-back copies of a minimal cytomegalovirus (CMVmin) promoter separated by a synthetic operator (TetO7), which drives transcription in the presence of a mutant transcriptional repressor plus tetracycline.

Results

Characterization of these vectors revealed an unexpected position effect, in which heterologous genes adjacent to the 3'- terminal region ("rightward" genes) were consistently expressed at higher levels than those adjacent to the 5'-terminal region ("leftward" genes) of thepiggyBacelement. This position effect was observed with all six heterologous genes examined and with both transcriptional control elements. Further analysis demonstrated that this position effect resulted from stimulation of rightward gene expression by the internal domain sequence of the 3'-terminal region ofpiggyBac. Inserting a copy of this sequence into the 5'- terminal repeat region of our newpiggyBacvectors in either orientation stimulated leftward gene expression. RepresentativepiggyBacvectors designed for constitutive or inducible expression of heterologous gene pairs were shown to be functional as insect transformation vectors.

Conclusion

This study is significant because (a) it demonstrates the utility of a strategy for the construction ofpiggyBacvectors that can provide constitutive or inducible heterologous gene pair expression and (b) it reveals the presence of a previously unrecognized transcriptional activator inpiggyBac, which is an important and increasingly utilized transposable element.
Antiproliferative and pro-apoptotic activity of eugenol-related biphenyls on malignant melanoma cells
Authors: Pisano Marina , Pagnan Gabriella , Loi Monica , Mura Maria Elena , Tilocca Maria Giovanna , Palmieri Giuseppe , Fabbri Davide , Dettori Maria Antonietta , Delogu Giovanna , Ponzoni Mirco , Rozzo Carla
Published: January 2007

Background

Malignant melanoma is one of the most aggressive skin cancer and chemotherapeutic agents currently in use are still unsatisfactory. Prevention and early diagnosis are the only effective tools against this tumour whose incidence and mortality rates are highly increased during the last decades in fair skin populations. Therefore the search for novel therapeutic approaches is warranted. Aim of this work was to identify and test new compounds with antiproliferative and cytotoxic activity on melanoma cells. We tested eugenol together with six natural and synthetic eugenol-related compounds for their capability to inhibit cell growth on primary melanoma cell lines established from patients' tissue samples.

Results

Eugenol and isoeugenol monomers and their respective O-methylated forms did not show to inhibit melanoma cells proliferation. Conversely, the dimeric forms (biphenyls) showed some antiproliferative activity which was mild for dehydrodieugenol, higher for its O,O'- methylated form (O,O'-dimethyl-dehydrodieugenol), and markedly pronounced for the racemic mixture of the brominated biphenyl (6,6'-dibromo-dehydrodieugenol) (S7), being its enantiomeric form (S) the most effective compared to the other compounds. Such activity resulted to be selective against tumour cells, without affecting cultured normal human skin fibroblasts. Dose and time dependence curves have been obtained for the enantiomeric form S7-(S). Then IC50 and minimal effective doses and times have been established for the melanoma cell lines tested. TUNEL and phosphatidylserine exposure assays demonstrated the occurrence of apoptotic events associated with the antiproliferative activity of S7-(S). Cytotoxic activity and apoptosis induced by treating melanoma cells with eugenol-related biphenyls was partially dependent by caspase activation.

Conclusion

Our findings demonstrate that the eugenol related biphenyl (S)-6,6'-dibromo-dehydrodieugenol elicits specific antiproliferative activity on neuroectodermal tumour cells partially triggering apoptosis and its activity should be further investigated on in vivo melanoma models in order to evaluate the real anticancer effectiveness on such tumour.
M ulticenter randomi zed trial of cell the rapy in car diopat hies – MiHeart Study
Authors: Tura Bernardo R , Martino Helena F , Gowdak Luis H , dos Santos Ricardo Ribeiro , Dohmann Hans F , Krieger José E , Feitosa Gilson , Vilas-Boas Fábio , Oliveira Sérgio A , Silva Suzana A , Bozza Augusto Z , Borojevic Radovan , de Carvalho Antonio C Campos
Published: January 2007

Background

Cardiovascular diseases are the major cause of death in the world. Current treatments have not been able to reverse this scenario, creating the need for the development of new therapies. Cell therapies have emerged as an alternative for cardiac diseases of distinct causes in experimental animal studies and more recently in clinical trials.

Method/Design

We have designed clinical trials to test for the efficacy of autologous bone marrow derived mononuclear cell therapies in four different cardiopathies: acute and chronic ischemic heart disease, and Chagasic and dilated cardiomyopathy. All trials are multicenter, randomized, double-blind and placebo controlled. In each trial 300 patients will be enrolled and receive optimized therapy for their specific condition. Additionally, half of the patients will receive the autologous bone marrow cells while the other half will receive placebo (saline with 5% autologous serum). For each trial there are specific inclusion and exclusion criteria and the method for cell delivery is intramyocardial for the chronic ischemic heart disease and intracoronary for all others. Primary endpoint for all studies will be the difference in ejection fraction (determined by Simpson's rule) six and twelve months after intervention in relation to the basal ejection fraction. The main hypothesis of this study is that the patients who receive the autologous bone-marrow stem cell implant will have after a 6 month follow-up a mean increase of 5% in absolute left ventricular ejection fraction in comparison with the control group.

Discussion

Many phase I clinical trials using cell therapy for cardiac diseases have already been performed. The few randomized studies have yielded conflicting results, rendering necessary larger well controlled trials to test for efficacy of cell therapies in cardiopathies.

The trials registration numbers at the NIH registry are the following: Chagasic cardiomyopathy (NCT00349271), dilated cardiomyopathy (NCT00333827), acute myocardial infarction (NCT00350766) and Chronic Ischemic Heart Disease (NCT00362388).
Novel dexamethasone-HPMA copolymer conjugate and its potential application in treatment of rheumatoid arthritis
Authors: Wang Dong , Miller Scott C , Liu Xin-Ming , Anderson Brian , Wang Xu Sherry , Goldring Steven R
Published: January 2007

Rheumatoid arthritis (RA) is a chronic autoimmune disease of unknown etiology. Effective treatment of this disorder has been hampered by the lack of availability of agents that selectively target affected joint tissue. We developed a novel pH-sensitive drug delivery system of dexamethasone (Dex) based on an N-(2-hydroxypropyl)methacrylamide copolymer (P-Dex) and have shown that the delivery system specifically accumulates in inflamed joints in an animal model of arthritis. We hypothesize that the arthrotropism of the delivery system and the local acidosis-mediated drug release provide superior therapeutic efficacy and potentially reduced side effects in RA treatment. The initial in vitro drug-release study confirmed that the Dex release is indeed dependent upon the environmental pH. At pH 5, 37°C, the conjugate shows the highest level of drug release. When administered systemically in an adjuvant-induced arthritis rat model, P-Dex offers superior and longer-lasting anti-inflammatory effects compared with systemically administered free Dex. In addition, greater bone and cartilage preservation was observed with the P-Dex treatment compared with free Dex treatment. Our data indicate that the differential effect of the conjugate is related to its selective accumulation, potential macrophage-mediated retention, and pH-sensitive drug release (extracellular and intracellular) in arthritic joints. This newly developed drug delivery system provides a unique method for selective targeting of glucocorticoids to inflamed joints which may potentially reduce systemic side effects.
Phase III Randomized Trial of Conventional-Dose Chemotherapy With or Without High-Dose Chemotherapy and Autologous Hematopoietic Stem-Cell Rescue As First-Line Treatment for Patients With Poor-Prognosis Metastatic Germ Cell Tumors
Authors: Motzer Robert J. , Nichols Craig J. , Margolin Kim A. , Bacik Jennifer , Richardson Paul G. , Vogelzang Nicholas J. , Bajorin Dean F. , Lara Primo N. , Einhorn Lawrence , Mazumdar Madhu , Bosl George J.
Published: January 2007

Purpose

To investigate the role of high-dose chemotherapy (HDCT) as first-line treatment in patients with metastatic germ cell tumor (GCT) and poor-prognostic clinical features. Serum tumor marker decline during chemotherapy was assessed prospectively as a predictor of treatment outcome.

Patients and Methods

In this randomized phase III trial, previously untreated patients with intermediate- or poor-risk GCT received either four cycles of standard bleomycin, etoposide, and cisplatin (BEP alone), or two cycles of BEP followed by two cycles of HDCT containing carboplatin and then by hematopoietic stem-cell rescue (BEP + HDCT). Serum tumor markers alpha-fetoprotein and human chorionic gonadotrophin were correlated with treatment outcome as a secondary end point.

Results

Two hundred nineteen patients were randomly assigned: 108 to BEP + HDCT and 111 to BEP alone. The 1-year durable complete response rate was 52% after BEP + HDCT and 48% after BEP alone (P = .53). Patients with slow serum tumor marker decline (alpha-fetoprotein and/or human chorionic gonadotrophin) during the first two cycles of chemotherapy had a shorter progression-free survival and overall survival compared with patients with satisfactory marker decline (P = .02 and P = .03, respectively). Among 67 patients with unsatisfactory marker decline, the 1-year durable complete response proportion was 61% for patients who received HDCT versus 34% for patients receiving BEP alone (P = .03).

Conclusion

The routine inclusion of HDCT in first-line treatment for GCT patients with metastases and a poor predicted outcome to chemotherapy did not improve treatment outcome. Frequent serum marker determinations to estimate marker decline during the first two cycles of BEP chemotherapy provide a clinically useful estimate of outcome.
Patterns and Correlates of Patient Referral to Surgeons for Treatment of Breast Cancer
Authors: Katz Steven J. , Hofer Timothy P. , Hawley Sarah , Lantz Paula M. , Janz Nancy K. , Schwartz Kendra , Liu Lihua , Deapen Dennis , Morrow Monica
Published: January 2007

Purpose

Characteristics of surgeons and their hospitals have been associated with cancer treatments and outcomes. However, little is known about factors that are associated with referral pathways.

Methods

We analyzed tumor registry and survey data from women with breast cancer diagnosed in 2002 and reported to the Detroit and Los Angeles Surveillance, Epidemiology, and End Results registries (n = 1,844; response rate, 77.4%) and their attending surgeons (n = 365; response rate 80.0%).

Results

About half of the patients (54.3%) reported that they were referred to the surgeon by another provider or health plan; 20.3% reported that they selected the surgeon; and 21.9% reported that they both were referred and were involved in selecting the surgeon. Patients who selected the surgeon based on reputation were more likely to have received treatment from a high-volume surgeon (adjusted odds ratio [OR], 2.2; 95% CI, 1.5 to 3.4) and more likely to have been treated in an American College of Surgeons–approved cancer program or a National Cancer Institute (NCI) –designated cancer center (adjusted OR, 2.0; 95% CI, 1.3 to 3.1; adjusted OR, 3.4; 95% CI, 1.9 to 6.2, respectively). Patients who were referred to the surgeon were less likely to be treated in an NCI-designated cancer center (adjusted OR, 0.5; 95% CI, 0.3 to 0.9).

Conclusion

Women with breast cancer who actively participate in the surgeon selection process are more likely to be treated by more experienced surgeons and in hospitals with cancer programs. Patients should be aware that provider or health plan–based referral may not connect them with the most experienced surgeon or comprehensive practice setting in their community.