bluuebunny/crossref_metadata_2025 huggingface dataset:
(Re)cycling in Sylvain Chomet’s Les Triplettes de Belleville (2003): Spokes in the wheels of French exceptionalism and global exploitation?
Authors: Cruickshank Ruth
Published: July 2012

Sylvain Chomet’s animated feature Les Triplettes de Belleville (2003) makes recurrent references to cycles and recycling. Putting spokes in interlinking wheels, these offer new perspectives on the exploitative cycles of the global market and challenge some of the constituent discourses of French exceptionalism: economic, philosophical and cinematic. Instead of figuring a big bad American Other, the film exposes French co-implication in the global market, past and present, and in its exploitative entertainment industry. The examination of these motifs reveals intersections with and divergences from altermondialiste debates and critics of (late) capitalism such as Barthes, Baudrillard, Debord and Derrida. Chomet also seeks to negotiate the ways in which his film in turn colludes in such cycles. Indeed Chomet’s recycling of cinematic techniques and images (feature and animation; French, Hollywood and anime; hand-drawn and CGI) invites questions as to the enduring critical potential of cinema.
Royal Navy Fleet Tactics on the Eve of the Second World War
Authors: Levy James P.
Published: July 2012

The Royal Navy’s 1939 ‘Fighting Instructions’ provide a unique and underutilized window onto British naval doctrine in the World War II era. A comparison with US and Japanese pre-war tactical/operational thinking clarifies and illuminates the ideas and issues faced by naval officers in the interwar period. Additionally, this line of inquiry foregrounds the question of how we assess naval tactical schemes.
The British Army and Wireless Communication, 1896–1918
Authors: Hall Brian N.
Published: July 2012

The First World War is often identified as a great industrial and technological struggle. However, in the course of explaining the Allied victory in 1918, scholarly opinion is divided over the extent to which the British army made the most effective use of the technology available to it. While much of the debate has centred on the more ‘lethal’ technologies, such as aeroplanes, tanks, and poison gas, very little analysis has been made of the interaction between British commanders and communications technology. This article seeks to redress this imbalance by assessing the extent to which British commanders embraced the latest communication device of the period – wireless – and whether they harnessed its full military potential.
European Monetary System and the Fiscal Crisis
Authors: Kumar Saurabh
Published: July 2012

The episode of fiscal crisis in the Euro zone has now become a recurrent theme of debate and has attracted a range of experiences regarding the nature of fiscal turmoil, its causes and effects, which vary widely across individual countries. The confidence in the European monetary system has been confounded with the European fiscal turmoil. The phases of its revival and by what method it will recoil, and at what velocity, are unanswered questions. At the centre of the European monetary system is the European Central Bank (ECB) which shapes and conducts a vigorous and complex set of policies and institutional arrangements that represent the image of neoliberal economic ideology. The debate over the European monetary system’s architecture has significant ideological, economic and political implications. This article approaches the debate by assessing the monetary policy strategy and in particular the organisational structure of the ECB, and what role they play in the conduct of economic and monetary course of action in the Euro zone.
Impact of an Oncology Palliative Care Clinic on Access to Home Care Services
Authors: Jang Raymond W. , Burman Debika , Swami Nadia , Kotler Jennifer , Banerjee Subrata , Ridley Julia , Mak Ernie , Bryson John , Rodin Gary , Le Lisa W. , Zimmermann Camilla
Published: July 2012

Home care (HC) is important for patients with cancer as performance status declines. Our study of 1224 patients at a Canadian cancer center examined the impact of an oncology palliative care clinic (OPCC) on HC referral. The HC referral frequency was calculated before and after the first OPCC consultation, in total and according to performance status (Palliative Performance Scale, PPS). Characteristics associated with HC referral were investigated. After the first OPCC consultation, there was an increase in HC referral from 39% (477 of 1224; 49% of those with PPS ≤60) to 69% (841 of 1224; 88% of those with PPS ≤60). Factors independently associated with HC referral were poor PPS ( P < .001) and older age ( P = .003). Thus OPCC involvement resulted in markedly increased HC referrals, particularly for older patients with poor performance status.
The Dimensionality of the Career Decision Self-Efficacy Scale–Short Form Among Chinese Graduate Students
Authors: Jin Leili , Ye Shengquan , Watkins David
Published: July 2012

The factorial structure of the Career Decision Self-Efficacy Scale–Short Form (CDSES-SF) was examined in a sample of 796 Chinese graduate students recruited from five universities in Beijing. A single-factor model is recommended on the basis of two of this study’s findings. First, confirmatory factor analyses revealed that the parsimonious single-factor model fit the data well as the competing multi-factor models did. Second, the original theoretical factors of the CDSES-SF were found to be highly homogeneous and to fail to demonstrate the necessary incremental validity over and beyond the total score. Consistent with the previous studies, the CDSES-SF was found to have sound internal consistency (α = .91). The implications of the current study are discussed.
Bevacizumab in lung cancer: Lackluster performance and unjustified expense?
Authors: Dasanu Constantin A
Published: July 2012

A recent retrospective analysis of a large cohort of patients aged 65 and older with advanced non-small cell lung cancer failed to demonstrate any improvement in survival with the addition of bevacizumab to the platinum doublet in the first-line therapy. A few points have to be made: 1) a vast majority of patients with lung cancer are 65 and older; 2) important including fatal toxicity can occur with the use of bevacizumab; and 3) costs of bevacizumab are significant. Integrating the conclusions of this study into clinical practice and further analysis of underlying physical, psychosocial, and economic hurdles of bevacizumab use in lung cancer patients are certainly justified.
A Preliminary Randomized Controlled Trial of Two Social Skills Interventions for Youth With High-Functioning Autism Spectrum Disorders
Authors: Lerner Matthew D. , Mikami Amori Y.
Published: July 2012

This study examined the effects of two social skills interventions, Sociodramatic Affective Relational Intervention (SDARI) and Skillstreaming, to compare their treatment mechanisms, social performance- and knowledge-training. A total of 13 youth with autism spectrum disorders were randomly assigned to 4 weeks of 1-day/week SDARI or Skillstreaming. Groups were matched on parent and child demographics, and intervention staff training. Participants were assessed on social behavior during treatment sessions, peer sociometrics, staff-reported social skills, and parent-reported social skill generalization. Results indicated that both groups increased in reciprocated friendship nominations and staff-reported social skills. Relative to Skillstreaming participants, SDARI participants liked and interacted more with each other after a single session. However, Skillstreaming participants increased in peer liking and interaction over the course of the intervention; SDARI participants decreased slightly. Parents reported no change in social functioning at home. Implications for research and practice are discussed.
‘It’s better than catching frogs’: Understanding the importance of local context in the development of inclusive school self-evaluation in Lao PDR
Authors: Grimes Peter , Sayarath Khomvanh , Outhaithany Sithath
Published: July 2012

This article is an account of a project in Laos which aimed to support schools in evaluating and developing responsiveness to diversity in student populations. Teachers, students and members of the community were involved in review, evaluation and leadership of change to improve learning and participation for all school-aged members of the community, including changing school cultures in terms of curriculum and pedagogy and also access to learning for those previously marginalized within communities. The project (in nine primary schools) led to greater shared leadership, participation and voice prompted by self-evaluation. Analysis enabled greater understanding of the challenges and issues in working across cultures to effect sustainable organizational change. Spaces needed to be created at local levels for teachers to construct meaning and develop a sense of agency in making and owning changes in practice. This shifting of responsibility is crucial in order to build sustainable development.
A case of educational reform from the ground up: Involving ethnic minority parents in the life of the school in South East Europe
Authors: Frost David
Published: July 2012

This article explores the challenge of education reform and presents an alternative to dominant approaches. In doing so, it draws on the work of three projects: first, the ‘Advancing Education Quality and Inclusion’ initiative; second, the APREME (Advancing the Participation and Representation of Ethnic Minorities in Education) project which followed it; and third, the International Teacher Leadership project with which these two projects had strong links. The article discusses the large-scale survey of parents and school principals across 10 countries in South East Europe and the follow-up case studies in five of these countries. The focus then shifts to the practical intervention which was based on the idea of non-positional teacher leadership. Reports of all three projects are analysed to support a particular view of education reform led by teachers’ own development initiatives.
Wide Externalism and the Roles of Biology and Culture in Human Emotional Development
Authors: Greenwood Jennifer
Published: July 2012

In both the philosophy and psychology of emotion there is disagreement regarding the role of biology/genetics and culture/sociality in emotional development and experience. Using recent insights from developmental psychology and biology, and particularly recent developments in metaphysics of mind, I argue that distinctly human emotionality requires the complex interaction of both. Human neonates and caregivers are genetically preadapted to enable emotional ontogenesis in the context only of a complexly interdependent linguistically-mediated social relationship. This relationship provides the requisite sensory-perceptual stimulation to excite intracellular genetic activity and the resultant development/maturation of emotion-related neural substrata. This genetic preadaptation and the close linguistically-mediated social relationship together provide the necessary and sufficient conditions for the gradual development of human adult emotionality.
How to engage? Assemblage as ethos/ethos as assemblage
Authors: Adey Peter
Published: July 2012

This commentary unpicks ethos and assemblage, and specifically explores the way assemblage becomes a kind of ethos in itself. By unravelling the use and maybe neglect of ethos within Anderson et al.’s (2012) paper and wider geographies – despite its animating force within them – the paper encourages more explicit concern for how we think, do, or live ethos within research and writing, and the promise of assemblage as ethos/ethos as assemblage, for broader geographical work.
On the agencement of the academic geographer
Authors: Greenhough Beth
Published: July 2012

This commentary draws a contrast between assemblage as Deleuzian agencement, orientated towards the possibilities for re-ordering and the emergence of new orders, and the forms of assemblage emphasized by actor-network theory, which focuses on the question of how orders are practised/performed. It is suggested that while focusing on agencement offers a means of opening up ‘naturalized’ social and spatial orders and placing their entrenched political and ethical values in question, it is also important to recognize that ‘assemblage thinking’ within an academic context is always also a form of intervention. This has two key implications: (1) we need to take into account geographers’ perceptual capacities and limited empirical skills, questions of how our own inherent biases, our abilities to sense and relate to others, and the structures and conventions of academic labour shape the assemblages which emerge through our work; (2) we need to acknowledge that research is a political and ethical act, for it constitutes an inevitable transformation of the assemblage under investigation. This in turn raises a question of how we respond to this responsibility; do we draw on our assemblage thinking to say this is important (make strategic cuts) or to say things are indeterminate, but watch this space because something interesting might happen?
‘Island life’: Basking in isolation
Authors: Taylor Michael
Published: July 2012

This paper offers a different perspective to Jamie Peck's on economic geography’s ‘island life’. It sees economic geography hiding from the storm created by economics’ foray into geography (so-called new economic geography), on an island of self-referential reasoning behind defences of multi-layered social theorising. It is critical of both economic geographies, with each transfixed by its own theoretical eccentricities and neither saying anything substantial about the key economic processes and monumental problems of deep and continuing recession within the global economy. The paper offers a range of issues that need to be addressed.
Making space for markets in economic geography
Authors: Hall Sarah
Published: July 2012

In this commentary, I respond to Peck’s (2012) call to position markets as central conceptual, methodological and political research objects within economic geography. In particular, I suggest that cultural economy work on market devices and market actors provides two fruitful ways of advancing such a research agenda. Drawing on work on money and finance, I reflect on both the opportunities and challenges of using this approach to foster interdisciplinary heterodox economics understandings of markets.
The Social Construction of Organizational Disintegration: Exploring Identity Dynamics and Restructuring through a Longitudinal Case Study of a Post-Socialist Enterprise
Authors: Soulsby Anna , Clark Ed
Published: July 2012

This article seeks to advance our understanding of organizational change by exploring the relationships between patterns of organizational restructuring and identity dynamics as they interrelate over time. Our arguments are set in the empirical context of post-socialist Central Europe and the data, derived from the longitudinal study of a former state-owned enterprise that has been visited many times from 1993 to 2011, tell the story of a process of vertical disintegration. The article contributes to the field by elaborating the dynamic effects of identity ambivalence and identity conflict on top management decision making and the consequent social construction of organizational change processes.
Persistent Economic Divergence and Institutional Dysfunction in Post-Communist Economies: An Alternative Synthesis
Authors: Upchurch Martin
Published: July 2012

This paper seeks to explain the continuing lack of economic convergence and the persistence of market dysfunctionality, or wild capitalism, in post-communist transformation. An overview of key statistics on economic convergence and market failure are presented. The paper then analyses the causes of malaise through the lens of institutionalist and radical perspectives. In doing so key data are assembled and presented from documents of the international financial institutions and other agencies monitoring crime and corruption. The paper concludes that, rather than encourage convergence and tame dysfunctionality, neoliberalism and its offspring of labour market reform have created the conditions for continuing economic divergence and for wild capitalism to survive and thrive.
Managing Competition Risk: A Critical Realist Philosophical Exploration
Authors: Ojiako Udechukwu , Marshall Alasdair , Luke Michelle A , Chipulu Max
Published: July 2012

As firms act to meet competitive challenges, they separately vary their exposure to objectively real risks, and their subjective risk perceptions. Hence the ‘fit’ between each firm's subjective risk map and its objective ‘riskscape’ is in constant flux. Realist thought, which emphasizes the separateness of mind from external reality, and sets itself the slow and painstaking task of improving the fit between the two, is therefore universally relevant for risk management. This simple ‘risk realism’ has value for academics wishing to analyse risk management practice and can provide useful working assumptions and procedural guidelines for practitioners. Mindful of both uses, this paper utilizes the philosophical thesis of critical realism to develop ontological and epistemological standpoints that relate specifically to what we call ‘competition risk’. Working from these standpoints we develop parallels between business and military engagements with competition risk. We explore what we treat as ontologically indistinct competition risk issues present across both contexts and conclude that firms can learn much from how the military deals with both ‘regular’ and ‘irregular’ forms of competition risk.
Effect of low voltage pulsed magnetic field on microstructure and wear behaviour of eutectic Al–Si alloys
Authors: Zhang L , Zhou Q
Published: July 2012

Effect of discharging frequency of low voltage pulsed magnetic field (LVPMF) on the morphology and size of eutectic Si in eutectic Al–Si (Al–12Si) alloys has been investigated, and some characteristic parameters the characterised the microstructure of the eutectic Si phase were obtained. Dry sliding wear behaviour of eutectic Al–Si alloys without and with LVPMF treatment were also tested using a pin-on-disc wear testing machine, and scanning electron microscopy and energy dispersive spectroscopy X-ray of worn surfaces were carried out to determine the governing mechanisms in the eutectic Al–Si alloys without and with LVPMF treatment. The results show that the eutectic Si became smaller with the increase in discharging frequency. Fine short rod-like or rounded particle-like eutectic silicon with 2·3 μm in length, 0·6 μm in the width, and 3·8 in aspect ratio was formed in eutectic Al–Si alloy treated by 6 Hz LVPMF. The wear resistance of eutectic Al–Si alloys increased with the increase in discharging frequency. The adhesive wear was observed in eutectic Al–Si alloy without LVPMF treatment under normal load of 80 N. However, mainly abrasive was observed in eutectic Al–Si alloy with 6 Hz LVPMF treatment.
Corrosion properties of Pt coatings by double glow plasma
Authors: Wu W P , Chen Z F , Cong X N
Published: July 2012

The deposition of platinum coatings by double glow plasma technique on titanium alloy substrates at different gas pressures is reported. The corrosion properties of platinum coatings were investigated. The coating deposited at gas pressures of 20 and 30 Pa had a preferred (220) orientation due to the initial nuclei with preferred growth on the surface of the substrate. The coating deposited at gas pressure of 25 Pa showed no evidence of preferential orientation. The platinum coatings showed better corrosion resistance than the titanium alloy. The electrochemical properties of the platinum coatings deposited at different gas pressures had some difference because the porosity in the coating increased with increasing gas pressure.
Clustered metallothionein genes are co-regulated in rice and ectopic expression of OsMT1e-Pconfers multiple abiotic stress tolerance in tobacco via ROS scavenging
Authors: Kumar Gautam , Kushwaha Hemant Ritturaj , Panjabi-Sabharwal Vaishali , Kumari Sumita , Joshi Rohit , Karan Ratna , Mittal Shweta , Pareek Sneh L Singla , Pareek Ashwani
Published: July 2012

Background

Metallothioneins (MT) are low molecular weight, cysteine rich metal binding proteins, found across genera and species, but their function(s) in abiotic stress tolerance are not well documented.

Results

We have characterized a rice MT gene, OsMT1e-P, isolated from a subtractive library generated from a stressed salinity tolerant rice genotype, Pokkali. Bioinformatics analysis of the rice genome sequence revealed that this gene belongs to a multigenic family, which consists of 13 genes with 15 protein products. OsMT1e-P is located on chromosome XI, away from the majority of other type I genes that are clustered on chromosome XII. Various members of this MT gene cluster showed a tight co-regulation pattern under several abiotic stresses. Sequence analysis revealed the presence of conserved cysteine residues in OsMT1e-P protein. Salinity stress was found to regulate the transcript abundance of OsMT1e-P in a developmental and organ specific manner. Using transgenic approach, we found a positive correlation between ectopic expression of OsMT1e-P and stress tolerance. Our experiments further suggest ROS scavenging to be the possible mechanism for multiple stress tolerance conferred by OsMT1e-P.

Conclusion

We present an overview of MTs, describing their gene structure, genome localization and expression patterns under salinity and development in rice. We have found that ectopic expression of OsMT1e-P enhances tolerance towards multiple abiotic stresses in transgenic tobacco and the resultant plants could survive and set viable seeds under saline conditions. Taken together, the experiments presented here have indicated that ectopic expression of OsMT1e-P protects against oxidative stress primarily through efficient scavenging of reactive oxygen species.
Association of an NFKB1 intron SNP (rs4648068) with gastric cancer patients in the Han Chinese population
Authors: Lu Renquan , Gao Xiang , Chen Yin , Ni Jian , Yu Yongfu , Li Sheng , Guo Lin
Published: July 2012

Background

Hyperactivation of nuclear factor-κB (NF-κB) is associated with various types of tumors. This study investigated the susceptibility of the rs4648068 A/G genotype in the intron region of NFKB1 to gastric cancer and the association of this polymorphism with clinicopathologic variables in gastric cancer patients.

Methods

A hospital-based case–control study of 248 gastric cancer patients and 192 control individuals was conducted in Fudan University Shanghai Cancer Center (Shanghai, China). Single nucleotide polymorphism (SNP) rs4648068 genotype in NFKB1 from blood samples of a total of 440 people was analyzed by polymerase chain reaction-based genotyping.

Results

The frequencies of the AA, AG, and GG genotypes of the rs4648068 polymorphism were 31.5%, 47.2%, and 21.3% in the gastric cancer patients and 29.7%, 59.9%, and 10.4% in the control individuals, respectively. We found that the GG genotype was associated with a significantly increased risk of gastric cancer (P = 0.042). Furthermore, among the gastric cancer cases, the rs4648068 GG genotype was associated with high clinical stage (AOR = 2.27, 95% CI: 1.11- 4.66), lymph node involvement (AOR = 2.90, 95% CI = 1.40- 6.03) and serosa invasion (AOR = 2.78, 95% CI = 1.34- 5.75). However, rs4648068 genotypes were not associated with tumor differentiation in gastric cancer patients.

Conclusions

Homozygous rs4648068 GG was associated with an increased risk of gastric cancer, especially for the lymph node status and serosa invasion in Han Chinese population.
Rapid genetic targeting of pial surface neural progenitors and immature neurons by neonatal electroporation
Authors: Breunig Joshua J , Gate David , Levy Rachelle , Rodriguez Javier , Kim Gi Bum , Danielpour Moise , Svendsen Clive N , Town Terrence
Published: July 2012

Background

Recent findings have indicated the presence of a progenitor domain at the marginal zone/layer 1 of the cerebral cortex, and it has been suggested that these progenitors have neurogenic and gliogenic potential. However, their contribution to the histogenesis of the cortex remains poorly understood due to difficulties associated with genetically manipulating these unique cells in a population-specific manner.

Results

We have adapted the electroporation technique to target pial surface cells for rapid genetic manipulation at postnatal day 2. In vivo data show that most of these cells proliferate and progressively differentiate into both neuronal and glial subtypes. Furthermore, these cells localize to the superficial layers of the optic tectum and cerebral cortex prior to migration away from the surface.

Conclusions

We provide a foundation upon which future studies can begin to elucidate the molecular controls governing neural progenitor fate, migration, differentiation, and contribution to cortical and tectal histogenesis. Furthermore, specific genetic targeting of such neural progenitor populations will likely be of future clinical interest.
ngLOC: software and web server for predicting protein subcellular localization in prokaryotes and eukaryotes
Authors: King Brian R , Vural Suleyman , Pandey Sanjit , Barteau Alex , Guda Chittibabu
Published: July 2012

Background

Understanding protein subcellular localization is a necessary component toward understanding the overall function of a protein. Numerous computational methods have been published over the past decade, with varying degrees of success. Despite the large number of published methods in this area, only a small fraction of them are available for researchers to use in their own studies. Of those that are available, many are limited by predicting only a small number of organelles in the cell. Additionally, the majority of methods predict only a single location for a sequence, even though it is known that a large fraction of the proteins in eukaryotic species shuttle between locations to carry out their function.

Findings

We present a software package and a web server for predicting the subcellular localization of protein sequences based on the ngLOC method. ngLOC is an n-gram-based Bayesian classifier that predicts subcellular localization of proteins both in prokaryotes and eukaryotes. The overall prediction accuracy varies from 89.8% to 91.4% across species. This program can predict 11 distinct locations each in plant and animal species. ngLOC also predicts 4 and 5 distinct locations on gram-positive and gram-negative bacterial datasets, respectively.

Conclusions

ngLOC is a generic method that can be trained by data from a variety of species or classes for predicting protein subcellular localization. The standalone software is freely available for academic use under GNU GPL, and the ngLOC web server is also accessible at http://ngloc.unmc.edu.
Structural styles and Neogene petroleum system around the Yusuf-Habibas Ridge (Alboran Basin, Mediterranean Sea)
Authors: Medaouri M. , Bracene R. , Deverchere J. , Graindorge D. , Ouabadi A. , Yelles-Chaouche A. K.
Published: July 2012

The Algerian offshore is part of the southern margin of the western Mediterranean Sea. The western part of this offshore area represents the transitional margin between the South Algero-Balearic Basin and the Alboran Basin. The study area includes the southern and eastern parts of the Alboran Basin and the northwestern part of the Algerian margin and is in the western part of the plate boundary between Eurasia and Africa (Figure 1). The Yusuf-Habibas Ridge is a major EW-striking structure of this complex plate boundary, separating the eastern and southern parts of the Alboran Basin from the South Algero-Balearic Basin (Martinez-Garcia et al., 2011, and references therein). The ridge played an important role during the Neogene Alboran westward block migration between the Africa and Iberia plates, while the Kabylies blocks migrated southward and accreted to Africa. Furthermore, the ongoing NW-SE convergence between Africa and Iberia has induced a new stress field, since 7 Ma ago, replacing an earlier stress field (Fernandez-Ibañez et al., 2007) and leading to reactivation and polyphased deformation on the main structures in the basin, including the Yusuf-Habibas Ridge.
The Italian Adriatic Sea: Bringing new life to an established region
Authors: Peace Dave , Brown Dave , Zappaterra Enzo , Spoors Rich , Scaife Gary , Rowlands Dave , Sewell Debbie
Published: July 2012

The Italian sector of the Adriatic Sea extends from the Gulf of Trieste in the north to the Otranto channel in the far southeast, with water depths generally less than 200 m especially in the northern part. It is a long-established hydrocarbon province and in the past has been a successful exploration area with numerous large biogenic gas fields discovered in the shallow Pliocene and Tertiary section. Many of these fields—such as Ravenna, Porto Corsini and Porto Garibaldi in the northern Adriatic (Zone B) offshore Po Valley region—were put into production decades ago and have been steadily supplying Italy with a large portion of her domestic gas requirements.
Structural analogy between the “piano key faults” of deep-water Lebanon and the extensional faults of the Canyonlands grabens, Utah, United States
Authors: Kosi Walter , Tari Gabor , Nader Fadi H. , Skiple Cecilie , Trudgill Bruce , Lazar Dana
Published: July 2012

The Levant Basin is a deep-water basin in the eastern Mediterranean region. A large part of the basin contains a characteristic set of closely spaced normal faults, informally called the “piano key faults.” These normal faults trending NW-SE have a fairly high-frequency map-view spacing of approximately 3–4 km on average and tens to hundreds of meters of interpreted throw. A large part of the pre-Messinian sedimentary strata is faulted, including the entire Miocene-to-Oligocene sequence. At depth, all the faults consistently die out at the same intra-Eocene detachment level. This stratigraphic level is interpreted to have a regionally developed shale sequence acting as the basal detachment surface for the piano key faults. The amount of throw on the individual faults appears to decrease toward the basin margin and the faults do not extend into the adjacent basins of the broader eastern Mediterranean area.
Management of Metabolic Effects Associated With Anticancer Agents Targeting the PI3K-Akt-mTOR Pathway
Authors: Busaidy Naifa L. , Farooki Azeez , Dowlati Afshin , Perentesis John P. , Dancey Janet E. , Doyle Laurence A. , Brell Joanna M. , Siu Lillian L.
Published: July 2012

Agents inhibiting the phosphoinositide 3–kinase–Akt–mammalian target of rapamycin (PAM) pathway are currently in various stages of clinical development in oncology, ranging from some in early-phase evaluations to others that have already received regulatory approval for treatment in advanced cancers. The administration of PAM pathway inhibitors has been associated with metabolic toxicities of hyperlipidemia and hyperglycemia. The PAM Task Force of the National Cancer Institute Investigational Drug Steering Committee convened an interdisciplinary expert panel to review the pathophysiology of hyperlipidemia and hyperglycemia induced by PAM pathway inhibitors, summarize the incidence of these metabolic toxicities induced by such agents in the current literature, advise on clinical trial screening and monitoring criteria, and provide management guidance and therapeutic goals on occurrence of these toxicities. The overarching aim of this consensus report is to raise awareness of these metabolic adverse events to enable their early recognition, regular monitoring, and timely intervention in clinical trials. Hyperglycemia and hyperlipidemia are generally not acutely toxic and most often reversible with therapeutic intervention. Dose modifications or discontinuation of PAM pathway inhibitors should only be considered in situations of severe events or if progressive metabolic derangement persists after therapeutic interventions have been attempted for a sufficient duration. Specialty consultation should be sought to aid clinical trial planning and the management of these metabolic adverse events.
Prospective Study of Bevacizumab Plus Temozolomide in Patients With Advanced Neuroendocrine Tumors
Authors: Chan Jennifer A. , Stuart Keith , Earle Craig C. , Clark Jeffrey W. , Bhargava Pankaj , Miksad Rebecca , Blaszkowsky Lawrence , Enzinger Peter C. , Meyerhardt Jeffrey A. , Zheng Hui , Fuchs Charles S. , Kulke Matthew H.
Published: July 2012

Purpose

Both tyrosine kinase inhibitors targeting the vascular endothelial growth factor (VEGF) receptor and bevacizumab, a monoclonal antibody targeting VEGF, have antitumor activity in neuroendocrine tumors (NETs). Temozolomide, an oral analog of dacarbazine, also has activity against NETs when administered alone or in combination with other agents. We performed a phase II study to evaluate the efficacy of temozolomide in combination with bevacizumab in patients with locally advanced or metastatic NETs.

Patients and Methods

Thirty-four patients (56% with carcinoid, 44% with pancreatic NETs) were treated with temozolomide 150 mg/m2 orally per day on days 1 through 7 and days 15 through 21, together with bevacizumab at a dose of 5 mg/kg per day intravenously on days 1 and 15 of each 28-day cycle. All patients received prophylaxis against Pneumocystis carinii and varicella zoster. Patients were followed for toxicity, biochemical and radiologic response, and survival.

Results

The combination of temozolomide and bevacizumab was associated with anticipated grade 3 to 4 toxicities, including lymphopenia (53%) and thrombocytopenia (18%). Although the overall radiographic response rate was 15% (five of 34), response rates differed between patients with pancreatic NETs (33%; five of 15) and those with carcinoid tumors (zero of 19). The median progression-free survival was 11.0 months (14.3 months for pancreatic NETs v 7.3 months for carcinoid tumors). The median overall survival was 33.3 months (41.7 months for pancreatic NETs v 18.8 months for carcinoid tumors).

Conclusion

Temozolomide and bevacizumab can be safely administered together in patients with advanced NETs, and the combination regimen appears promising for patients with pancreatic NETs. Studies evaluating the relative contributions of these two agents to the observed antitumor activity are warranted.
Change in Working Time in a Population-Based Cohort of Patients With Breast Cancer
Authors: Høyer Marie , Nordin Karin , Ahlgren Johan , Bergkvist Leif , Lambe Mats , Johansson Birgitta , Lampic Claudia
Published: July 2012

Purpose

We examined changes in working time 16 months after a breast cancer diagnosis and identified factors associated with job discontinuation and/or decreased working time.

Patients and Methods

This was a population-based cohort study with 735 patients identified in the Regional Breast Cancer Quality Register of Central Sweden. The study sample consisted of 505 women (age < 63 years at diagnosis) who completed questionnaires at baseline and at follow-up (on average 4 and 16 months after diagnosis, respectively). Clinical register data and questionnaire data on sociodemographic factors were obtained at baseline. Self-reported work-related data were obtained at follow-up. Odds ratios were estimated by using logistic regression models.

Results

Compared with prediagnosis working time, 72% reported no change in working time, 2% reported an increase, 15% reported a decrease, and 11% did not work at follow-up. Chemotherapy increased the likelihood (odds ratio [OR], 2.45; 95% CI, 1.38 to 4.34) of job discontinuation/decreased working time. Among chemotherapy recipients, associated factors included full-time work prediagnosis (OR, 3.25; 95% CI, 1.51 to 7.01), cancer-related work limitations (OR, 5.26; 95% CI, 2.30 to 12.03), and less value attached to work (OR, 3.69; 95% CI, 1.80 to 7.54). In the nonchemotherapy group, older age (OR, 1.09; 95% CI, 1.02 to 1.17) and less value attached to work (OR, 5.00; 95% CI, 2.01 to 12.45) were associated with the outcome.

Conclusion

The majority of women treated for breast cancer returned to their prediagnosis working time. Chemotherapy and cancer-related work limitations are important factors to take into account in identifying women in need of support. Moreover, it is important to consider the woman's own valuation of labor market participation.
The Role of Anti-Müllerian Hormone (AMH) During Follicle Development in a Monovulatory Species (Sheep)
Authors: Campbell Bruce K. , Clinton M. , Webb R.
Published: July 2012

Knockout studies in mice have suggested that anti-Müllerian hormone (AMH) modulates primordial follicle recruitment and the response of growing follicles to FSH. Little is known of the physiology of AMH in monovular species, despite intense clinical interest in this factor. Using sheep as a model, we sought to investigate the functional role of AMH in modulating follicle development in monovular species. In contrast to the rodent, the results indicate that AMH does not affect the rate of primordial follicle recruitment but appears to regulate the rate at which follicles progress through the gonadotropin-responsive phase, during which it is maximally expressed. Thus, knockdown of AMH bioactivity by active immunization lead to a decline in the population of gonadotropin-responsive preantral and small antral follicles (P < 0.01) and increases in both the number of gonadotropin-dependent antral follicles (P < 0.01) and ovulation rate (P < 0.05). These in vivo findings were consistent with the results of other studies examining the pattern of expression of AMH, which was negatively correlated with aromatase (P < 0.001), and in vitro supplementation experiments, which supported an inhibitory role for AMH in modulating the response of both theca and granulosa cells to LH and FSH, respectively. The elucidation of a functional relationship between AMH and LH-stimulated thecal androgen production may be significant in terms of the etiology of common forms of anovulatory infertility in women. Furthermore, the observed increase in both the number of recruitable antral follicles and ovulatory quota in response to AMH knockdown may have therapeutic value in women who respond poorly to ovarian stimulation.
Prenatal Exposure to Low Levels of Androgen Accelerates Female Puberty Onset and Reproductive Senescence in Mice
Authors: Witham Emily A. , Meadows Jason D. , Shojaei Shadi , Kauffman Alexander S. , Mellon Pamela L.
Published: July 2012

Sex steroid hormone production and feedback mechanisms are critical components of the hypothalamic-pituitary-gonadal (HPG) axis and regulate fetal development, puberty, fertility, and menopause. In female mammals, developmental exposure to excess androgens alters the development of the HPG axis and has pathophysiological effects on adult reproductive function. This study presents an in-depth reproductive analysis of a murine model of prenatal androgenization (PNA) in which females are exposed to a low dose of dihydrotestosterone during late prenatal development on embryonic d 16.5–18.5. We determined that PNA females had advanced pubertal onset and a delay in the time to first litter, compared with vehicle-treated controls. The PNA mice also had elevated testosterone, irregular estrous cyclicity, and advanced reproductive senescence. To assess the importance of the window of androgen exposure, dihydrotestosterone was administered to a separate cohort of female mice on postnatal d 21–23 [prepubertal androgenization (PPA)]. PPA significantly advanced the timing of pubertal onset, as observed by age of the vaginal opening, yet had no effects on testosterone or estrous cycling in adulthood. The absence of kisspeptin receptor in Kiss1r-null mice did not change the acceleration of puberty by the PNA and PPA paradigms, indicating that kisspeptin signaling is not required for androgens to advance puberty. Thus, prenatal, but not prepubertal, exposure to low levels of androgens disrupts normal reproductive function throughout life from puberty to reproductive senescence.
Nursing During the First Two Days of Life Is Essential for the Expression of Proteins Important for Growth and Remodeling of the Neonatal Porcine Cervix
Authors: Frankshun Amy-Lynn , Chen Joseph , Barron Lauren A. , Ho Teh-Yuan , Miller Dori J. , Rahman Kathleen M. , Bartol Frank F. , Bagnell Carol A.
Published: July 2012

The neonatal porcine cervix is sensitive to hormones, including relaxin (RLX), from birth. Whether nursing is required to establish the cervical developmental program or to determine cervical developmental trajectory is unknown. The objective of study 1 was to determine effects of age and nursing on expression of molecular markers and mediators of porcine cervical growth and remodeling from birth to postnatal day (PND) 2 and to document effects of RLX treatment during this period on expression of targeted gene products in nursed vs. replacer-fed gilts. Study 2 was conducted to determine effects of age at first nursing and duration of nursing from birth on expression of targeted transcripts or proteins at PND 14. Nursing supported cervical estrogen receptor-α, vascular endothelial growth factor, matrix metalloproteinase (MMP)9, and antiapoptotic B-cell lymphoma-2 protein expression on PND 2. These proteins were undetectable in replacer-fed gilts. Returning replacer-fed gilts to nursing after PND 2 did not restore cervical expression of these proteins by PND 14. RLX increased (P < 0.05) cervical estrogen receptor-α, vascular endothelial growth factor, and B-cell lymphoma-2 protein in nursed gilts, MMP2 protein in nursed and replacer-fed gilts, and decreased (P < 0.05) pro-MMP9 protein in nursed gilts, and RXFP1 mRNA levels in nursed and replacer-fed gilts at PND 2. Replacer feeding for 2 wk from birth increased (P < 0.05) RXFP1 mRNA levels on PND 14. Results support the lactocrine hypothesis for maternal programming of neonatal tissues. Nursing from birth is required to establish the neonatal cervical developmental program and to maintain cervical developmental trajectory to PND 14.
Hypothalamic CB1 Cannabinoid Receptors Regulate Energy Balance in Mice
Authors: Cardinal Pierre , Bellocchio Luigi , Clark Samantha , Cannich Astrid , Klugmann Matthias , Lutz Beat , Marsicano Giovanni , Cota Daniela
Published: July 2012

Cannabinoid type 1 (CB1) receptor activation is generally considered a powerful orexigenic signal and inhibition of the endocannabinoid system is beneficial for the treatment of obesity and related metabolic diseases. The hypothalamus plays a critical role in regulating energy balance by modulating both food intake and energy expenditure. Although CB1 receptor signaling has been implicated in the modulation of both these mechanisms, a complete understanding of its role in the hypothalamus is still lacking. Here we combined a genetic approach with the use of adeno-associated viral vectors to delete the CB1 receptor gene in the adult mouse hypothalamus and assessed the impact of such manipulation on the regulation of energy balance. Viral-mediated deletion of the CB1 receptor gene in the hypothalamus led to the generation of Hyp-CB1-KO mice, which displayed an approximately 60% decrease in hypothalamic CB1 receptor mRNA levels. Hyp-CB1-KO mice maintained on a normocaloric, standard diet showed decreased body weight gain over time, which was associated with increased energy expenditure and elevated β3-adrenergic receptor and uncoupling protein-1 mRNA levels in the brown adipose tissue but, surprisingly, not to changes in food intake. Additionally, Hyp-CB1-KO mice were insensitive to the anorectic action of the hormone leptin (5 mg/kg) and displayed a time-dependent hypophagic response to the CB1 inverse agonist rimonabant (3 mg/kg). Altogether these findings suggest that hypothalamic CB1 receptor signaling is a key determinant of energy expenditure under basal conditions and reveal its specific role in conveying the effects of leptin and pharmacological CB1 receptor antagonism on food intake.
Estradiol Treatment and Hormonal Fluctuations During the Estrous Cycle Modulate the Expression of Estrogen Receptors in the Auditory System and the Prepulse Inhibition of Acoustic Startle Response
Authors: Charitidi Konstantina , Meltser Inna , Canlon Barbara
Published: July 2012

Estrogens' effects on hearing are documented across species, but the responsible molecular mechanisms remain unknown. The presence of estrogen receptors (ER) throughout the auditory system offers a potential pathway of direct estrogenic effects on auditory function, but little is known about how each ER's expression is regulated by the overall hormonal status of the body. In the present study, we determined the effects of ovariectomy and chronic 17β-estradiol treatment on mRNA and protein expression of ERα and ERβ in peripheral (cochlea) and central (inferior colliculus) auditory structures of mice, as well as on auditory-related behavior using the acoustic startle response (ASR), prepulse inhibition (PPI), and habituation of the startle response. 17β-Estradiol treatment down-regulated ERα but not ERβ and increased PPI and latency of the ASR. Neither the magnitude nor the habituation of ASR was affected. Furthermore, ER's mRNA and protein expression in the inner ear were analyzed throughout the estrous cycle (proestrus, estrus, metestrus, and diestrus), revealing a negative correlation of circulating estrogens with ERα expression, whereas ERβ was stable. Our findings show that ER not only are present in both the peripheral and central auditory system but also that circulating estrogen levels down-regulate ERα expression in the auditory system and affect PPI and the latency of ASR, suggesting a key role of ERα as a hormone-induced modulator of the auditory system and behavior.
Zebrafish Cxcr4a determines the proliferative response to Hedgehog signalling
Authors: Stückemann Tom , Wegleiter Thomas , Stefan Eduard , Nägele Olivier , Tarbashevich Katsiaryna , Böck Günther , Raz Erez , Aanstad Pia
Published: July 2012

The Hedgehog (Hh) pathway plays dual roles in proliferation and patterning during embryonic development, but the mechanism(s) that distinguish the mitogenic and patterning activities of Hh signalling are not fully understood. An additional level of complexity is provided by the observation that Hh signalling can both promote and inhibit cell proliferation. One model to account for this apparent paradox is that Hh signalling primarily regulates cell cycle kinetics, such that activation of Hh signalling promotes fast cycling and an earlier cell cycle exit. Here we report that activation of Hh signalling promotes endodermal cell proliferation but inhibits proliferation in neighbouring non-endodermal cells, suggesting that the cell cycle kinetics model is insufficient to account for the opposing proliferative responses to Hh signalling. We show that expression of the chemokine receptor Cxcr4a is a critical parameter that determines the proliferative response to Hh signalling, and that loss of Cxcr4a function attenuates the transcription of cell cycle regulator targets of Hh signalling without affecting general transcriptional targets. We show that Cxcr4a inhibits PKA activity independently of Hh signalling, and propose that Cxcr4a enhances Hh-dependent proliferation by promoting the activity of Gli1. Our results indicate that Cxcr4a is required for Hh-dependent cell proliferation but not for Hh-dependent patterning, and suggest that the parallel activation of Cxcr4a is required to modulate the Hh pathway to distinguish between patterning and proliferation.