bluuebunny/crossref_metadata_2025 huggingface dataset:
The EuroVotePlus experiment
Authors: Laslier Jean-François , Blais André , Bol Damien , Golder Sona N , Harfst Philipp , Stephenson Laura B , Van der Straeten Karine
Published: April 2015

This paper reports on an online experiment that took place in several European countries during the three weeks before the 2014 elections for the European Parliament. We created a website where visitors could obtain information about the electoral rules used in different European Member States for this election. Participants were then invited to cast (simulated) ballots for the election according to three voting rules: closed list proportional representation, open list proportional representation with preferential voting, and open list proportional representation with cumulative voting and panachage. Participants were also invited to think about, and experiment with, the idea of electing some members of the European Parliament through pan-European party lists. The data gathered from this study enable researchers to consider the effects of electoral systems on outcomes in individual countries, and also to investigate the potential popularity and effects of Europe-wide European Parliament constituencies.
Introduction: Analytic, Continental and the question of a bridge
Authors: Chin Clayton , Thomassen Lasse
Published: April 2015

In philosophy and political theory, divisions come and go, but some persist despite being obviously problematic. The analytic and Continental divide is one such division. In political philosophy and political theory, the division has been particularly pronounced. Analytic and Continental thinkers are divided not only over substantial issues but also over the very nature of political theorising. In spite of this fundamental nature, theorists often seem to assume that, as a division, the analytic/Continental divide requires no explanation. We suggest that, as a central division within political theory, and despite being acknowledged as problematic for quite some time, it has persisted because it has not been adequately examined. Once examined, the division turns out to be operationally weaker than it once was. In recent years, there has been a growing interest in engaging thinkers from the other side. This has been accompanied by a corresponding tendency, among both analytic and Continental philosophers and political thinkers, to reflect on the nature of their own tradition and ‘philosophy’. Both traditions have entered a self-conscious period of meta-reflection. Such questioning indicates the possibility of transformation within both groups, in the absence of settled frameworks and divisions. However, it is also clear that such signs are the beginning of the possibility of a new relation rather than a sign of the eclipse of the division. The continued institutional separation and the space between their respective philosophical vocabularies suggest that, while the time is ripe for work here, there is still much to be done.
Inhibition of Hepatocellular Carcinoma by Total Alkaloids of Rubus alceifolius Poir Involves Suppression of Hedgehog Signaling
Authors: Zhao Jinyan , Liu Liya , Wan Yun , Zhang Yuchen , Zhuang Qunchuan , Zhong Xiaoyong , Hong Zhenfeng , Peng Jun
Published: April 2015

Objective. We evaluated the effects of total alkaloids of Rubus alceifolius Poir (TARAP) on the migration and invasion of hepatocellular carcinoma (HCC) and furthermore investigated the possible molecular mechanisms mediating its anticancer activity. Methods. We implanted nude mice with human HCC HepG2 cells and fed them with vehicle (physiological saline) or 3 g/kg/day dose of TARAP 5 days per week for 21 days. We determined the in vitro effect of TARAP on the migration and invasion of HepG2 cells by transwell assay. We evaluated SHH signaling components’ (SHH, PTCH, SMO, and Gli1) expression levels by reverse transcriptase–polymerase chain reaction and immunohistochemistry. Activity of the matrix metalloproteinases (MMPs) in supernatants was analyzed by zymography. The expression of the MMPs and their specific tissue inhibitor (tissue inhibitor of matrix metalloproteinases, TIMP-1, 2) in HCC tissues was detected by immunohistochemistry. Results. We discovered that TARAP inhibited hepatocellular migration and invasion in a dose-dependent manner in vitro. In addition, TARAP decreased the expression of SHH, PTCH, SMO, and Gli1 in HCC mouse tumors at both transcriptional and translational levels. Moreover, TARAP inhibited the activity of MMP2 and MMP9. We found that TARAP reduced the expression of MMP2 and MMP9, as well as the tissue inhibitor of MMPs. Conclusion. Our study showed that TARAP inhibits HCC migration and invasion likely through suppression of the hedgehog pathway. This may, in part, explain its anticancer properties. These results suggest that total alkaloids in Rubus alceifolius may have potential as a novel antimetastasis drug in the treatment of HCC.
Vivekananda Yoga Program for Patients With Advanced Lung Cancer and Their Family Caregivers
Authors: Milbury Kathrin , Mallaiah Smitha , Lopez Gabriel , Liao Zhongxing , Yang Chunyi , Carmack Cindy , Chaoul Alejandro , Spelman Amy , Cohen Lorenzo
Published: April 2015

Background. The primary purpose of this study was to establish the feasibility of a couple-based Vivekananda Yoga (VKC) intervention in lung cancer patients and caregivers. Secondly, we examined preliminary efficacy regarding quality of life (QOL) outcomes. Method. In this single-arm feasibility trial, patients with lung cancer undergoing radiotherapy and their caregivers participated in a 15-session VKC program that focused on the interconnectedness of the dyad. We assessed pre-and post-intervention levels of fatigue, sleep disturbances, psychological distress, overall QOL, spirituality, and relational closeness. We tracked feasibility data, and participants completed program evaluations. Results. We approached 28 eligible dyads of which 15 (53%) consented and 9 (60%) completed the intervention. Patients (mean age = 73 years, 63% female, all stage III) and caregivers (mean age = 62 years, 38% female, 63% spouses) completed a mean of 10 sessions and 95.5% of them rated the program as very useful. Paired t tests revealed a significant increase in patients’ mental health ( d = 0.84; P = .04) and a significant decrease in caregivers’ sleep disturbances ( d = 1.44; P = .02). Although not statistically significant, for patients, effect sizes for change scores were medium for benefit finding and small for distress ( d = 0.65 and 0.37, respectively). For caregivers, medium effects were found for improvement in physical functioning ( d = 0.50). Conclusion. This novel supportive care program appears to be safe, feasible, acceptable, and subjectively useful for lung cancer patients and their caregivers and lends support for further study.
Moffitt’s Developmental Taxonomy and Gang Membership
Authors: Petkovsek Melissa A. , Boutwell Brian B. , Barnes J. C. , Beaver Kevin M.
Published: April 2015

Moffitt’s taxonomy remains an influential theoretical framework within criminology. Despite much empirical scrutiny, comparatively less time has been spent testing the snares component of Moffitt’s work. Specifically, are there factors that might engender continued criminal involvement for individuals otherwise likely to desist? The current study tested whether gang membership increased the odds of contact with the justice system for each of the offender groups specified in Moffitt’s original developmental taxonomy. Our findings provided little evidence that gang membership increased the odds of either adolescence-limited or life-course persistent offenders being processed through the criminal justice system. Moving forward, scholars may wish to shift attention to alternative variables—beyond gang membership—when testing the snares hypothesis.
LigLAP
Authors: Yousefian Reza , Jones Paul , Kia Michael A. , Zadeh Mehrdad Hosseini
Published: April 2015

This article proposes a potential automatic ligation (LigLAP) method to occlude vessels and ducts in several laparoscopic surgical procedures. Currently, stapling devices are widely used for this purpose. However, there are some complications associated with stapling devices, including biliary leak and tissue damage. In this article, we examine the feasibility of an alternative method that uses a double-layer suture to encircle and occlude a vessel. A heating element melts the outer layer of the suture at the cross-point of the suture to create a seal. Several electromechanical mechanisms have been proposed to carry out this ligation process. In addition, some parts have been prototyped for experimental verification and visualization. Several double-layered sutures have been created, and their tensile strength and sealing capabilities have been measured. Moreover, a simple leakage experiment has been performed to verify experimentally the idea of using the double-layer suture. The results show that the new suture and the thermal sealing method provide the required strength to occlude balloons filled with water. Although the results suggest that the proposed method and the double-layer suture may be used in surgical ligation processes, much more rigorous testing of leakage is required.
Japanese Console Games Popularization in China
Authors: Liao Sara X. T.
Published: April 2015

This article attempts to explore the popularization of Japanese console games in China in the past two decades, which reveals the tripartite relationship of the nation-state, transnational cultural power, and local agents.1 This study focuses on the formation and development of the console game industry in a non-Western context, where the society has undergone dramatic transformations and has been largely influenced by the globalization process. Encountering social anti-gaming discourse and cultural protectionism, the importation and distribution of Japanese console games did not get support from the state. However, it found its way to the audience and gained popularity through piracy, the black market, and the local agents’ appropriation, becoming an integrated part of many Chinese early gamers’ lives. This article draws upon the intersection of cultural globalization with game studies, calling for an investigation into the complexity of the game industry through its sociohistorical, political, and cultural environment.
Observing observers: Using video to prompt and record reflections on teachers’ pedagogies in four regions of Canada
Authors: Reid David A , Simmt Elaine , Savard Annie , Suurtamm Christine , Manuel Dominic , Lin Terry Wan Jung , Quigley Brenna , Knipping Christine
Published: April 2015

Regional differences in performance in mathematics across Canada prompted us to conduct a comparative study of middle-school mathematics pedagogy in four regions. We built on the work of Tobin, using a theoretical framework derived from the work of Maturana. In this paper, we describe the use of video as part of the methodology used. We used videos of teaching activities as prompts for discussions among teachers and the video recordings of such discussions became the data sources for our comparative research. Our use of video revealed a number of advantages and disadvantages which influenced the research.
Video analysis in cross-cultural environments and methodological issues
Authors: Montandon Christiane
Published: April 2015

This paper addresses the use of videography combined with group interviews, as a way to better understand the informal learnings of 11–12 year old children in cross-cultural encounters during French–German school exchanges. The complete, consistent video data required the researchers to choose the most significant sequences to highlight the processes by which the pupils communicated and expressed feelings and meanings within their experiences. The target of these paradigmatic situations was focused on two important questions relevant in the science of education:

- First, an epistemological and ethical question arose about the relationship between the researchers and the subjects of the research: How could cooperative research with pupils be led so that they were considered actors within the situation, and could share with the researchers the meaning of what happened in their cross-cultural experience?

- The second question arose from a methodological problem, which caused the researchers to develop a mixed apparatus involving a special recall technique using video data combined with group interviews to help the children remember what they were experiencing during the filmed interaction.
Chronic low back pain
Authors: Mills Sarah E E
Published: April 2015

The care of patients with persistent non-specific low back pain is a common situation in general practice. Chronic non-specific low back pain is defined as back pain persisting for more than 6 weeks in the absence of an underlying pathology. Multiple different permutations of the structures in the back, such as joints, discs, muscles, tendons and ligaments, play a part in the development of chronic non-specific low back pain. With the right management, low back pain resolves or improves significantly in the majority of cases. However, if patients do not receive appropriate management in a timely fashion, there is a higher risk of them going on to experience significant negative physical, social, psychological and economic outcomes.
When Bad Emotions Seem Better
Authors: Netzer Liat , Igra Libby , Anan Yoav Bar , Tamir Maya
Published: April 2015

Evaluations of objects change as a function of our experience with them. We suggest that this also applies to the evaluation of emotions. In three studies, we show that the evaluation of anger changes as a function of direct experience with anger. We found that the experience of anger in a context in which it could be beneficial (i.e., an aggressive computer game) led people to perceive anger as more useful (Study 1). Moreover, people came to evaluate anger less negatively after experiencing anger in a context in which it could be beneficial. These changes did not result from the mere experience of anger or from exposure to an aggressive context (Study 2). Rather, the more anger improved their performance, the less negatively participants came to evaluate anger (Study 3). These findings suggest that how bad anger seems may depend on our direct experience with it.
A Powerful Nudge? Presenting Calculable Consequences of Underpowered Research Shifts Incentives Toward Adequately Powered Designs
Authors: Gervais Will M. , Jewell Jennifer A. , Najle Maxine B. , Ng Ben K. L.
Published: April 2015

If psychologists have recognized the pitfalls of underpowered research for decades, why does it persist? Incentives, perhaps: underpowered research benefits researchers individually (increased productivity), but harms science collectively (inflated Type I error rates and effect size estimates but low replication rates). Yet, researchers can selectively reward power at various scientific bottlenecks (e.g., peer review, hiring, funding, and promotion). We designed a stylized thought experiment to evaluate the degree to which researchers consider power and productivity in hiring decisions. Accomplished psychologists chose between a low sample size candidate and a high sample size candidate who were otherwise identical. We manipulated the degree to which participants received information about (1) productivity, (2) sample size, and (3) directly calculable Type I error and replication rates. Participants were intolerant of the negative consequences of low-power research, yet merely indifferent regarding the practices that logically produce those consequences, unless those consequences were made quite explicit.
What If They’re Right About the Afterlife? Evidence of the Role of Existential Threat on Anti-Atheist Prejudice
Authors: Cook Corey L. , Cohen Florette , Solomon Sheldon
Published: April 2015

Terror management theory posits that the uniquely human awareness of death gives rise to potentially paralyzing terror that is assuaged by embracing cultural worldviews that provide a sense that one is a valuable participant in a meaningful universe. We propose that pervasive and pronounced anti-atheist prejudices stem, in part, from the existential threat posed by conflicting worldview beliefs. Two studies were conducted to establish that existential concerns contribute to anti-atheist sentiments. Experiment 1 found that a subtle reminder of death increased disparagement, social distancing, and distrust of atheists. Experiment 2 found that asking people to think about atheism increased the accessibility of implicit death thoughts. These studies provide the first empirical link between existential concerns and anti-atheist prejudices.
Bedaquiline for the treatment of multidrug-resistant tuberculosis: great promise or disappointment?
Authors: Field Stephen K.
Published: April 2015

Acquired drug resistance by Mycobacterium tuberculosis (MTB) may result in treatment failure and death. Bedaquiline was recently approved for the treatment of multidrug-resistant tuberculosis (MDR-TB). This report examines the available data on this novel drug for the treatment of MDR-TB. PubMed searches, last updated 18 February 2015, using the terms bedaquiline, TMC 207 and R207910 identified pertinent English citations. Citation reference lists were reviewed to identify other relevant reports. Pertinent MDR-TB treatment reports on the US Food and Drug Administration, Centers for Disease Control and Prevention (CDC), World Health Organization (WHO) and Cochrane websites were also evaluated. Bedaquiline is an adenosine triphosphate (ATP) synthase inhibitor specific for MTB and some nontuberculous mycobacteria. The early bactericidal activity (EBA) of bedaquiline is delayed until ATP stores are depleted but subsequently it is similar to the EBA of isoniazid and rifampin. Bedaquiline demonstrated excellent minimum inhibitory concentrations (MICs) against both drug-sensitive and MDR-TB. Adding it to the WHO-recommended MDR-TB regimen reduced the time for sputum culture conversion in pulmonary MDR-TB. Rifampin, other cytochrome oxidase 3A4 inducers or inhibitors alter its metabolism. Adverse effects are common with MDR-TB treatment regimens with or without bedaquiline. Nausea is more common with bedaquiline and it increases the QTcF interval. It is not recommended for children, pregnant or lactating women. More patients died in the bedaquiline-treatment arms despite better microbiological outcomes in two recent trials. The WHO and CDC published interim guidelines that recommend restricting its use to patients with MDR-TB or more complex drug resistance who cannot otherwise be treated with a minimum of three effective drugs. It should never be added to a regimen as a single drug nor should it be added to a failing regimen to prevent the emergence of bedaquiline-resistant strains.
Potential for specific dihydropyridine calcium channel blockers to have a positive impact on cognitive function in humans: a systematic review
Authors: Peters Jean , Booth Andrew , Peters Ruth
Published: April 2015

Background:

There is some evidence to suggest a possible association between calcium channel blocker (CCB) use and a lower decline in cognitive function compared with use of other hypertensive treatments. In particular, there is an emerging interest in the potential for specific CCBs, particularly the dihydropyridine CCBs nitrendipine, nicardipine, cilnidipine, lercandipine, nimodipine, azelnidipine and nilvadipine. The aim of this review was to assess the evidence relating to these specific CCBs and incident cognitive decline or dementia in humans.

Methods:

A systematic review of the literature was carried out. The databases MEDLINE, Embase and PsychINFO were searched from 1980 to 18 April 2014. All abstracts were reviewed by two independent reviewers.

Results:

From 753 unique records, 16 full text articles were examined and three retained. The three articles reported data from two studies. A 12-week double-blind randomized controlled trial of nitrendipine compared with cilazapril and a longer and larger double-blind placebo-controlled trial also of nitrendipine, namely the Systolic Hypertension in Europe trial (SYST-EUR). Nitrendipine was associated with a reduction in incident dementia in the SYST-EUR trial. There was no association seen for cognitive outcomes in the smaller trial.

Conclusion:

At present there is limited evidence to suggest that nitrendipine may be associated with reduction in incident dementia. This association comes from a single trial and needs to be replicated. Furthermore, there is no high-quality evidence for any of the other potential candidate CCBs.
Improved weld macrosection, microstructure and mechanical properties of 2024Al-T4 butt joints in ultrasonic vibration enhanced friction stir welding
Authors: Liu X. C. , Wu C. S. , Padhy G. K.
Published: April 2015

Ultrasonic vibration enhanced friction stir welding (UVeFSW) is a new variant of friction stir welding (FSW) in which a sonotrode transmits ultrasonic energy directly into the localised area of the workpiece near and ahead of the rotating tool. This study investigated the influence of ultrasonic vibration on the formation, microstructure and mechanical properties of butt welded 2024Al-T4 joints, and attempted to unveil the underlying mechanism of UVeFSW by experimental methods. Morphology inspection, X-ray detection and metallographic inspection of the welds revealed that ultrasonic vibration can improve the weld formation at higher welding speeds. The stir zone in the UVeFSW broadened, while the grains in the heat affected zone had no obvious growth contrary to that in the base metal. Results of the mechanical tests indicated that the tensile strength and elongation of joints, and the microhardness value in the stir zone increased at the same welding parameters.
Fracture localisation in retreating side of friction stir welded magnesium alloy
Authors: Liu G. , Xin R. , Li J. , Liu D. , Liu Q.
Published: April 2015

Friction stir welding was successfully applied to joint Mg–3Al–1Zn alloy sheets. Serious strain localisation was observed during transverse tensile tests of the welds. Fracture was initiated from the interface of thermal–mechanical affected zone and stir zone in retreating side. The reasons for such localised fracture behaviour were explained by analysing the texture, Schmid factor, grain size and strain localisation characteristics in retreating side and advancing side. The results suggest that the coarser grain size and higher Schmid factor resulted in the easier activation of basal slip in retreating side than advancing side, which caused more serious strain localisation and stress concentration, and hence promoted fracture initiation from the interface of thermal–mechanical affected zone and stir zone in retreating side.
The burden of primary headache disorders in Zambia: national estimates from a population-based door-to-door survey
Authors: Mbewe Edward , Zairemthiama Pachuau , Paul Ravi , Birbeck Gretchen L , Steiner Timothy J
Published: April 2015

Background

Three headache disorders – migraine, tension-type headache (TTH) and medication-overuse headache (MOH) – are major contributors to population ill-health. Policy-makers need local knowledge of these to guide priority-setting. Earlier we reported the prevalence of these disorders in Zambia; here we describe the burdens attributable to them.

Methods

This was a cross-sectional population-based survey of adults aged 18-65 years, selected by cluster-randomized sampling in the mostly urban Lusaka Province and mostly rural Southern Province. Interviewers visiting households used a structured questionnaire. Diagnoses made algorithmically applied ICHD-II criteria. Burden enquiry focused on the previous 3 months and the day before interview. Disability was estimated by applying disability weights (DWs) from the Global Burden of Disease Survey 2010.

Results

From 1,134 households, 1,085 unrelated adults (450 male, 635 female) were interviewed (refusal rate 4.3%). The gender- and habitation-adjusted 1-year prevalence of migraine was 22.9%, of TTH 22.8%, of headache on ≥15 days/month 11.5%, of probable MOH (pMOH) 7.1%. Reported mean intensity of migraine attacks was 2.7, representing severe pain. People with migraine spent 10.0% of their time in the ictal state (DW: 0.433); they were therefore 4.3% disabled overall. Disability from TTH was much lower. People with pMOH (time with headache: 37.5%; DW: 0.220) were 8.3% disabled overall. Average lost productive time in the preceding 3 months for migraine was 4.1 days from work (6.3% loss) and 4.2 days (4.7% loss) from household work. Losses for pMOH were 4.8 days (7.4% loss) from work and 4.5 days (5.0% loss) from household work. In the population aged 18-65 years (effectively the working population), estimated disability from migraine was 0.98%, with 1.4% of workdays lost, and from pMOH was 0.59%, with 0.53% of workdays lost. Headache yesterday was reported by 28.3% of participants, whose average productivity yesterday was 55.9% of expectation.

Conclusions

Zambia loses 1.93% of GDP to headache, and action is required to mitigate this loss and the associated suffering. Structured headache services with their basis in primary care are the most efficient, effective, affordable and equitable solution. They could be implemented within the existing health-care infrastructure of Zambia. These matters require urgent political attention.
BMP2 gene delivery to bone mesenchymal stem cell by chitosan-g-PEI nonviral vector
Authors: Yue Jianhui , Wu Jun , Liu Di , Zhao Xiaoli , Lu William W
Published: April 2015

Nanotechnology has made a significant impact on the development of nanomedicine. Nonviral vectors have been attracting more attention for the advantage of biosafety in gene delivery. Polyethylenimine (PEI)-conjugated chitosan (chitosan-g-PEI) emerged as a promising nonviral vector and has been demonstrated in many tumor cells. However, there is a lack of study focused on the behavior of this vector in stem cells which hold great potential in regenerative medicine. Therefore, in this study, in vitro gene delivering effect of chitosan-g-PEI was investigated in bone marrow stem cells. pIRES2-ZsGreen1-hBMP2 dual expression plasmid containing both the ZsGreen1 GFP reporter gene and the BMP2 functional gene was constructed for monitoring the transgene expression level. Chitosan-g-PEI-mediated gene transfer showed 17.2% of transfection efficiency and more than 80% of cell viability in stem cells. These values were higher than that of PEI. The expression of the delivered BMP2 gene in stem cells enhanced the osteogenic differentiation. These results demonstrated that chitosan-g-PEI is capable of applying in delivering gene to stem cells and providing potential applications in stem cell-based gene therapy.
Cloning-free CRISPR/Cas system facilitates functional cassette knock-in in mice
Authors: Aida Tomomi , Chiyo Keiho , Usami Takako , Ishikubo Harumi , Imahashi Risa , Wada Yusaku , Tanaka Kenji F , Sakuma Tetsushi , Yamamoto Takashi , Tanaka Kohichi
Published: April 2015

Although the CRISPR/Cas system has enabled one-step generation of knockout mice, low success rates of cassette knock-in limit its application range. Here we show that cloning-free, direct nuclear delivery of Cas9 protein complex with chemically synthesized dual RNAs enables highly efficient target digestion, leading to generation of knock-in mice carrying a functional cassette with up to 50% efficiency, compared with just 10% by a commonly used method consisting of Cas9 mRNA and single guide RNA. Our cloning-free CRISPR/Cas system facilitates rapid one-step generation of cassette knock-in mice, accelerating functional genomic research by providing various in vivo genetic tools.
Defining functional signatures of dysbiosis in periodontitis progression
Authors: Wang Gary P
Published: April 2015

Periodontitis is a common inflammatory disease that leads to tooth loss and has been linked to cardiovascular disease and diabetes mellitus. The periodontal microbiome is highly diverse, and metatranscriptomic studies have indicated that the genes that are expressed by the microbiota are more relevant than the microbial composition in the pathogenesis of periodontitis. A recent study of early metabolic activities in the dysbiotic microbiome reveals a functional signature that distinguishes periodontal sites that will become inflamed, supporting the idea that microbial communities as a whole drive disease progression.
Activation and regulation of the granulation tissue derived cells with stemness-related properties
Authors: Chen Zelin , Dai Tingyu , Chen Xia , Tan Li , Shi Chunmeng
Published: April 2015

Introduction

Skin as the largest and easily accessible organ of the body represents an abundant source of adult stem cells. Among them, dermal stem cells hold great promise in tissue repair and the skin granulation tissue has been recently proposed as a promising source of dermal stem cells, but their biological characteristics have not been well investigated.

Methods

The 5-bromo-2′-deoxyuridine (BrdU) lineage tracing approach was employed to chase dermal stem cells in vivo. Granulation tissue derived cells (GTCs) were isolated and their in vitro proliferation, self-renewing, migration, and multi-differentiation capabilities were assessed. Combined radiation and skin wound model was used to investigate the therapeutic effects of GTCs. MicroRNA-21 (miR-21) antagomir was used to antagonize miR-21 expression. Reactive oxygen species (ROS) were scavenged by N-acetyl cysteine (NAC).

Results

The quiescent dermal stem/progenitor cells were activated to proliferate upon injury and enriched in granulation tissues. GTCs exhibited enhanced proliferation, colony formation and multi-differentiation capacities. Topical transplantation of GTCs into the combined radiation and skin wound mice accelerated wound healing and reduced tissue fibrosis. Blockade of the miR-21 expression in GTCs inhibited cell migration and differentiation, but promoted cell proliferation and self-renewing at least partially via a ROS dependent pathway.

Conclusions

The granulation tissue may represent an alternative adult stem cell source in tissue replacement therapy and miR-21 mediated ROS generation negatively regulates the stemness-related properties of granulation tissue derived cells.
A generalized metric space and related fixed point theorems
Authors: Jleli Mohamed , Samet Bessem
Published: April 2015

We introduce a new concept of generalized metric spaces for which we extend some well-known fixed point results including Banach contraction principle, Ćirić’s fixed point theorem, a fixed point result due to Ran and Reurings, and a fixed point result due to Nieto and Rodríguez-López. This new concept of generalized metric spaces recover various topological spaces including standard metric spaces, b-metric spaces, dislocated metric spaces, and modular spaces.
Overview of aluminum alloy mechanical properties during and after fires
Authors: Summers Patrick T , Chen Yanyun , Rippe Christian M , Allen Ben , Mouritz Adrian P , Case Scott W , Lattimer Brian Y
Published: April 2015

Aluminum alloys are increasingly being used in a broad spectrum of load-bearing applications such as lightweight structures, light rail, bridge decks, marine crafts, and off-shore platforms. A major concern in the design of land-based and marine aluminum structures is fire safety, at least in part due to mechanical property reduction at temperatures significantly lower than that for steel. A substantial concern also exists regarding the integrity and stability of an aluminum structure following a fire; however, little research has been reported on this topic. This paper provides a broad overview of the mechanical behavior of aluminum alloys both during and following fire. The two aluminum alloys discussed in this work, 5083-H116 and 6061-T651, were selected due to their prevalence as lightweight structural alloys and their differing strengthening mechanisms (5083 – strain hardened, 6061 – precipitation hardened). The high temperature quasi-static mechanical and creep behavior are discussed. A creep model is presented to predict the secondary and tertiary creep strains followed by creep rupture. The residual mechanical behavior following fire (with and without applied stress) is elucidated in terms of the governing kinetically-dependent microstructural mechanisms. A review is provided on modeling techniques for residual mechanical behavior following fire including empirical relations, physically-based constitutive models, and finite element implementations. The principal objective is to provide a comprehensive description of select aluminum alloys, 5083-H116 and 6061-T651, to aid design and analysis of aluminum structures during and after fire.
A study on quantitative structure–activity relationship and molecular docking of metalloproteinase inhibitors based on L-tyrosine scaffold
Authors: Abbasi Maryam , Ramezani Fatemeh , Elyasi Maryam , Sadeghi-Aliabadi Hojjat , Amanlou Massoud
Published: April 2015

Background

MMP-2 enzyme is a kind of matrix metalloproteinases that digests the denatured collagens and gelatins. It is highly involved in the process of tumor invasion and has been considered as a promising target for cancer therapy. The structural requirements of an MMP-2 inhibitor are: (1) a functional group that binds the zinc ion, and (2) a functional group which interacts with the enzyme backbone and the side chains which undergo effective interactions with the enzyme subsites.

Methods

In the present study, a QSAR model was generated to screen new inhibitors of MMP-2 based on L–hydroxy tyrosine scaffold. Descriptors generation were done by Hyperchem 8, DRAGON and Gaussian98W programs. SPSS and MATLAB programs have been used for multiple linear regression (MLR) and genetic algorithm partial least squares (GA-PLS) analyses and for theoretical validation. Applicability domain of the model was performed to screen new compounds. The binding site potential of all inhibitors was verified by structure-based docking according to their binding energy and then the best inhibitors were selected.

Results

The best QSAR models in MLR and GA-PLS were reported, with the square correlation coefficient for leave-one-out cross-validation (Q2
LOO) larger than 0.921 and 0.900 respectively. The created MLR and GA-PLS models indicated the importance of molecular size, degree of branching, flexibility, shape, three-dimensional coordination of different atoms in a molecule in inhibitory activities against MMP-2.

The docking study indicated that lipophilic and hydrogen bonding interactions among the inhibitors and the receptor are involved in a ligand-receptor interaction. The oxygen of carbonyl and sulfonyl groups is important for hydrogen bonds of ligand with Leu82 and Ala83. R2 and R3 substituents play a main role in hydrogen bonding interactions. R1 is sited in the hydrophobic pocket. Methylene group can help a ligand to be fitted in the lipophilic pocket, so two methylene groups are better than one. The Phenyl group can create a π-π interaction with Phe86.

Conclusions

The QSAR and docking analyses demonstrated to be helpful tools in the prediction of anti-cancer activities and a guide to the synthesis of new metalloproteinase inhibitors based on L-tyrosine scaffold.
PTHrP-Related Hypercalcaemia in Infancy and Congenital Anomalies of the Kidney and Urinary Tract (CAKUT)
Authors: Kodous Nardeen , Filler Guido , Sharma Ajay Parkash , Van Hooren Tamara Angela
Published: April 2015

Background:

Severe hypercalcaemia is a rare but clinically significant condition in infancy and childhood. Parathyroid hormone-related peptide (PTHrP)-mediated hypercalcaemia resulting from a malignancy is rare and only a handful of case reports have outlined its incidence alongside a benign condition.

Objectives:

To describe the diagnostic workup and management of an infant with hypercalcaemia, renal dysplasia, and elevated PTHrP levels.

Design:

Case report.

Setting:

The Victoria Hospital campus of the London Health Sciences Centre in London, Ontario, Canada.

Patients:

A child with congenital anomalies of the kidneys and urinary tract (CAKUT), stage 2 chronic kidney disease (CKD), and renal dysplasia who presented with severe hypercalcaemia.

Measurements:

Weight, renal ultrasound, creatinine, cystatin C, eGFR, calcium, urea, bicarbonate, serum sodium, fractional sodium excretion, urine calcium to creatinine ratio, PTH, TSH, Free T4, AM cortisol, HMA, VMA, 25-vitamin D, 1,25 dihydroxy-vitamin D, calcitriol, vitamin A, ACE levels, skull and chest x-rays, alkaline phosphatase, CBC, tumour lysis profile, catecholamine breakdown, whole-body MRI, PTHrP.

Methods:

Full diagnostic workup and patient management. Patient treated with intravenous hydration, furosemide, calcitonin and CalciLo.

Results:

PTHrP was elevated and no evidence of a malignancy was found. Treatment consisting of a low-calcium CalciLo diet (in place of breast milk) adequately controlled the patient's hypercalcaemia. Hypercalcaemia associated with CAKUT in infancy is not all that uncommon and was reported in 15/99 infants in another study, most of whom had a suppressed PTH similar to that of our patient. PTHrP was not measured in these cases and may have also been elevated.

Limitations:

The study is limited in that it is a description of a single patient case. Future measurement of PTHrP in similar patients is necessary to confirm our results.

Conclusions:

The possibility of elevated PTHrP levels must be considered in patients with known renal dysplasia who are differentially diagnosed with hypercalcaemia.
And the geophysicist replied: “Which model do you want?”
Authors: Constable Steven , Orange Arnold , Key Kerry
Published: April 2015

Marine controlled-source electromagnetic (CSEM) and magnetotelluric (MT) soundings were carried out between 1997 and 2003 over the Gemini prospect in the Gulf of Mexico during early development of marine instrumentation. The resulting data sets provide a good test bed for examining the effect of the data type and misfit choice on regularized inversion solutions. We inverted the data sets individually and jointly for isotropic and anisotropic resistivity at a variety of data misfits. We found that multifrequency CSEM inversions vastly improved structural resolution over single-frequency inversions, suggesting that variation in skin depth added significant information. Joint MT and CSEM inversion appeared to improve resolution over MT-only inversions at depths considerably deeper than the CSEM data can resolve, probably by constraining shallow structure in the parts of the model to which the MT data were sensitive. The addition of model anisotropy improved data fit, but introduced an arbitrary scaling between the regularization penalty on model roughness and the penalty on anisotropy. A small relative penalty on anisotropy produced two independent models for horizontal and vertical resistivity, whereas a large penalty reproduced the isotropic models. Intermediate penalties produced pleasing models, but there was no objective criterion to choose one particular model. Inverted models also depend significantly on the choice of target data misfit, but the optimum misfit is difficult to determine even with well-estimated errors. So-called L-curves do not provide an objective choice of misfit because they are both heuristic and depend on the choice of data that is plotted. Various measures of structure in data residuals were tested in an attempt to guide the misfit choice, with some success, but this too was somewhat heuristic. Ultimately, of the 100 or so inversions that were run, no single model could be considered “preferred,” but together they provided a good understanding of the information contained in the data.
Current Status of Single-Agent Phase I Trials in Japan: Toward Globalization
Authors: Mizugaki Hidenori , Yamamoto Noboru , Fujiwara Yutaka , Nokihara Hiroshi , Yamada Yasuhide , Tamura Tomohide
Published: April 2015

Purpose

In Japan, phase I trials, except first-in-human trials, are usually initiated from approximately 50% of the maximum-tolerated dose (MTD) or maximum administered dose (MAD) determined during the initial phase I trials in North America and Europe (the West). However, the key findings of phase I trials in Japan and the West, such as dose-limiting toxicity (DLT) profiles and MTD or MAD levels, have not been compared.

Patients and Methods

We retrospectively analyzed data for patients enrolled onto single-agent phase I trials at the National Cancer Center Hospital between 1995 and 2012. DLT profiles, MTDs, and MADs of single-agent phase I trials in Japan were compared with those from trials in the West that were obtained from the literature.

Results

A total of 777 patients were enrolled onto 54 single-agent phase I trials, including five first-in-human trials. DLTs were observed in 11.1% of the patients. Importantly, 66.4% of the DLTs were observed within a dose range (80% to 120%) similar to those reported for the trials in the West. The majority of MTDs or MADs could be considered similar between patients, and 80.3% of the drugs had similar MTDs or MADs in the West.

Conclusion

The toxicity profiles of single-agent phase I agents determined from trials conducted in Japan were comparable to those obtained from trials in the West. We believe that phase I trials in Japan could be conducted over timelines similar to those in the West, allowing for global or parallel phase I clinical trials.
Controversies in the Treatment of Local and Locally Advanced Gastric and Esophageal Cancers
Authors: Cohen Deirdre J. , Leichman Lawrence
Published: April 2015

Despite overall progress in the therapy of local and locally advanced esophageal, gastroesophageal junction, and gastric adenocarcinomas, death as a result of these tumors remains a common outcome. Most randomized phase III trials on which level-one evidence has been built have included the heterogeneous histologies and locations associated with these tumors. However, the different etiologies, molecular biology, and recurrence patterns associated with gastroesophageal malignancies suggest the need to split rather than lump. Biologic and response differences exist between squamous and adenocarcinomas, as well as diffuse and intestinal histologies. This may be a cause behind conflicting outcomes in similar trials. The accepted standard of chemoradiotherapy for locally advanced esophageal and gastroesophageal junction cancers is based on a few positive trials, with the best chemotherapy and total dose of radiation remaining controversial. In the West, the staging evaluations of locally advanced gastric cancer are not uniform. Yet, these evaluations will inform the results of preoperative and perioperative treatments. Although postoperative chemoradiotherapy for gastric cancer has been an accepted treatment option for the last decade, more recent studies have called into question the need for radiotherapy. In perioperative strategies, it has yet to be determined whether histologic or molecular changes in the operative specimen should inform postoperative treatment. An appropriate place for targeted therapy needs to be found in preoperative and postoperative treatment regimens. Finally, because so much is lost when trials are forced to close for lack of accrual, it is imperative to build multidisciplinary consensus before they are launched.
Personalizing Colon Cancer Adjuvant Therapy: Selecting Optimal Treatments for Individual Patients
Authors: Dienstmann Rodrigo , Salazar Ramon , Tabernero Josep
Published: April 2015

For more than three decades, postoperative chemotherapy—initially fluoropyrimidines and more recently combinations with oxaliplatin—has reduced the risk of tumor recurrence and improved survival for patients with resected colon cancer. Although universally recommended for patients with stage III disease, there is no consensus about the survival benefit of postoperative chemotherapy in stage II colon cancer. The most recent adjuvant clinical trials have not shown any value for adding targeted agents, namely bevacizumab and cetuximab, to standard chemotherapies in stage III disease, despite improved outcomes in the metastatic setting. However, biomarker analyses of multiple studies strongly support the feasibility of refining risk stratification in colon cancer by factoring in molecular characteristics with pathologic tumor staging. In stage II disease, for example, microsatellite instability supports observation after surgery. Furthermore, the value of BRAF or KRAS mutations as additional risk factors in stage III disease is greater when microsatellite status and tumor location are taken into account. Validated predictive markers of adjuvant chemotherapy benefit for stage II or III colon cancer are lacking, but intensive research is ongoing. Recent advances in understanding the biologic hallmarks and drivers of early-stage disease as well as the micrometastatic environment are expected to translate into therapeutic strategies tailored to select patients. This review focuses on the pathologic, molecular, and gene expression characterizations of early-stage colon cancer; new insights into prognostication; and emerging predictive biomarkers that could ultimately help define the optimal adjuvant treatments for patients in routine clinical practice.
Advances and Challenges in Treatment of Locally Advanced Rectal Cancer
Authors: Smith J. Joshua , Garcia-Aguilar Julio
Published: April 2015

Dramatic improvements in the outcomes of patients with rectal cancer have occurred over the past 30 years. Advances in surgical pathology, refinements in surgical techniques and instrumentation, new imaging modalities, and the widespread use of neoadjuvant therapy have all contributed to these improvements. Several questions emerge as we learn of the benefits or lack thereof for components of the current multimodality treatment in subgroups of patients with nonmetastatic locally advanced rectal cancer (LARC). What is the optimal surgical technique for distal rectal cancers? Do all patients need postoperative chemotherapy? Do all patients need radiation? Do all patients need surgery, or is a nonoperative, organ-preserving approach warranted in selected patients? Answering these questions will lead to more precise treatment regimens, based on patient and tumor characteristics, that will improve outcomes while preserving quality of life. However, the idea of shifting the treatment paradigm (chemoradiotherapy, total mesorectal excision, and adjuvant therapy) currently applied to all patients with LARC to a more individually tailored approach is controversial. The paradigm shift toward organ preservation in highly selected patients whose tumors demonstrate clinical complete response to neoadjuvant treatment is also controversial. Herein, we highlight many of the advances and resultant controversies that are likely to dominate the research agenda for LARC in the modern era.
Immune Therapy in GI Malignancies: A Review
Authors: Wang Judy , Reiss Kim A. , Khatri Rina , Jaffee Elizabeth , Laheru Dan
Published: April 2015

The balance between tumor-promoting and tumor-suppressing immune responses and the difference between them ultimately determine whether a cancer escapes immune recognition mechanisms. Defining the complex relationships between the tumor itself, the tumor environment, and the immune system has been critical in facilitating the development of successful immunotherapies. This review explores the role of oncogenes in inducing cancer-associated inflammation, the local and systemic factors that lead to immune suppression, and immunotherapy approaches to overcome immune privilege.