bluuebunny/crossref_metadata_2025 huggingface dataset:
Gendering Global Finance
Authors: Griffin Penny
Published: March 2013

This article examines the relationship between discussions of responsibility in and for financial crisis and the locations and effects of gendered power and privilege in the global political economy. Most of these discussions have absented the ways in which power in the global political economy was, is and might continue to be gendered, which has served to reinforce the ‘natural fact’ of economic liberalization, integration and human progress through the expansion of Western-style financial capitalism and has obscured the highly masculinized and ethnocentric model of human activity on which this has been built. This article suggests that accounts of crisis that do not interrogate the ways in which organizations, actors, ideas and norms interact to actively construct the social setting(s) of financial discourse will fail to see contributory factors to crisis as a whole. This article takes seriously the effects of the culture of privilege, competitive success and masculine prowess that contemporary financial discourse has created and sustained and interrogates, against the abstractionism of contemporary neoliberalism and its advocates, where gendered configurations of power, knowledge, representation and identity have enabled contemporary global financial discourse to configure and reproduce ideas and practices of individual, collective and moral responsibility.
Psychosocial factors associated with depressive mood in Israeli obese adolescents
Authors: Yackobovitch-Gavan Michal , Meshy-Tamir Revital , Nagelberg Nessia , Phillip Moshe , Meyerovitch Joseph
Published: March 2013

This study aimed to compare levels of depressive symptoms between normal-weight and obese Israeli adolescents and to identify sociodemographic factors that may explain differences in depression between these groups. Thirty normal-weight and 49 obese patients aged 12–18 years participated in this study. The obese group had a significantly higher depression score. On linear regression analysis, obesity, lower parental income, and lower self-esteem were significantly associated with a higher depression score. This model explained 32.4 percent of the variance. The results indicate that psychosocial assessment and identification of depressive signs should be considered integral components in the management of adolescent obesity.
Gender differences in perception of quality of life in adults with and without chronic health conditions: The role of depressive symptoms
Authors: da Rocha Neusa S , Schuch Felipe B , de Almeida Fleck Marcelo P
Published: March 2013

Previous studies have shown that chronic conditions have a negative impact on quality of life. Furthermore, this impact appears to be different in males and females, but it is not yet clear what factors may mediate this relationship. Females with chronic health conditions had poorer quality of life in the physical and psychological domains as compared to males with chronic health conditions. The difference between male and female patients in the psychological domain disappeared when the analysis was adjusted for confounding factors such as age, presence of a chronic health condition, socioeconomic status, and depressive symptoms.
Citizens and the cigarette: The civic dimensions of America’s earliest, youth-targeted, mass-mediated anti-cigarette campaign
Authors: Keirle Philip
Published: March 2013

In the USA, the development of the mass production techniques that enabled the mass manufacture of cigarettes in the 1880s coincided with an intense focus on the civic qualities and capacities of the nation’s male youth. As the popularity of the cigarette grew, especially among urban youth, so too did concerns that the habit was crippling the physical, mental and moral faculties required of the good citizen. To date, the few histories that have tackled the nation’s earliest anti-cigarette campaigns have focused on the various legislative enactments designed to regulate the sale and use of the ‘little white slaver’. While incredibly important, these studies have passed over the important and ancillary role of education campaigns that sought to structure the way American youth conceived of the cigarette and the risks of cigarette smoking. In this article, I explore one of the nation’s first mass-mediated anti-cigarette campaigns, conducted through the pages of the nation’s most popular youth periodical – the Youth’s Companion – to show how central ideas of citizenship were to early efforts to shape the ways American youth negotiated the mass market and one of its most nefarious products.
Chemotherapy-related cardiotoxicity
Authors: Aggarwal Saurabh , Kamboj Jasmine , Arora Rohit
Published: March 2013

Cardiovascular toxicity caused by cancer therapy is a challenging area which needs thorough evaluation and research. Numerous studies, meta-analyses and reviews have been published in the past discussing cardiotoxicity caused by chemotherapeutic agents. A brief review of the on-target and off-target cardiotoxicities caused by chemotherapeutic agents is presented here. Cardiotoxicities are broadly outlined in terms of left ventricular dysfunction, hypertension and thromboembolic events. The mechanisms leading to the cardiotoxicity profiles of various chemotherapeutic agents are discussed. The management of various cardiotoxicities of chemotherapeutic agents is also discussed.
Management and Prevention of Recurrent Clostridium Difficile Infection in Patients After Total Joint Arthroplasty
Authors: Stein Benjamin E. , Greenough William B. , Mears Simon C.
Published: March 2013

Clostridium difficile infection (CDI) is the most common infectious cause of nosocomial diarrhea in elderly patients, accounting for 15% to 25% of all cases of antibiotic-induced diarrhea in those patients. Virulent forms of this organism have developed, increasing the associated morbidity, mortality, and complication rates. The average patient undergoing total joint arthroplasty is at particular risk of CDI because of advanced age, the use of prophylactic antibiotic coverage in the perioperative period, multiple comorbid conditions, and length of hospital stay. In addition, patients who have had one CDI are at risk of another; the rate of recurrent CDI (RCDI) is 15% to 30%. To review the available information on RCDI, we conducted an extensive literature search, focusing on its epidemiology and the management strategies for its treatment and prevention. We found the management of RCDI is a controversial topic, with as yet no consensus regarding specific treatment guidelines. Several experienced clinicians have published suggested treatment algorithms, but they are based on anecdotal experience. With regard to the prevention of RCDI, the literature is scarce, and currently, the only effective strategies remain judicious use of perioperative antibiotics and appropriate implementation of infection control procedures. There are several vaccination medications that are currently being studied but are not yet ready for clinical use. We agree with the approach to management of RCDI that has been proposed in several articles, that is, on confirmation of a first recurrence of CDI by a stool toxin assay and clinical symptoms, a 14-day course of metronidazole or vancomycin; for a second recurrence, a tapered-pulsed course of vancomycin; and, for 3 or more recurrences, a repeat course of the tapered-pulsed vancomycin and adjunctive Saccharomyces boulardii or cholestyramine.
A European collaborative study of treatment outcomes in 346 patients with cardiac stage III AL amyloidosis
Authors: Wechalekar Ashutosh D. , Schonland Stefan O. , Kastritis Efstathios , Gillmore Julian D. , Dimopoulos Meletios A. , Lane Thirusha , Foli Andrea , Foard Darren , Milani Paolo , Rannigan Lisa , Hegenbart Ute , Hawkins Philip N. , Merlini Giampaolo , Palladini Giovanni
Published: March 2013

Key Points

Deep clonal responses improve outcomes and can change the natural history of advanced (cardiac stage III) AL amyloidosis. NT-proBNP >8500 ng/L and SBP <100 mm Hg identify a very poor risk subgroup of stage III AL amyloidosis.
Integrated analysis of cytochrome P450 gene superfamily in the red flour beetle, Tribolium castaneum
Authors: Zhu Fang , Moural Timothy W , Shah Kapil , Palli Subba Reddy
Published: March 2013

Background

The functional and evolutionary diversification of insect cytochrome P450s (CYPs) shaped the success of insects. CYPs constitute one of the largest and oldest gene superfamilies that are found in virtually all aerobic organisms. Because of the availability of whole genome sequence and well functioning RNA interference (RNAi), the red flour beetle,Tribolium castaneumserves as an ideal insect model for conducting functional genomics studies. Although severalT. castaneumCYPs had been functionally investigated in our previous studies, the roles of the majority of CYPs remain largely unknown. Here, we comprehensively analyzed the phylogenetic relationship of allT. castaneumCYPs with genes in other insect species, investigated theCYP6BQgene cluster organization, function and evolution, as well as examined the mitochondrial CYPs gene expression patterns and intron-exon organization.

Results

A total 143 CYPs were identified and classified into 26 families and 59 subfamilies. The phylogenetic trees of CYPs among insects across taxa provided evolutionary insight for the genetic distance and function. The percentage of singleton (33.3%) inT. castaneumCYPs is much less than those inDrosophila melanogaster(52.5%) andBombyx mori(51.2%). Most members in the largest CYP6BQ gene cluster may make contribution to deltamethrin resistance in QTC279 strain.T. castaneumgenome encodes nine mitochondrial CYPs, among themCYP12H1is only expressed in the final instar larval stage. The intron-exon organizations of these mitochondrial CYPs are highly diverse.

Conclusion

Our studies provide a platform to understand the evolution and functions ofT. castaneumCYP gene superfamily which will help reveal the strategies employed by insects to cope with their environment.
Cell stress molecules in the skeletal muscle of GNE myopathy
Authors: Fischer Charlotte , Kleinschnitz Konstanze , Wrede Arne , Muth Ingrid , Kruse Niels , Nishino Ichizo , Schmidt Jens
Published: March 2013

Background

Mutations of the UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine-kinase (GNE)-gene are causally related to GNE myopathy. Yet, underlying pathomechanisms of muscle fibre damage have remained elusive. In sporadic inclusion body myositis (sIBM), the pro-inflammatory cell-stress mediators αB-crystallin and inducible nitric oxide synthase (iNOS) are crucial markers of the disease pathology.

Methods

10 muscle biopsies from GNE myopathy patients were analyzed for mRNA-expression of markers of cell-stress, inflammation and β-amyloid and compared to non-myopathic controls. Using double-labeling immunohistochemistry, serial sections of skeletal muscle biopsies were stained for amyloid precursor protein (APP), major histocompatibility complex (MHC)-I, αB-crystallin, neural cell adhesion molecule (NCAM), interleukin (IL)-1β, β-amyloid, iNOS, and phosphorylated neurofilament (P-neurofilament) as well as hematoxylin/eosin histochemistry. Corresponding areas of all biopsies with a total of 2,817 muscle fibres were quantitatively assessed for all markers.

Results

mRNA-expression of APP, NCAM, iNOS, TNF-α and TGF-β was higher in GNE myopathy compared to controls, yet this was not statistically significant. The mRNA-expression of APP and αB-crystallin significantly correlated with the expression of several pro-inflammatory and cell-stress-associated markers as NCAM, IL-1β, TGF-β, CCL-3, and CCL4. By immunohistochemistry, αB-crystallin and iNOS were co-upregulated and the number of fibres positive for αB-crystallin, NCAM, MHC-I and iNOS significantly correlated with each other. A large fraction of fibres positive for αB-crystallin were double positive for iNOS and vice-versa. Moreover, several fibres with structural abnormalities were positive for αB-crystallin and iNOS. Notably, particularly normal appearing fibres displayed an overexpression of these molecules.

Conclusions

The cell-stress molecules αB-crystallin and iNOS are overexpressed in GNE myopathy muscle and may identify early disease mechanisms. The data help to better understand the pathology of GNE myopathy.
Dietary patterns and risk of colorectal cancer in Tehran Province: a case–control study
Authors: Safari Akram , Shariff Zalilah Mohd , Kandiah Mirnalini , Rashidkhani Bahram , Fereidooni Foroozandeh
Published: March 2013

Background

Colorectal cancer is the third and fourth leading cause of cancer incidence and mortality among men and women, respectively in Iran. However, the role of dietary factors that could contribute to this high cancer incidence remains unclear. The aim of this study was to determine major dietary patterns and its relationship with colorectal cancer.

Methods

This case–control study was conducted in four hospitals in Tehran city of Iran. A total of 71 patients (35 men and 36 women, aged 40–75 years) with incident clinically confirmed colorectal cancer (CRC) and 142 controls (70 men and 72 women, aged 40–75 years) admitted to hospital for acute, non-neoplastic diseases were recruited and interviewed. Dietary data were assessed by 125-item semi-quantitative food frequency questionnaire. Multivariate logistic regression was used to estimate the relationship between dietary patterns and risk of colorectal cancer.

Results

Two major dietary patterns (Healthy pattern and Western pattern) were derived using principal component analysis. Each dietary pattern explained 11.9% (Healthy pattern) and 10.3% (Western pattern) of the variation in food intake, respectively. After adjusting for confounding factors, the Healthy dietary pattern was significantly associated with a decreased risk of colorectal cancer (OR= 0.227; 95% CI=0.108–0.478) while an increased risk of colorectal cancer was observed with the Western dietary pattern (OR=2.616; 95% CI= 1.361-5.030).

Conclusion

Specific dietary patterns, which include healthy and western patterns, may be associated with the risk of colorectal cancer. This diet-disease relationship can be used for developing interventions that aim to promote healthy eating for the prevention of chronic disease, particularly colorectal cancer in the Iranian population.
Anti-inflammatory, gastroprotective and anti-ulcerogenic effects of red algae Gracilaria changii (Gracilariales, Rhodophyta) extract
Authors: Shu Meng-Hooi , Appleton David , Zandi Keivan , AbuBakar Sazaly
Published: March 2013

Background

Gracilaria changii (Xia et Abbott) Abbott, Zhang et Xia, a red algae commonly found in the coastal areas of Malaysia is traditionally used for foods and for the treatment of various ailments including inflammation and gastric ailments. The aim of the study was to investigate anti-inflammatory, gastroprotective and anti-ulcerogenic activities of a mass spectrometry standardized methanolic extract of Gracilaria changii.

Methods

Methanolic extract of Gracilaria changii (MeOHGCM6 extract) was prepared and standardized using mass spectrometry (MS). Anti-inflammatory activities of MeOHGCM6 extract were examined by treating U937 cells during its differentiation with 10 μg/ml MeOHGCM6 extract. Tumour necrosis factors-α (TNF-α) response level and TNF-α and interleukin-6 (IL-6) gene expression were monitored and compared to that treated by 10 nM betamethasone, an anti-inflammatory drug. Gastroprotective and anti-ulcerogenic activities of MeOHGCM6 extract were examined by feeding rats with MeOHGCM6 extract ranging from 2.5 to 500 mg/kg body weight (b.w.) following induction of gastric lesions. Production of mucus and gastric juice, pH of the gastric juice and non-protein sulfhydryls (NP-SH) levels were determined and compared to that fed by 20 mg/kg b.w. omeprazole (OMP), a known anti-ulcer drug.

Results

MS/MS analysis of the MeOHGCM6 extracts revealed the presence of methyl 10-hydroxyphaeophorbide a and 10-hydroxypheophytin a, known chlorophyll proteins and several unidentified molecules. Treatment with 10 μg/ml MeOHGCM6 extract during differentiation of U937 cells significantly inhibited TNF-α response level and TNF-α and IL-6 gene expression. The inhibitory effect was comparable to that of betamethasone. No cytotoxic effects were recorded for cells treated with the 10 μg/ml MeOHGCM6 extract. Rats fed with MeOHGCM6 extract at 500 mg/kg b.w. showed reduced absolute ethanol-induced gastric lesion sizes by > 99% (p < 0.05). This protective effect was comparable to that conferred by OMP. The pH of the gastric mucus decreased in dose-dependent manner from 5.51 to 3.82 and there was a significant increase in NP-SH concentrations.

Conclusions

Results from the study, suggest that the mass spectrometry standardized methanolic extract of Gracillaria changii possesses anti-inflammatory, gastroprotective and anti-ulcerogenic properties. Further examination of the active constituent of the extract and its mechanism of action is warranted in the future.
The cloud paradigm applied to e-Health
Authors: Vilaplana Jordi , Solsona Francesc , Abella Francesc , Filgueira Rosa , Rius Josep
Published: March 2013

Background

Cloud computing is a new paradigm that is changing how enterprises, institutions and people understand, perceive and use current software systems. With this paradigm, the organizations have no need to maintain their own servers, nor host their own software. Instead, everything is moved to the cloud and provided on demand, saving energy, physical space and technical staff. Cloud-based system architectures provide many advantages in terms of scalability, maintainability and massive data processing.

Methods

We present the design of an e-health cloud system, modelled by an M/M/m queue with QoS capabilities, i.e. maximum waiting time of requests.

Results

Detailed results for the model formed by a Jackson network of two M/M/m queues from the queueing theory perspective are presented. These results show a significant performance improvement when the number of servers increases.

Conclusions

Platform scalability becomes a critical issue since we aim to provide the system with high Quality of Service (QoS). In this paper we define an architecture capable of adapting itself to different diseases and growing numbers of patients. This platform could be applied to the medical field to greatly enhance the results of those therapies that have an important psychological component, such as addictions and chronic diseases.
Prospective cohort study protocol to evaluate the validity and reliability of the Quality of Trauma Care Patient-Reported Experience Measure (QTAC-PREM)
Authors: Bobrovitz Niklas , Santana Maria , Kline Theresa , Kortbeek John , Stelfox Henry T
Published: March 2013

Background

Patient-centeredness is a key component of health care quality. However, patient-centered measures of quality have not been developed in injury care. In response to this challenge, we developed the Quality of Trauma Adult Care Patient-Reported Experience Measure (QTAC-PREM) to measure injured patient experiences with trauma care and pilot-tested the instrument at a single Level 1 trauma centre. The objective of this study is to test the reliability, validity, and feasibility of the QTAC-PREM in multiple Canadian trauma centers and to refine the measure based on the results.

Methods/design

This will be a prospective cohort study of consecutive adult (age ≥ 18 years) patients discharged from three trauma centres in Alberta, Canada with a primary diagnosis of injury. The target sample size is 400 participants to ensure precision for evaluating test-retest reliability. We will assess the psychometric properties of the measure (test-retest reliability, construct validity, internal consistency) and whether these properties vary by patient characteristics. We will also evaluate the predictive validity, convergent validity, and discriminant validity of the measure against other established tools (HCAHPS).

Discussion

A reliable and valid measure of patient reported experiences with injury care may be a valuable tool to evaluate quality of care and guide improvement efforts.
Insights into the role of the junctional region of Plasmodium falciparum dihydrofolate reductase-thymidylate synthase
Authors: Chaianantakul Natpasit , Sirawaraporn Rachada , Sirawaraporn Worachart
Published: March 2013

Background

Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (pf DHFR-TS) is a well-defined target of anti-malarial drug, such as pyrimethamine and cycloguanil. Emergence of malaria parasites resistant to these drugs has been shown to be associated with point mutations of the gene coding for the target enzymes. Although the 3D-structure of P. falciparum bifunctional pf DHFR-TS has been reported previously, relatively little is known about the interactions between the pf DHFR and pf TS domains and the roles of the junctional region that links the two domains together. Therefore, a thorough understanding of the interaction of the two domains and the role of the junctional region of this target is important as the knowledge could assist the development of new effective anti-malarial drugs aimed at overcoming drug-resistant malaria.

Methods

A system was developed to investigate the interaction between pf DHFR and pf TS domains and the role of the junctional region on the activity of the recombinant pf TS. Based on the ability of co-transformed plasmids coding for pf DHFR and pf TS with truncated junctional region to complement the growth of TS-deficient Escherichia coli strain χ2913recA(DE3) on minimum media without thymidine supplementation, active pf TS mutants with minimal length of junctional region were identified. Interactions between active pf DHFR and the pf TS domains were demonstrated by using a bacterial two-hybrid system.

Results

Using TS-deficient E. coli strain χ2913recA(DE3), the authors have shown for the first time that in P. falciparum a junctional region of at least 44 amino acids or longer was necessary for the pf TS domain to be active for the synthesis of thymidylate for the cells. Truncation of the junctional region of the bifunctional pf DHFR-TS further confirmed the above results, and suggested that a critical length of the junctional peptide of pf DHFR-TS would be essential for the activity of TS to catalyze the synthesis of thymidylate.

Conclusion

The present study demonstrated the interactions between the pf DHFR and pf TS domains of the bifunctional pf DHFR-TS, and revealed that the junctional region linking the two protein domains is essential for the expression of catalytically active pf TS domain. The findings could be useful since inhibition of the pf DHFR-TS domain-domain interaction could form a basis for the development of new anti-malarial drugs based on targeting the non-active site region of this important enzyme.
Analyzing the performance of Aloha in string multi-hop underwater acoustic sensor networks
Authors: Yu Hongyang , Yao Nianmin , Cai Shaobin , Han Qilong
Published: March 2013

In this article, we intend to investigate the performance of channel access protocols in multi-hop underwater acoustic sensor networks, which are characterized by long propagation delays and limited channel bandwidth. An analytical model specifically designed for contention-based protocols in multi-hop underwater acoustic networks is identified and validated. The model is based on an underwater network model, called string topology network model, which provides a method for computing the expected network throughput and the probability of packets’ delivery to the gateway from an arbitrary sensor. This study demonstrates an improvement of an existing model, in which a node is implicitly assumed to be able to transmit two packets at the same time, which is not realistic due to the half-duplex character of underwater acoustic channels. Based on our findings, we propose a modified analytical model and evaluate it using NS-3 simulator. Results show that our analytical model is more precise than the existing one.
A boundary integral equation with the generalized Neumann kernel for a mixed boundary value problem in unbounded multiply connected regions
Authors: Al-Hatemi Samer AA , Murid Ali HM , Nasser Mohamed MS
Published: March 2013

In this paper we propose a new method for solving the mixed boundary value problem for the Laplace equation in unbounded multiply connected regions. All simple closed curves making up the boundary are divided into two sets. The Dirichlet condition is given for one set and the Neumann condition is given for the other set. The mixed problem is reformulated in the form of a Riemann-Hilbert (RH) problem which leads to a uniquely solvable Fredholm integral equation of the second kind. Three numerical examples are presented to show the effectiveness of the proposed method.
Application of real-time reverse transcription polymerase chain reaction to the detection the matrix, H5 and H7 genes of avian influenza viruses in field samples from South Korea
Authors: Kim Hye-Ryoung , Oem Jae-Ku , Bae You-Chan , Kang Min-Su , Lee Hee-Soo , Kwon Yong-Kuk
Published: March 2013

Background

The rapid and accurate identification of the H5 and H7 subtypes of avian influenza (AI) virus is an important step for the control and eradication of highly pathogenic AI outbreaks and for the surveillance of AI viruses that have the potential to undergo changes in pathogenicity in poultry and wild birds. Currently, real-time reverse transcription polymerase chain reaction (RRT-PCR) is routinely used for the rapid detection of the H5 and H7 genes, but misidentification is frequent for emergent isolates and viruses isolated from diverse regions due to the high sequence variation among AI viruses.

Findings

In this study, an RRT-PCR method was tested for the detection of matrix, H5 and H7 genes from diverse subtypes of AI viruses and from field samples obtained through AI surveillance in South Korea over the last four years. Both RRT-PCR and conventional experiment (virus isolation using egg inoculation followed by reverse transcription polymerase chain reaction) agreed on the virus-positive samples. And the comparison of the results with 174 clinical samples showed a high level of agreement without decreasing the specificity and sensitivity.

Conclusions

This assay could be useful tool for the rapid detection of AI using the field samples from domestic poultry and wild birds in South Korea, and continuous regional updates is needed to validate primer sets as the AI virus evolves.
MOMENT – Management of Otitis Media with Effusion in Cleft Palate: protocol for a systematic review of the literature and identification of a core outcome set using a Delphi survey
Authors: Harman Nicola L , Bruce Iain A , Callery Peter , Tierney Stephanie , Sharif Mohammad Owaise , O’Brien Kevin , Williamson Paula R
Published: March 2013

Background

Cleft palate (CP) has an incidence of approximately 1 in 700. Children with CP are also susceptible to otitis media with effusion (OME), with approximately 90% experiencing nontrivial OME. There are several approaches to the management of OME in children with CP. The Management of Otitis Media with Effusion in Children with Cleft Palate (MOMENT) study is a feasibility study that includes the development of a core outcome set for use in future trials of the management of OME in children with CP.

Methods/Design

The MOMENT study will include a systematic review of the literature to identify a list of outcomes that have previously been reported. This list of outcomes will be used in a Delphi study with cleft clinicians. The Delphi study is anticipated to include three rounds. The first round will ask clinicians to score the outcome list and to add any outcomes they think are relevant. The second round involves presentation of scores according to stakeholder group and the opportunity for participants to rescore outcomes. To ensure that the opinion of parents and children are sought, qualitative interviews will be completed with a purposive sample in parallel. In the final round of the Delphi process, participants will be shown the distribution of scores, for each outcome, for all stakeholder groups separately as well as a summary of the results concerning outcomes from the qualitative interviews with parents. A final consensus meeting will be held with all stakeholders, including parents and children, to review outcomes.

Discussion

A core outcome set represents the minimum that should be measured in a clinical trial for a particular condition. The MOMENT study will aim to identify a core outcome set that can be used in future trials of the management of OME, improving the consistency of research in this clinical area.
Prognostic variables in patients with primary soft tissue sarcoma of the extremity and trunk treated with neoadjuvant radiotherapy or neoadjuvant sequential chemoradiotherapy
Authors: Bedi Meena , King David M , Shivakoti Mikesh , Wang Tao , Zambrano Eduardo V , Charlson John , Hackbarth Donald , Neilson John , Whitfield Robert , Wang Dian
Published: March 2013

Background

Neoadjuvant radiotherapy (NRT) is an effective strategy to treat soft tissue sarcomas (STS). However, the role of neoadjuvant chemoradiotherapy (NCRT) remains to be determined.

Methods

From May 1999 to July 2010, 112 patients with localized STS of the extremity and trunk who were treated with NRT or NCRT followed by surgery were retrospectively reviewed. Clinical outcomes including overall survival (OS), disease-free survival (DFS), and distant metastasis free survival (DMFS) were calculated using Kaplan-Meier survival analyses. Prognostic variables were determined by univariate (UVA) and multivariate analyses (MVA).

Results

Median follow-up was 37 months. Median RT dose was 50 Gy. Forty-nine patients received NCRT. Overall limb-preservation rate was 99% and local control was 97%. The estimated 3-year OS, DFS, and DMFS were 86%, 68%, and 72%, respectively. Age was the only variable to predict for OS, DFS and DMFS on UVA. Age ≥ 70 predicted for poor OS, stage III disease predicted for poor DFS and DMFS, and the addition of chemotherapy predicted for improved DMFS on MVA.

Conclusions

Excellent rates of local control and limb-preservation were observed in patients with primary STS treated with neoadjuvant therapy followed by surgery. Neoadjuvant sequential chemotherapy followed by radiotherapy may be considered for young patients with stage III STS.
Preoperative hospital length of stay as a modifiable risk factor for mediastinitis after cardiac surgery
Authors: Leung Wai Sang Stephane , Chaturvedi Rakesh , Alam Ahsan , Samoukovic Gordan , de Varennes Benoit , Lachapelle Kevin
Published: March 2013

Background

As high-risk cardiac patients frequently remain within hospital while waiting for surgery, the aim of the present study was to determine the role of preoperative length of hospital stay on mediastinitis, and also, to assess contemporary risk factors for this complication.

Methods

The source population consisted of 6653 consecutive patients undergoing coronary bypass surgery, valve surgery, or both between September 2000 and September 2009 at a single tertiary care hospital. A retrospective cohort analysis was used to assess the effect of 18 preoperative variables, including length of stay, on mediastinitis.

Results

Mediastinitis developed in 108 patients (1.6%) resulting in an in-hospital mortality rate of 13.9%. Independent predictors of mediastinitis included obesity (2.59, CI 1.58-4.23), COPD (2.44, CI 1.55-3.84), diabetes (2.16, CI 1.44-3.24), and impaired estimated glomerular filtration rate. Preoperative hospital stay was also found to be an independent risk factor leading to a 15% increased risk of mediastinitis per week of stay. The primary wound pathogen was coagulase negative staphylococcus (82%) followed by multi-flora isolates (49%), but was unrelated to hospital stay.

Conclusions

In addition to the traditional risk factors, prolonged preoperative hospital stay is also a significant and potentially modifiable predictor for the development of mediastinitis following cardiac surgery. All efforts should be made to minimize the delay in operating on hospitalized patients awaiting heart surgery.
Label-free integrative pharmacology on-target of opioid ligands at the opioid receptor family
Authors: Morse Megan , Sun Haiyan , Tran Elizabeth , Levenson Robert , Fang Ye
Published: March 2013

Background

In vitro pharmacology of ligands is typically assessed using a variety of molecular assays based on predetermined molecular events in living cells. Many ligands including opioid ligands pose the ability to bind more than one receptor, and can also provide distinct operational bias to activate a specific receptor. Generating an integrative overview of the binding and functional selectivity of ligands for a receptor family is a critical but difficult step in drug discovery and development. Here we applied a newly developed label-free integrative pharmacology on-target (iPOT) approach to systematically survey the selectivity of a library of fifty-five opioid ligands against the opioid receptor family. All ligands were interrogated using dynamic mass redistribution (DMR) assays in both recombinant and native cell lines that express specific opioid receptor(s). The cells were modified with a set of probe molecules to manifest the binding and functional selectivity of ligands. DMR profiles were collected and translated to numerical coordinates that was subject to similarity analysis. A specific set of opioid ligands were then selected for quantitative pharmacology determination.

Results

Results showed that among fifty-five opioid ligands examined most ligands displayed agonist activity in at least one opioid receptor expressing cell line under different conditions. Further, many ligands exhibited pathway biased agonism.

Conclusion

We demonstrate that the iPOT effectively sorts the ligands into distinct clusters based on their binding and functional selectivity at the opioid receptor family.
DACT1, an antagonist to Wnt/β-catenin signaling, suppresses tumor cell growth and is frequently silenced in breast cancer
Authors: Yin Xuedong , Xiang Tingxiu , Li LiLi , Su Xianwei , Shu Xingsheng , Luo Xinrong , Huang Jianbo , Yuan Ying , Peng Weiyan , Oberst Michael , Kelly Kathleen , Ren Guosheng , Tao Qian
Published: March 2013

Introduction

Aberrant activation of Wnt/β-catenin signaling plays an important role in the pathogenesis of breast cancer. DACT1 (Dapper/Frodo) has been identified as involved in antagonizing Wnt/β-catenin signaling through interacting with Dishevelled (Dvl), a central mediator of Wnt signaling, whereas its role in breast tumorigenesis remains unclear.

Methods

We examined DACT1 expression in breast cancer cell lines and primary tumors with semiquantitative or quantitative RT-PCR and immunochemistry, and further evaluated the promoter methylation of DACT1 with methylation-specific PCR (MSP). We also explored the tumor-suppressive functions of DACT1 in vivo and in vitro, and its related mechanism in breast cancer.

Results

We identified DACT1 as a methylated target in our breast cancer epigenome study. Here, we further investigated DACT1 expression in multiple breast cell lines and primary tumors, and further studied its function and molecular mechanisms. We found that DACT1 expression was silenced in eight (88.9%) of nine breast cancer cell lines, and its protein levels were obviously reduced in breast tumors compared with paired surgical-margin tissues. Promoter CpG methylation of DACT1 was detected in five (55.6%) of nine breast cancer cell lines and 40 (29.9%) of 134 primary tumors, but not in surgical-margin tissues and normal breast tissues. Demethylation treatment of breast cancer cell lines restored DACT1 expression along with promoter demethylation, suggesting that an epigenetic mechanism mediates DACT1 silencing in breast cancer. Functional assays showed that ectopic expression of DACT1 could inhibit breast tumor cell proliferation in vivo and in vitro through inducing apoptosis, and further suppress tumor cell migration through antagonizing the Wnt/β-catenin signaling pathway.

Conclusions

Our study demonstrates that DACT1 could function as a tumor suppressor but was frequently downregulated in breast cancer.
DNA methylation of distal regulatory sites characterizes dysregulation of cancer genes
Authors: Aran Dvir , Sabato Sivan , Hellman Asaf
Published: March 2013

Background

Abnormal epigenetic marking is well documented in gene promoters of cancer cells, but the study of distal regulatory siteshas lagged behind.We performed a systematic analysis of DNA methylation sites connected with gene expression profilesacross normal and cancerous human genomes.

Results

Utilizing methylation and expression data in 58 cell types, we developed a model for methylation-expression relationships in gene promoters and extrapolated it to the genome. We mapped numerous sites at which DNA methylation was associated with expression of distal genes. These sites bind transcription factors in a methylation-dependent manner, and carry the chromatin marks of a particular class of transcriptional enhancers. In contrast to the traditional model of one enhancer site per cell type, we found that single enhancer sites may define gradients of expression levels across many different cell types. Strikingly, the identified sites were drastically altered in cancers: hypomethylated enhancer sites associated with upregulation of cancer-related genes and hypermethylated sites with downregulation. Moreover, the association between enhancer methylation and gene deregulation in cancerwas significantly stronger than the association of promoter methylationwith gene deregulation.

Conclusions

Methylation of distal regulatory sites is closely related to gene expression levels across the genome. Single enhancers may modulate ranges of cell-specific transcription levels, from constantlyopen promoters. In contrast to the remote relationships between promoter methylation and gene dysregulation in cancer, altered methylation of enhancer sites is closely related to gene expression profiles of transformed cells.
Increased heme-oxygenase 1 expression in mesenchymal stem cell-derived adipocytes decreases differentiation and lipid accumulation via upregulation of the canonical Wnt signaling cascade
Authors: Vanella Luca , Sodhi Komal , Kim Dong Hyun , Puri Nitin , Maheshwari Mani , Hinds Terry D , Bellner Lars , Goldstein Dov , Peterson Stephen J , Shapiro Joseph I , Abraham Nader G
Published: March 2013

Introduction

Heme oxygenase (HO), a major cytoprotective enzyme, attenuates oxidative stress and obesity. The canonical Wnt signaling cascade plays a pivotal role in the regulation of adipogenesis. The present study examined the interplay between HO-1and the Wnt canonical pathway in the modulation of adipogenesis in mesenchymal stem cell (MSC)-derived adipocytes.

Methods

To verify the role of HO-1 in generating small healthy adipocytes, cobalt protoporphyrin (CoPP), inducer of HO-1, was used during adipocyte differentiation. Lipid accumulation was measured by Oil red O staining and lipid droplet size was measured by BODIPY staining.

Results

During adipogenesis in vitro, differentiating pre-adipocytes display transient increases in the expression of genes involved in canonical Wnt signaling cascade. Increased levels of HO-1 expression and HO activity resulted in elevated levels of β-catenin, pGSK3β, Wnt10b, Pref-1, and shh along with increased levels of adiponectin (P < 0.05). In addition, induction of HO-1 resulted in a reduction in C/EBPα, PPARγ, Peg-1/Mest, aP2, CD36 expression and lipid accumulation (P < 0.05). Suppression of HO-1 gene by siRNA decreased Wnt10b, pGSK3β and β-catenin expression, and increased lipid accumulation. The canonical Wnt responsive genes, IL-8 and SFRP1, were upregulated by CoPP and their expression was decreased by the concurrent administration of tin mesoporphyrin (SnMP), an inhibitor of HO activity. Furthermore, knockdown of Wnt10b gene expression by using siRNA showed increased lipid accumulation, and this effect was not decreased by concurrent treatment with CoPP. Also our results show that blocking the Wnt 10b antagonist, Dickkopf 1 (Dkk-1), by siRNA decreased lipid accumulation and this effect was further enhanced by concurrent administration of CoPP.

Conclusions

This is the first study to demonstrate that HO-1 acts upstream of canonical Wnt signaling cascade and decreases lipogenesis and adipocyte differentiation suggesting that the HO-1 mediated increase in Wnt10b can modulate the adipocyte phenotype by regulating the transcriptional factors that play a role in adipogenesis. This is evidenced by a decrease in lipid accumulation and inflammatory cytokine levels, increased adiponectin levels and elevation of the expression of genes of the canonical Wnt signaling cascade.
Which parameterization is suitable for acoustic vertical transverse isotropic full waveform inversion? Part 1: Sensitivity and trade-off analysis
Authors: Gholami Yaser , Brossier Romain , Operto Stéphane , Ribodetti Alessandra , Virieux Jean
Published: March 2013

In most geologic environments, accounting for anisotropy is necessary to perform acoustic full waveform inversion (FWI) of wide-azimuth and wide-aperture seismic data because of the potential dependence of wave speeds on the direction of the wave propagation. In the framework of multiparameter FWI, the subsurface parameterization controls the influence of the different parameter classes on the modeled seismic data as a function of the scattering angle and hence the resolution with which the parameters can be reconstructed and the potential trade-off between different parameters. We have evaluated a numerical procedure based on computation of the scattering patterns of the different parameters to assess the sensitivity of the seismic data to different parameterizations of vertical transverse isotropic media in the acoustic approximation. Among the different categories we have tested, a monoparametric FWI was found for imaging one wave speed with a broad wavenumber content, keeping the Thomsen parameters fixed, which have a small influence on the data relative to the wave speed. This raises the question of the initial information required in the background models of the Thomsen parameters to perform reliable monoparameter FWI. Alternatively, simultaneously inverting the horizontal and vertical wave speeds introduces limited trade-off effects because these wave speeds have significant influence on the data for distinct ranges of scattering angles, while the influence of the Thomsen parameter [Formula: see text] remains weak. With such parameterization, the short-to-intermediate wavelengths of the vertical velocity are updated from the short-to-intermediate scattering angles, while the long-to-intermediate wavelengths of the horizontal velocity are updated from the wide-to-intermediate scattering angles. We concluded that the choice of the subsurface parameterization can be driven by the acquisition geometry, which controls the scattering-angle coverage and hence the resolving power of FWI, and by the accuracy of the available initial FWI models.
Graft-Versus-Host Disease and Graft-Versus-Tumor Effects After Allogeneic Hematopoietic Cell Transplantation
Authors: Storb Rainer , Gyurkocza Boglarka , Storer Barry E. , Sorror Mohamed L. , Blume Karl , Niederwieser Dietger , Chauncey Thomas R. , Pulsipher Michael A. , Petersen Finn B. , Sahebi Firoozeh , Agura Edward D. , Hari Parameswaran , Bruno Benedetto , McSweeney Peter A. , Maris Michael B. , Maziarz Richard T. , Langston Amelia A. , Bethge Wolfgang , Vindeløv Lars , Franke Georg-Nikolaus , Laport Ginna G. , Yeager Andrew M. , Hübel Kai , Deeg H. Joachim , Georges George E. , Flowers Mary E.D. , Martin Paul J. , Mielcarek Marco , Woolfrey Ann E. , Maloney David G. , Sandmaier Brenda M.
Published: March 2013

Purpose

We designed a minimal-intensity conditioning regimen for allogeneic hematopoietic cell transplantation (HCT) in patients with advanced hematologic malignancies unable to tolerate high-intensity regimens because of age, serious comorbidities, or previous high-dose HCT. The regimen allows the purest assessment of graft-versus-tumor (GVT) effects apart from conditioning and graft-versus-host disease (GVHD) not augmented by regimen-related toxicities.

Patients and Methods

Patients received low-dose total-body irradiation ± fludarabine before HCT from HLA-matched related (n = 611) or unrelated (n = 481) donors, followed by mycophenolate mofetil and a calcineurin inhibitor to aid engraftment and control GVHD. Median patient age was 56 years (range, 7 to 75 years). Forty-five percent of patients had comorbidity scores of ≥ 3. Median follow-up time was 5 years (range, 0.6 to 12.7 years).

Results

Depending on disease risk, comorbidities, and GVHD, lasting remissions were seen in 45% to 75% of patients, and 5-year survival ranged from 25% to 60%. At 5 years, the nonrelapse mortality (NRM) rate was 24%, and the relapse mortality rate was 34.5%. Most NRM was a result of GVHD. The most significant factors associated with GVHD-associated NRM were serious comorbidities and grafts from unrelated donors. Most relapses occurred early while the immune system was compromised. GVT effects were comparable after unrelated and related grafts. Chronic GVHD, but not acute GVHD, further increased GVT effects. The potential benefit associated with chronic GVHD was outweighed by increased NRM.

Conclusion

Allogeneic HCT relying on GVT effects is feasible and results in cures of an appreciable number of malignancies. Improved results could come from methods that control progression of malignancy early after HCT and effectively prevent GVHD.
Abagovomab As Maintenance Therapy in Patients With Epithelial Ovarian Cancer: A Phase III Trial of the AGO OVAR, COGI, GINECO, and GEICO—The MIMOSA Study
Authors: Sabbatini Paul , Harter Philipp , Scambia Giovanni , Sehouli Jalid , Meier Werner , Wimberger Pauline , Baumann Klaus H. , Kurzeder Christian , Schmalfeldt Barbara , Cibula David , Bidzinski Mariusz , Casado Antonio , Martoni Andrea , Colombo Nicoletta , Holloway Robert W. , Selvaggi Luigi , Li Andrew , del Campo Jose , Cwiertka Karel , Pinter Tamas , Vermorken Jan B. , Pujade-Lauraine Eric , Scartoni Simona , Bertolotti Monica , Simonelli Cecilia , Capriati Angela , Maggi Carlo Alberto , Berek Jonathan S. , Pfisterer Jacobus
Published: March 2013

Purpose

To determine whether abagovomab maintenance therapy prolongs recurrence-free (RFS) and overall survival (OS) in patients with ovarian cancer in first clinical remission.

Patients and Methods

Patients with International Federation of Gynecology and Obstetrics stage III to IV ovarian cancer in complete clinical remission after primary surgery and platinum- and taxane-based chemotherapy were randomly assigned at a ratio of 2:1 in a phase III, double-blind, placebo-controlled, multicenter study. Abagovomab 2 mg or placebo was administered as 1-mL suspension once every 2 weeks for 6 weeks (induction phase) and then once every 4 weeks (maintenance phase) until recurrence or up to 21 months after random assignment of the last patient. The primary end point was RFS; secondary end points were OS and immunologic response.

Results

Characteristics of the 888 patients included: mean age, 56.3 years; Eastern Cooperative Oncology Group performance status, ≤ 1 in > 99% of patients; serous papillary subtype, 81.5%; stage III, 85.9%; and cancer antigen 125 ≤ 35U/mL after third cycle, 80.9%. Mean exposure to study treatment (± standard deviation) was 449.7 ± 333.08 days. Hazard ratio (HR) of RFS for the treatment group using tumor size categorization (≤ 1 cm, > 1 cm) was 1.099 (95% CI, 0.919 to 1.315; P = .301). HR of OS using tumor size categorization (≤ 1 cm, > 1 cm) was 1.150 (95% CI, 0.872 to 1.518; P = .322). The most frequently reported type of adverse event was an injection site reaction in 445 patients (50.2%), followed by injection site erythema and fatigue in 227 (25.6%) and 212 patients (23.9%), respectively. By the final visit, median anti–anti-idiotypic antibody level was 493,000.0 ng/mL, indicating a robust response.

Conclusion

Abagovomab administered as repeated monthly injections is safe and induces a measurable immune response. Administration as maintenance therapy for patients with ovarian cancer in first remission does not prolong RFS or OS.