bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract SY40-01: Anti-CD40 as an anticancer agent
Authors: Vonderheide Robert H.
Published: August 2012

Pancreatic ductal adenocarcinoma (PDA) is an almost uniformly lethal disease for which novel effective therapies are critically needed. Although immunotherapy offers a distinct and promising therapeutic approach, the ability of pancreas carcinoma to orchestrate immune suppression represents a significant clinical obstacle. Previous studies to model pancreatic tumor immune responses in mice have been limited by the use of implantable tumor models or non-PDA tumors of islet cells. To circumvent these obstacles, we have evaluated immune surveillance in PDA using a genetically engineered mouse (GEM) model of this disease in which endogenous expression of KrasG12D and Trp53R172H is targeted to the pancreas of immune competent mice and for which the salient clinical, histopathologic, and molecular features of the human disease are strikingly recapitulated. In this ‘KPC’ model, progression to PDA is intimately associated with a suppressive immune reaction, particularly in the myeloid compartment, such that adaptive anti-tumor immunity is essentially non-existent. Because CD40 activation can reverse immune suppression and drive potent anti-tumor T cell responses, we tested the combination of an agonist CD40 antibody with gemcitabine chemotherapy in the KPC model. We observed tumor regression in 30% of mice and found further that tumor regression required macrophages but not T cells or gemcitabine. CD40-activated macrophages rapidly infiltrated tumors, became tumoricidal, and facilitated the depletion of tumor stroma. T cells, as expected, were activated following CD40 therapy but never infiltrate the tumor. Based on these preclinical findings, we performed a clinical study to test the hypothesis that CD40 activation in humans can cooperate with chemotherapy for the treatment of chemotherapy-naïve, surgically incurable PDA. Twenty-one patients (90% with metastatic disease) received gemcitabine weekly on days 1, 8, and 15 with the agonist CD40 mAb CP-870,893 (Pfizer) administered on day 3 of each 28 day cycle. Treatment was well-tolerated overall, and the most common side effect was mild-to-moderate cytokine release syndrome managed in the outpatient clinic. Metabolic responses were observed by FDG-PET/CT in both the primary and metastatic lesions in 88% of patients evaluated after 2 cycles of therapy. By RECIST, 5 of 21 patients developed a partial response. Thus, productive cancer immune surveillance does not necessarily depend on T cells; rather, our findings demonstrate a CD40-dependent mechanism for targeting cancer-associated inflammation in the treatment of cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY40-01. doi:1538-7445.AM2012-SY40-01
Multicenter Transversal Two-Phase Study to Determine a National Prevalence of Epilepsy in Algeria
Authors: Moualek Dalila , Pacha Lamia Ali , Abrouk Samira , Kediha Mohamed Islam , Nouioua Sonia , Aissa Leila Ait , Bellatache Mounia , Belarbi Soreya , Slimani Saddek , Khennouf Houria , Fellahi Lynda , El Amine Hamimed Mohamed , Benali Nadia , Chekkour Mohamed Chahine , Maamoun Ramdane , Dameche Rachida , Assami Salima , Tazir Meriem
Published: August 2012

Background/Aims: The prevalence of epilepsy in Algeria is unknown. The aims of this multicenter transversal study were to determine the national prevalence and clinical characteristics of epilepsy in the Algerian population. Methods: This two-phase study was conducted in 5 circumscriptions and included 8,046 subjects aged over 2 months who attended the randomly selected public and private primary care clinics. In the phase 1 study, a questionnaire was submitted to the sample of patients. In the phase 2 study, all potentially epileptic people were examined by neurologists and a second questionnaire was submitted, eventually assessed by appropriate investigations. Results: Sixty-seven patients were identified as having active epilepsy, giving a crude prevalence ratio of 8.32 per 1,000 (95% CI, 6.34–10.3) and an age-adjusted prevalence ratio of 8.9 per 1,000. The highest age-specific ratio was found in patients aged 10–19 years (16.92 per 1,000). Generalized seizures (68.7%) were more common than partial seizures (29.8%). Perinatal injuries were the major leading putative causes (11.9%). Conclusion: The prevalence of epilepsy of 8.32 determined in this study is relatively high. These results provide new epidemiological data and suggest that epilepsy remains an important public health issue to consider in Algeria.
Epicardial Adipose Tissue Increased in Patients with Newly Diagnosed Subclinical Hypothyroidism
Authors: Korkmaz Levent , Sahin Sinan , Akyuz Ali Riza , Ziyrek Murat , Anaforoglu Inan , Kose Mustafa , Erkan Hakan , Ağaç Mustafa Tarık , Acar Zeydin
Published: August 2012

Objective: To investigate whether or not patients with subclinical hypothyroidism (SH) have increased epicardial adipose tissue (EAT). Subjects and Methods: Sixty-one patients with newly diagnosed SH and without any known cardiovascular disease were enrolled. Twenty-four subjects matched for age, gender and body mass index without any thyroid dysfunctions were included as a control group. The EAT was measured by echocardiography and thyroid functions were assessed by routine blood examination. Results: Patients with SH had higher EAT values than control subjects (3.6 ± 0.9 vs. 2.8 ± 1.4, p = 0.005). Also, SH patients with thyroid-stimulating hormone (TSH) ≥10 mU/l had higher EAT than those with SH with TSH <10 mU/l and control subjects (p = 0.013). In addition, while there was significant correlation between EAT and TSH (r = 0.31, p = 0.014) in patients with SH, there was no significant relation between EAT and TSH in normal subjects (r = 0.09, p = 0.64). Conclusions: There was a higher level of EAT in patients with SH compared with normal subjects and a significant correlation between EAT and TSH was found.
The Index of Microcirculatory Resistance Predicts Myocardial Infarction Related to Percutaneous Coronary Intervention
Authors: Ng Martin K. C. , Yong Andy S. C. , Ho Michael , Shah Maulik G. , Chawantanpipat Chirapan , O’Connell Rachel , Keech Anthony , Kritharides Leonard , Fearon William F.
Published: August 2012

Background—

Periprocedural myocardial infarction (MI) occurs in a significant proportion of patients undergoing percutaneous coronary intervention (PCI) and portends poor outcomes. Currently, no clinically applicable method predicts periprocedural MI in the cardiac catheterization laboratory before it occurs. We hypothesized that impaired baseline coronary microcirculatory reserve, which reduces the ability to tolerate ischemic insults, is a risk for periprocedural MI and that the index of microcirculatory resistance (IMR) measured during PCI can predict occurrence of periprocedural MI.

Methods and Results—

Consecutive patients undergoing elective PCI of a single lesion in the left anterior descending coronary artery were recruited. A pressure-temperature sensor wire was used to measure IMR before PCI. Of the 50 patients studied, 10 had periprocedural MI. From binary logistic regression analyses of all clinical, procedural, and physiological parameters, univariable predictors of periprocedural MI were pre-PCI IMR (
P
=0.003) and the number of stents used (
P
=0.039). Pre-PCI IMR was the only independent predictor in bivariable regression analyses performed by adjusting for each available covariate one at a time (all
P
≤0.02). Pre-PCI IMR ≥27 U had 80.0% sensitivity and 85.0% specificity for predicting periprocedural MI (C statistic, 0.80;
P
=0.003). Pre-PCI IMR ≥27 U was independently associated with a 23-fold risk of developing periprocedural MI (odds ratio, 22.7; 95% CI, 3.8–133.9).

Conclusions—

These data suggest that the status of the coronary microcirculation plays a role in determining susceptibility toward periprocedural MI at the time of elective PCI. The IMR can predict subsequent risk of developing myocardial necrosis and may guide adjunctive prevention strategies.
Disintegration and possibilities for rebuilding of war-affected communities: The Vojnić Municipality case
Authors: Miljenović Ana , Žganec Nino
Published: August 2012

War and war-related events can cause disintegration of vital community dimensions at the micro-level (related to everyday life of habitants), meso-level (regarding social relations) and macro-level (factors that make community autonomous entity). This article presents an example of a community that manifests characteristics of a disintegrated community in Croatia: at the micro-level with reduced living standards; at the meso-level with divided ethnic groups and non-functional social ties; at the macro-level with incomplete institutional development and underdeveloped economy. Approaches in community rebuilding tackling all three dimensions are proposed. On those grounds, the role of social work in rebuilding post-war communities is suggested.
The Effect of Treating Institution on Outcomes in Head and Neck Cancer
Authors: Lassig Amy Anne D. , Joseph Anne M. , Lindgren Bruce R. , Fernandes Patricia , Cooper Sarah , Schotzko Chelsea , Khariwala Samir , Reynolds Margaret , Yueh Bevan
Published: August 2012

Objective

Factors leading patients with head and neck cancer (HNCA) to seek radiation or chemoradiation in an academic center versus the community are incompletely understood, as are the effects of site of treatment on treatment completion and survival.

Study Design

Historical cohort study.

Setting

Tertiary academic center, community practices.

Methods

A historical cohort study was completed of patients with mucosal HNCA identified by International Classification of Disease, Ninth Revision (ICD‐9) codes receiving consultation at the authors’ institution from 2003 to 2008. Patients who received primary and adjuvant radiation at an academic center or in the community were included. The authors compared treatment completion rates and performed univariate and multivariate analyses of treatment outcomes.

Results

Of 388 patients, 210 completed treatment at an academic center and 145 at a community center (33 excluded, location unknown). Patients with HNCA undergoing radiation at an academic site had more advanced disease (P =. 024) and were more likely to receive concurrent chemotherapy. Academic hospitals had a higher percentage of noncurrent smokers, higher median income, and higher percentage of oropharyngeal tumors. There was no significant difference in the rate of planned treatment completion between community and academic centers (93.7% vs 94.7%, P >. 81) or rate of treatment breaks (22.4% vs 28.4%, P >. 28). On Kaplan‐Meier analysis, the 5‐year survival rate was 53.2% (95% confidence interval [CI], 45.3%‐61.1%) for academic centers and 32.8% (95% CI, 22.0%‐43.6%) for community hospitals (P <. 001).

Conclusion

In this cohort, although treatment completion and treatment breaks were similar between academic and community centers, survival rates were higher in patients treated in an academic setting.
Geographies of circulation and exchange III
Authors: Boeckler Marc , Berndt Christian
Published: August 2012

This report is a plea for ‘geographies of marketization’, a perspective that rests on the assumption that a world ‘after markets’ will only emerge on the terrain of ‘markets’ themselves. To sustain this claim we speculate about the role of economics in the breakdown and stabilization of neoliberal marketization. In an attempt to re-establish their discipline at a time of crisis and a loss of faith in information-efficient markets, economists increasingly turn to behavioural economics. Starting with the observation that people do not act as neoclassical theory says they do, behaviouralism allows mainstream economics to keep the core foundational principles intact. With an assemblage of ‘reinforcement learning’ and well-timed ‘nudges’ the choice architects of libertarian paternalism once again try to conform individual behaviour to the assumptions of the neoclassical laboratory. In so doing neoliberalism may have entered a new stage we tentatively call ‘neoliberalism after markets’, an era where radical market orientation has not come to an end but where the belief in the forces of free markets is restabilized by a shift of regulation. Emphasis is moved from the context of regulation/deregulation of markets to regulating human behaviour through ‘technologies of calculation’ that render the self an effect of sociotechnically distributed rational action.
An investigation into potential fuel savings for 110–130 seat passenger transport aircraft due to the incorporation of natural laminar flow or hybrid laminar flow control on the engine nacelles
Authors: Young Trevor M
Published: August 2012

A computer program, capable of accurately determining the required fuel for a given mission profile, has been developed for two ‘project’ aircraft types. The program was initially validated against reference aircraft and then modified to study the potential impact on trip fuel due to the incorporation of natural laminar flow or hybrid laminar flow control on the engine nacelles, by implementing changes the aircraft’s drag coefficient ( CD), specific fuel consumption and operating empty weight. Trade studies, with changes to CD, specific fuel consumption and operating empty weight, were conducted using trip fuel as the objective function. The results can be superimposed, permitting estimates of the trip fuel reduction due to the incorporation of alternative drag reduction designs. The impact of trip distance on the fuel-saving potential of laminar flow technologies has also been explored. The potential fuel savings for the aircraft fleet (with the incorporation of hybrid laminar flow control or natural laminar flow) has been estimated using an aircraft utilisation model (representing the probability of the aircraft flying a given stage length). It was concluded that there would be a net fuel saving based on the utilisation model. Finally, to obtain a realistic assessment of the potential benefit of these technologies, the probable time-in-cloud, which will result in a loss of laminar flow, has been considered.
Radical political unionism in France and Britain: A comparative study of SUD-Rail and the RMT
Authors: Connolly Heather , Darlington Ralph
Published: August 2012

Many recent pessimistic academic assessments of the prospects for the revival of European trade unionism fail adequately to capture evidence of continuing union resilience and combativity in certain areas of employment. An example is the distinctive and relatively successful form of highly militant and politicized trade unionism which has emerged in both the French and British railway sectors over the last 10 years. This has involved the repeated mobilization of members through strike action, combined with vigorous left-wing ideological opposition to both employers and government, as the pathway both to both advancing workers’ interests and to revitalizing union organization. This article provides a comparative analysis of SUD-Rail and the RMT, documenting the dynamics, causes, effectiveness, limits and potential of such ‘radical political unionism’ and considers its implications for debates about union renewal.
Effect of silica fume on fracture properties of high-performance concrete containing fly ash
Authors: Zhang Peng , Li Qing-Fu
Published: August 2012

A parametric experimental study has been conducted to investigate the effect of silica fume on the fracture properties of high-performance concrete containing fly ash, with four silica fume contents (3%, 6%, 9% and 12%) used. By means of three-point bending method, the fracture toughness, fracture energy, effective crack length, critical crack opening displacement and maximum crack opening displacement of the specimen were measured, respectively. The results indicate that silica fume has great adverse effect on the fracture toughness, fracture energy, effective crack length, critical crack opening displacement and maximum crack opening displacement, and these fracture parameters decrease gradually when the content of silica fume increases from 3% to 12%. Besides, as the silica fume content increases from 3% to 12%, the relational curves between the vertical load and the mid-span deflection ( PV–δ), crack mouth opening displacement ( PV–[Formula: see text]) and crack tip opening displacement ( PV–[Formula: see text]) are becoming thinner and thinner, which indicates that the capability of high-performance concrete containing fly ash to resist crack propagation is becoming weaker and weaker. It seems that the content of silica fume of high-performance concrete containing fly ash should be controlled strictly, and the silica fume content should be as low as possible on condition that the other properties of high-performance concrete can meet practical requirements.
College Students’ Justification for Digital Piracy
Authors: Yu Szde
Published: August 2012

A mixed methods project was devoted to understanding college students’ justification for digital piracy. The project consisted of two studies, a qualitative one and a quantitative one. Qualitative interviews were conducted to identify main themes in students’ justification for digital piracy, and then the findings were tested in a quantitative manner using a different sample. This project thus proposes a model in which quantitative measures are guided by qualitative findings, and qualitative findings are in turn reexamined based on quantitative findings. This project offers a mixed methods model for theory testing in criminology.
Here Is a Tip
Authors: Torfason Magnus Thor , Flynn Francis J. , Kupor Daniella
Published: August 2012

We investigated the link between tipping, an altruistic act, and bribery, an immoral act. We found a positive relationship between these two seemingly unrelated behaviors, using archival cross-national data for 32 countries, and controlling for per capita gross domestic product, income inequality, and other factors. Countries that had higher rates of tipping behavior tended to have higher rates of corruption. We suggest that this surprising association may be accounted for by temporal focus—people may tip and bribe others in order to receive special services in the future. Indeed, in a pair of follow-up survey studies, we find evidence that the link between tipping and bribery can be partly accounted for by prospective orientation.
T-cell independent, B-cell receptor-mediated induction of telomerase activity differs among IGHV mutation-based subgroups of chronic lymphocytic leukemia patients
Authors: Damle Rajendra N. , Temburni Sonal , Banapour Taraneh , Paul Santanu , Mongini Patricia K. A. , Allen Steven L. , Kolitz Jonathan E. , Rai Kanti R. , Chiorazzi Nicholas
Published: August 2012

Although B-cell chronic lymphocytic leukemia (B-CLL) clones with unmutated IGHV genes (U-CLL) exhibit greater telomerase activity than those with mutated IGHV genes (M-CLL), the extent to which B-cell receptor (BCR) triggering contributes to telomerase up-regulation is not known. Therefore, we studied the effect of BCR stimulation on modulating telomerase activity. The multivalent BCR ligand, dextran conjugated anti-μ mAb HB57 (HB57-dex), increased telomerase activity and promoted cell survival and proliferation preferentially in U-CLL cases, whereas the PI3K/Akt inhibitor LY294002 blocked HB57-dex induced telomerase activation. Although both U-CLL and M-CLL clones exhibited similar membrane proximal signaling responses to HB57-dex, telomerase activity and cell proliferation, when inducible in M-CLL, differed. B-CLL cells stimulated using bivalent F(ab′)2 -goat anti-μ antibody (goat anti-μ) exhibited higher membrane proximal response in U-CLL than M-CLL cells, whereas telomerase activity, cell survival, and proliferation were induced to lower levels than those induced by HB57-dex. In normal B lymphocytes, HB57-dex induced less protein phosphorylation but more cell proliferation and survival than goat anti-μ. Although both anti-BCR stimuli induced comparable telomerase activity, normal CD5+ B cells preferentially exhibited higher hTERT positivity than their CD5− counterparts. These findings provide an understanding of how BCR-mediated signals impact telomerase modulation in IGHV mutation-based subgroups of B-CLL and normal B cells.
Inferring high-confidence human protein-protein interactions
Authors: Yu Xueping , Wallqvist Anders , Reifman Jaques
Published: August 2012

Background

As numerous experimental factors drive the acquisition, identification, and interpretation of protein-protein interactions (PPIs), aggregated assemblies of human PPI data invariably contain experiment-dependent noise. Ascertaining the reliability of PPIs collected from these diverse studies and scoring them to infer high-confidence networks is a non-trivial task. Moreover, a large number of PPIs share the same number of reported occurrences, making it impossible to distinguish the reliability of these PPIs and rank-order them. For example, for the data analyzed here, we found that the majority (>83%) of currently available human PPIs have been reported only once.

Results

In this work, we proposed an unsupervised statistical approach to score a set of diverse, experimentally identified PPIs from nine primary databases to create subsets of high-confidence human PPI networks. We evaluated this ranking method by comparing it with other methods and assessing their ability to retrieve protein associations from a number of diverse and independent reference sets. These reference sets contain known biological data that are either directly or indirectly linked to interactions between proteins. We quantified the average effect of using ranked protein interaction data to retrieve this information and showed that, when compared to randomly ranked interaction data sets, the proposed method created a larger enrichment (~134%) than either ranking based on the hypergeometric test (~109%) or occurrence ranking (~46%).

Conclusions

From our evaluations, it was clear that ranked interactions were always of value because higher-ranked PPIs had a higher likelihood of retrieving high-confidence experimental data. Reducing the noise inherent in aggregated experimental PPIs via our ranking scheme further increased the accuracy and enrichment of PPIs derived from a number of biologically relevant data sets. These results suggest that using our high-confidence protein interactions at different levels of confidence will help clarify the topological and biological properties associated with human protein networks.
Implantation of undifferentiated and pre-differentiated human neural stem cells in the R6/2 transgenic mouse model of Huntington’s disease
Authors: El-Akabawy Gehan , Rattray Ivan , Johansson Saga M , Gale Richard , Bates Gillian , Modo Michel
Published: August 2012

Background

Cell therapy is a potential therapeutic approach for several neurodegenetative disease, including Huntington Disease (HD). To evaluate the putative efficacy of cell therapy in HD, most studies have used excitotoxic animal models with only a few studies having been conducted in genetic animal models. Genetically modified animals should provide a more accurate representation of human HD, as they emulate the genetic basis of its etiology.

Results

In this study, we aimed to assess the therapeutic potential of a human striatal neural stem cell line (STROC05) implanted in the R6/2 transgenic mouse model of HD. As DARPP-32 GABAergic output neurons are predominately lost in HD, STROC05 cells were also pre-differentiated using purmorphamine, a hedgehog agonist, to yield a greater number of DARPP-32 cells. A bilateral injection of 4.5x105cells of either undifferentiated or pre-differentiated DARPP-32 cells, however, did not affect outcome compared to a vehicle control injection. Both survival and neuronal differentiation remained poor with a mean of only 161 and 81 cells surviving in the undifferentiated and differentiated conditions respectively. Only a few cells expressed the neuronal marker Fox3.

Conclusions

Although the rapid brain atrophy and short life-span of the R6/2 model constitute adverse conditions to detect potentially delayed treatment effects, significant technical hurdles, such as poor cell survival and differentiation, were also sub-optimal. Further consideration of these aspects is therefore needed in more enduring transgenic HD models to provide a definite assessment of this cell line’s therapeutic relevance. However, a combination of treatments is likely needed to affect outcome in transgenic models of HD.
Genome-scale identification of cell-wall related genes in Arabidopsis based on co-expression network analysis
Authors: Wang Shan , Yin Yanbin , Ma Qin , Tang Xiaojia , Hao Dongyun , Xu Ying
Published: August 2012

Background

Identification of the novel genes relevant to plant cell-wall (PCW) synthesis represents a highly important and challenging problem. Although substantial efforts have been invested into studying this problem, the vast majority of the PCW related genes remain unknown.

Results

Here we present a computational study focused on identification of the novel PCW genes in Arabidopsis based on the co-expression analyses of transcriptomic data collected under 351 conditions, using a bi-clustering technique. Our analysis identified 217 highly co-expressed gene clusters (modules) under some experimental conditions, each containing at least one gene annotated as PCW related according to the Purdue Cell Wall Gene Families database. These co-expression modules cover 349 known/annotated PCW genes and 2,438 new candidates. For each candidate gene, we annotated the specific PCW synthesis stages in which it is involved and predicted the detailed function. In addition, for the co-expressed genes in each module, we predicted and analyzed their cis regulatory motifs in the promoters using our motif discovery pipeline, providing strong evidence that the genes in each co-expression module are transcriptionally co-regulated. From the all co-expression modules, we infer that 108 modules are related to four major PCW synthesis components, using three complementary methods.

Conclusions

We believe our approach and data presented here will be useful for further identification and characterization of PCW genes. All the predicted PCW genes, co-expression modules, motifs and their annotations are available at a web-based database: http://csbl.bmb.uga.edu/publications/materials/shanwang/CWRPdb/index.html.
Cocktail sedation containing propofol versus conventional sedation for ERCP: a prospective, randomized controlled study
Authors: Angsuwatcharakon Phonthep , Rerknimitr Rungsun , Ridtitid Wiriyaporn , Kongkam Pradermchai , Poonyathawon Sahadol , Ponauthai Yuwadee , Sumdin Sakolkan , Kullavanijaya Pinit
Published: August 2012

Background

ERCP practically requires moderate to deep sedation controlled by a combination of benzodiazepine and opiod. Propofol as a sole agent may cause oversedation. A combination (cocktail) of infused propofol, meperidine, and midazolam can reduce the dosage of propofol and we hypothesized that it might decrease the risk of oversedation. We prospectively compare the efficacy, recovery time, patient satisfactory, and side effects between cocktail and conventional sedations in patients undergoing ERCP.

Methods

ERCP patients were randomized into 2 groups; the cocktail group (n = 103) and the controls (n = 102). For induction, a combination of 25 mg of meperidine and 2.5 mg of midazolam were administered in both groups. In the cocktail group, a bolus dose of propofol 1 mg/kg was administered and continuously infused. In the controls, 25 mg of meperidine or 2.5 mg/kg of midazolam were titrated to maintain the level of sedation.

Results

In the cocktail group, the average administration rate of propofol was 6.2 mg/kg/hr. In the control group; average weight base dosage of meperidine and midazolam were 1.03 mg/kg and 0.12 mg/kg, respectively. Recovery times and patients’ satisfaction scores in the cocktail and control groups were 9.67 minutes and 12.89 minutes (P = 0.045), 93.1and 87.6 (P <0.001), respectively. Desaturation rates in the cocktail and conventional groups were 58.3% and 31.4% (P <0.001), respectively. All desaturations were corrected with temporary oxygen supplementation without the need for scope removal.

Conclusions

Cocktail sedation containing propofol provides faster recovery time and better patients’ satisfaction for patients undergoing ERCP. However, mild degree of desaturation may still develop.

Trial registration

ClinicalTrials.gov, NCT01540084
MicroRNA-196a promotes non-small cell lung cancer cell proliferation and invasion through targeting HOXA5
Authors: Liu Xiang-hua , Lu Kai-hua , Wang Ke-ming , Sun Ming , Zhang Er-bao , Yang Jin-song , Yin Dan-dan , Liu Zhi-li , Zhou Jing , Liu Zhi-jun , De Wei , Wang Zhao-xia
Published: August 2012

Background

MicroRNAs (miRNAs) are short, non-coding RNAs (~22 nt) that play important roles in the pathogenesis of human diseases by negatively regulating gene expression. Although miR-196a has been implicated in several other cancers, its role in non-small cell lung cancer (NSCLC) is unknown. The aim of the present study was to examine the expression pattern of miR-196a in NSCLC and its clinical significance, as well as its biological role in tumor progression.

Methods

Expression of miR-196a was analyzed in 34 NSCLC tissues and five NSCLC cell lines by quantitative reverse-transcription polymerase chain reaction (qRT-PCR). The effect of DNA methylation on miR-196a expression was investigated by 5-aza-2-deoxy-cytidine treatment and bisulfite sequencing. The effect of miR-196a on proliferation was evaluated by MTT and colony formation assays, and cell migration and invasion were evaluated by transwell assays. Analysis of target protein expression was determined by western blotting. Luciferase reporter plasmids were constructed to confirm the action of miR-196a on downstream target genes, including HOXA5. Differences between the results were tested for significance using Student’s t-test (two-tailed).

Results

miR-196a was highly expressed both in NSCLC samples and cell lines compared with their corresponding normal counterparts, and the expression of miR-196a may be affected by DNA demethylation. Higher expression of miR-196a in NSCLC tissues was associated with a higher clinical stage, and also correlated with NSCLC lymph-node metastasis. In vitro functional assays demonstrated that modulation of miR-196a expression affected NSCLC cell proliferation, migration and invasion. Our analysis showed that miR-196a suppressed the expression of HOXA5 both at the mRNA and protein levels, and luciferase assays confirmed that miR-196a directly bound to the 3’untranslated region of HOXA5. Knockdown of HOXA5 expression in A549 cells using RNAi was shown to promote NSCLC cell proliferation, migration and invasion. Finally, we observed an inverse correlation between HOXA5 and miR-196a expression in NSCLC tissues.

Conclusions

Our findings indicate that miR-196a is significantly up-regulated in NSCLC tissues, and regulates NSCLC cell proliferation, migration and invasion, partially via the down-regulation of HOXA5. Thus, miR-196a may represent a potential therapeutic target for NSCLC intervention.
Acceptance patterns and decision-making for human papillomavirus vaccination among parents in Vietnam: an in-depth qualitative study post-vaccination
Authors: Cover Jane K , Nghi Nguyen Quy , LaMontagne D Scott , Huyen Dang Thi Thanh , Hien Nguyen Tran , Nga Le Thi
Published: August 2012

Background

The GAVI Alliance’s decision in late 2011 to invite developing countries to apply for funding for human papillomavirus (HPV) vaccine introduction underscores the importance of understanding levels of HPV vaccine acceptance in developing country settings. In this paper, we present findings from qualitative research on parents’ rationales for vaccinating or not vaccinating their daughters (vaccine acceptance) and their decision-making process in the context of an HPV vaccination demonstration project in Vietnam (2008–2009).

Methods

We designed a descriptive qualitative study of HPV vaccine acceptability among parents of girls eligible for vaccination in four districts of two provinces in Vietnama. The study was implemented after each of two years of vaccinations was completed. In total, 133 parents participated in 16 focus group discussions and 27 semi-structured interviews.

Results

Focus group discussions and in-depth interviews with parents of girls vaccinated revealed that they were generally very supportive of immunization for disease prevention and of vaccinating girls against HPV. The involvement of the National Expanded Program of Immunization in the demonstration project lent credibility to the HPV vaccine, contributing to high levels of acceptance. For parents who declined participation, concerns about side effects, the possibility that the vaccine was experimental, and the possible impact of the vaccine on future fertility rose to the surface. In terms of the decision-making process, many parents exhibited ‘active decision-making,’ reaching out to friends, family, and opinion leaders for guidance prior to making their decision.

Conclusion

Vietnam’s HPV vaccination experience speaks to the importance of close collaboration with the government to make the most of high levels of trust, and to reduce suspicions about new vaccines that may arise in the context of vaccine introduction in developing country settings.
Psychometric testing of the short version of the world health organization quality of life (WHOQOL-BREF) questionnaire among pulmonary tuberculosis patients in Taiwan
Authors: Chung Wei-Sheng , Lan Yu-Ling , Yang Ming-Chin
Published: August 2012

Background

Studies on the effects of tuberculosis on a patient’s quality of life (QOL) are scant. The objective of this study was to evaluate the psychometric properties of the Taiwan short version of the World Health Organization Quality of Life (WHOQOL-BREF) questionnaire using patients with tuberculosis in Taiwan and healthy referents.

Methods

The Taiwanese short version of the WHOQOL-BREF was administered to patients with tuberculosis undergoing treatment and healthy referents from March 2007 to July 2007. Patients with tuberculosis (n = 140) and healthy referents (n = 130), matched by age, sex, and ethnicity, agreed to an interview. All participants lived in eastern Taiwan. Reliability assessments included internal consistency, whereas validity assessments included construct validity, convergent validity, and discriminant validity.

Results

More than half of these patients and referents were men (70.7% and 66.2%, respectively), and their average ages were 50.1 and 47.9 years, respectively. Approximately 60% of patients and referents were aboriginal Taiwanese (60.7% and 61.1%, respectively). The proportion with low socioeconomic status was greater for these patients. The internal consistency reliability coefficients were .92 and .93 for the patients and healthy referents, respectively. Exploratory factor analysis on the healthy referents displayed a 4-domain model, which was compatible with the original WHOQOL-BREF 4-domain model. However, for the TB patient group, after deleting 3 items, both exploratory and confirmatory factor analysis revealed a 6-domain model.

Conclusion

Psychometric evaluation of the Taiwan short version of the WHOQOL-BREF indicates that it has adequate reliability for use in research with TB patients in Taiwan. However, the factor structure generated from this TB patient sample differed from the WHO’s original 4-factor model, which raised a validity concern to apply the Taiwan short version of the WHOQOL-BREF to Taiwanese TB patients. Future research recruiting another sample to revisit this validity issue must be conducted to determine the validity of the WHOQOL-BREF TW in patients with TB.
Development of an in vitro drug screening assay using Schistosoma haematobium schistosomula
Authors: Marxer Monika , Ingram Katrin , Keiser Jennifer
Published: August 2012

Background

The development of novel antischistosomal drugs is crucial, as currently no vaccine and only a single drug is available for the treatment of schistosomiasis. Fast and accurate in vitro assays are urgently needed to identify new drug candidates and research efforts should include Schistosoma haematobium. The aim of the present study was to develop a S. haematobium drug sensitivity assay based on newly transformed schistosomula (NTS).

Methods

We first undertook comparative studies on the cercarial emergence rhythms of the intermediate host snails Biomphalaria glabrata (S. mansoni) and Bulinus truncatus (S. haematobium). Two transformation methods as well as three purification methods were studied on S. haematobium cercariae in order to produce a large number of viable and clean NTS. Known antischistosomal drugs were tested in the established NTS assay in vitro. Drug effects were evaluated either microscopically or fluorometrically, using a resazurin based viability marker. Microscopically obtained IC50 values were compared with results obtained for S. mansoni.

Results

A circadian rhythm existed in both snail species. Infected B. truncatus snails shed less cercariae than B. glabrata during the testing period. The highest transformation rate (69%) of S. haematobium cercariae into NTS was obtained with the vortex transformation (mechanical input) and the highest purification factor was observed using Percoll®. The fluorimetric readout based on resazurin was very precise in detecting dead or/and severely damaged schistosomula.

Conclusions

With the use of viability markers such as resazurin, drug screening assays using S. haematobium NTS can be efficiently performed. However, drugs acting on the morphology and motility of S. haematobium NTS, such as metrifonate are missed. Drug sensitivity assays with NTS of both species, S. haematobium and S. mansoni, showed very similar results using known antischistosomal drugs. The S. mansoni NTS assay might be more suitable as primary screen in drug discovery efforts, which ultimately aim for a broad-spectrum antischistosomal drug as a larger number of S. mansoni NTS can be generated.
Development of an embryonic skeletogenic mesenchyme lineage in a sea cucumber reveals the trajectory of change for the evolution of novel structures in echinoderms
Authors: McCauley Brenna S , Wright Erin P , Exner Cameron , Kitazawa Chisato , Hinman Veronica F
Published: August 2012

Background

The mechanisms by which the conserved genetic “toolkit” for development generates phenotypic disparity across metazoans is poorly understood. Echinoderm larvae provide a great resource for understanding how developmental novelty arises. The sea urchin pluteus larva is dramatically different from basal echinoderm larval types, which include the auricularia-type larva of its sister taxon, the sea cucumbers, and the sea star bipinnaria larva. In particular, the pluteus has a mesodermally-derived larval skeleton that is not present in sea star larvae or any outgroup taxa. To understand the evolutionary origin of this structure, we examined the molecular development of mesoderm in the sea cucumber, Parastichopus parvimensis.

Results

By comparing gene expression in sea urchins, sea cucumbers and sea stars, we partially reconstructed the mesodermal regulatory state of the echinoderm ancestor. Surprisingly, we also identified expression of the transcription factor alx1 in a cryptic skeletogenic mesenchyme lineage in P. parvimensis. Orthologs of alx1 are expressed exclusively within the sea urchin skeletogenic mesenchyme, but are not expressed in the mesenchyme of the sea star, which suggests that alx1
+ mesenchyme is a synapomorphy of at least sea urchins and sea cucumbers. Perturbation of Alx1 demonstrates that this protein is necessary for the formation of the sea cucumber spicule. Overexpression of the sea star alx1 ortholog in sea urchins is sufficient to induce additional skeleton, indicating that the Alx1 protein has not evolved a new function during the evolution of the larval skeleton.

Conclusions

The proposed echinoderm ancestral mesoderm state is highly conserved between the morphologically similar, but evolutionarily distant, auricularia and bipinnaria larvae. However, the auricularia, but not bipinnaria, also develops a simple skelotogenic cell lineage. Our data indicate that the first step in acquiring these novel cell fates was to re-specify the ancestral mesoderm into molecularly distinct territories. These new territories likely consisted of only a few cells with few regulatory differences from the ancestral state, thereby leaving the remaining mesoderm to retain its original function. The new territories were then free to take on a new fate. Partitioning of existing gene networks was a necessary pre-requisite to establish novelty in this system.
The Arab Spring: Implications for Israeli Security
Authors: Morton Jeffrey S. , Shortt Nicole
Published: August 2012

The popular uprising that started in Tunisia in December 2010 quickly spread across the Arab world, culminating in a historic regional realignment with far-reaching implications. This essay details the implications of the Arab Spring for Israeli security. After highlighting the history of Israel’s defense strategy and reviewing the Arab Spring revolts, the authors find that the recent uprisings exacerbate several issues faced by Israel, including geopolitical relations with other countries in the region, energy issues, and growing threats presented by nonstate actors.
A Cold Chill Comes Over the Arab Spring
Authors: Sale Richard T.
Published: August 2012

Islam is on the march in the Middle East. For the past few years, in every Mideast election, the Islamic parties have won: in the Gaza Strip in 2006 and in Iraq and Tunisia in 2010. In 2011, they won again in Turkey and Morocco, and in Egypt the Islamist parties confirmed an overwhelming victory in the first parliamentary elections since the overthrow of Hosni Mubarak. The Muslim Brotherhood won the biggest share with the hard-line Salafist al Nour Party of Light. The youth groups that staged the demonstrations that toppled Mubarak took only seven seats. What are the implications for US policy and its ideals of self-determination and human rights? Will the liberals triumph, or will the Egyptian people face a hard-line Islamic future? This article attempts to answer these questions.
The Arab Spring: Should Turkey Coordinate Its Foreign Policy with the European Union?
Authors: Noi Aylin Unver
Published: August 2012

In this article, Turkey’s and the European Union’s foreign policy approaches to the Middle East and North Africa region are analyzed by focusing on “normative power” and “soft power” concepts, the historical relations among the countries of the region, and the projects developed by the EU and Turkey. The Arab Spring and its repercussions on the EU’s and Turkey’s foreign policy approaches to the region, along with a brief historical background of the Turkey-EU relationship, are evaluated in order to determine whether Turkey should coordinate its foreign policy with the EU.
Spatiotemporal manipulation of retinoic acid activity in zebrafish hindbrain development via photo-isomerization
Authors: Xu Lijun , Feng Zhiping , Sinha Deepak , Ducos Bertrand , Ebenstein Yuval , Tadmor Arbel D. , Gauron Carole , Le Saux Thomas , Lin Shuo , Weiss Shimon , Vriz Sophie , Jullien Ludovic , Bensimon David
Published: August 2012

All-trans retinoic acid (RA) is a key player in many developmental pathways. Most methods used to study its effects in development involve continuous all-trans RA activation by incubation in a solution of all-trans RA or by implanting all-trans RA-soaked beads at desired locations in the embryo. Here we show that the UV-driven photo-isomerization of 13-cis RA to the trans-isomer (and vice versa) can be used to non-invasively and quantitatively control the concentration of all-trans RA in a developing embryo in time and space. This facilitates the global or local perturbation of developmental pathways with a pulse of all-trans RA of known concentration or its inactivation by UV illumination. In zebrafish embryos in which endogenous synthesis of all-trans RA is impaired, incubation for as little as 5 minutes in 1 nM all-trans RA (a pulse) or 5 nM 13-cis RA followed by 1-minute UV illumination is sufficient to rescue the development of the hindbrain if performed no later than bud stage. However, if subsequent to this all-trans RA pulse the embryo is illuminated (no later than bud stage) for 1 minute with UV light (to isomerize, i.e. deactivate, all-trans RA), the rescue of hindbrain development is impaired. This suggests that all-trans RA is sequestered in embryos that have been transiently exposed to it. Using 13-cis RA isomerization with UV light, we further show that local illumination at bud stage of the head region (but not the tail) is sufficient to rescue hindbrain formation in embryos whose all-trans RA synthetic pathway has been impaired.
Blunted renal dopaminergic system in a mouse model of diet-induced obesity
Authors: Moreira-Rodrigues Mónica , Quelhas-Santos Janete , Roncon-Albuquerque Roberto , Serrão Paula , Leite-Moreira Adelino , Sampaio-Maia Benedita , Pestana Manuel
Published: August 2012

Obesity has reached epidemic proportions in the Western world and is implicated in the pathophysiology of essential hypertension. The aim of the present study was to evaluate sodium handling, blood pressure and renal dopaminergic system activity in a mouse model of obesity induced by exposure to a hypercaloric diet. From six to 18 weeks of age, animals were fed with a control diet or a high-fat high-simple-carbohydrate (HFHSC) diet. Renal function, blood pressure and urinary and plasmatic catecholamines and biochemical parameters were evaluated in both groups. In parallel, the effects of high sodium intake (HS, 1.0% NaCl, 3 days) on natriuresis, urinary catecholamine excretion and aromatic l-amino acid decarboxylase (AADC) activity were evaluated in control and obese mice. Mice exposed to the HFHSC diet presented obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia and increased blood pressure. This was accompanied, in obese mice, by decreases in urinary excretion of dopamine and metabolites as well as reduced AADC activity in renal tissues. During HS intake, absolute urinary dopamine excretion increased in control, but not in obese mice. This was accompanied in obese mice by a natriuretic resistance on day 1 of the HS diet. In addition, obese mice presented increased urinary and plasmatic noradrenaline levels, as well as an increased heart rate when compared with control mice. In conclusion, in this model of diet-induced obesity hyperinsulinemia, insulin resistance and increased sympathetic tone are associated with blunted renal dopaminergic activity. It is suggested that this may contribute to compromised sodium excretion and increased blood pressure in obesity.