bluuebunny/crossref_metadata_2025 huggingface dataset:
Linkage Politics: the Role of the European Community in Greek Politics in 1973
Authors: Verney Susannah , Tsakaloyannis Panos
Published: June 2013

The convulsions which began to shake the Greek military regime with the first student protests at the end of 1972 and which reached their climax in 1973 with the uprising at the Polytechnic in November, have been exhaustively analysed and discussed. However, they have always been viewed either through the prism of internal political developments or in the light of events in Cyprus. The international context remains largely unexplored.

The only element which has been taken into account is the ‘American factor’, yet the reasons for the change in American policy towards the regime in the Autumn of 1973 have not been sufficiently analysed. Such testimony as we have comes from representatives of the Greek or American governments. Spyros Markezinis, the junta’s civilian Prime Minister, attributes the fall of his government to the war in the Middle East. Certainly, Kissinger in his memoirs does not conceal his displeasure at the junta’s refusal to facilitate the transportation of war materiel to Israel at the most critical phase of the Arab-Israeli War in the Autumn of 1973.
Cavafy’s Barbarians and their Western Genealogy
Authors: Tziovas Dimitris
Published: June 2013

‘Waiting for the Barbarians’ is probably the most discussed of Cavafy’s poems after ‘The God abandons Antony’. Its sources, its date of composition and its diachronic symbolism, along with Cavafy’s unfathomable intentions, have generated a large number of interpretations and debates. Reading the poem today one cannot escape from these layers of interpretation, a kind of metadiscourse which regulates the new approaches either compliant or defiant to those already existent. It seems that the accumulated interpretations of a literary text sometimes discomfort those who seek stable and obvious meanings rather than a multiplicity of opinions and conflicting approaches. The very bulk of scholarship related to a certain poem or poet discourages a new reading and makes the critic hesitant and apprehensive. Nevertheless the diversity of interpretive approaches helps us both to realize their relativity and to ascribe them entirely to the various interpreters.
Fugitives and ethnography in Priscus of Panium1
Authors: Maas Michael
Published: June 2013

Because the historical writings of Priscus of Panium survive only in fragments, we regrettably lack knowledge of the full complexity of this fifth century historian’s concerns. Widely cited in Byzantine sources, the greatest part of Priscus’ work is found in the Excerpta de Legationibus, which was compiled from ancient texts by the emperor Constantine VII Porphyrogenitos in the middle of the tenth century as part of an encyclopedic collation of educational and practical information. The Excerpta, which dealt with international relations, found much of interest in Priscus, whose history included a detailed account of the struggle between the Romans and Attila the Hun. Of particular value is Priscus’ first-hand account of an embassy to Attila in 449 to discuss the exchange of fugitives and other matters. On this journey Priscus served as an assistant to Maximinus, the leader of the diplomatic mission sent from Constantinople. Envoys to foreign lands regularly included in their reports detailed observations of the societies they visited, and in this tradition the fragments preserved in the Excerpta constitute an invaluable source of information about Hunnic life as well as diplomatic matters. Priscus later reworked his acute observations of the Huns made on the embassy and mixed them with other information in the larger framework of his historical treatise, adapting part of his diplomatic intelligence report to the needs of a different sort of literary enterprise. We cannot know with any certainty the thematic architectonics of this historical work, but its fragments make it clear that Priscus’ treatment of the relations between Rome and the Empire of the Huns and his development of cultural issues implicit in those relations were more subtle than the tenth century editors’ focus on diplomatics might suggest.
AIMA: the blood of the Grand Komnenoi1
Authors: Shukurov Rustam
Published: June 2013

The emperor Manuel I Komnenos (1143-80) asked a certain fortune teller, how long the dynasty of Alexios I Komnenos (1081-1118) would reign. The prophetic response was the word (blood), the first three letters designating the first initials of the Komnenian emperors in the order of succession, namely, Alexios I, John II (1118-43), Manuel I, the last alpha for the name of Manuel’s future successor.
Enhancing metallurgical and mechanical properties of friction stir lap welding of Al–Cu using intermediate layer
Authors: Akbari M , Bahemmat P , Haghpanahi M , Besharati Givi M-K
Published: June 2013

In this paper, the material behaviour and mechanical characteristics of lap joint friction stir welding (FSW) between dissimilar alloys, namely, Cu and Al, is investigated. In order to produce welds of a higher quality, a layer of Cu is anodised on the aluminium alloy. The mechanical and the microstructural characterisations are performed on the welds, which are produced using various welding parameters. Scanning electron microscope with energy dispersive X-ray spectroscopy is used to identify the elemental compositions of phases that are formed. The results reveal that the use of the copper anodised layer prevented formation of brittle intermetallic compounds due to the direct FSW of 6061 aluminium alloy to copper and, as a result, enhanced the weld metallurgical and mechanical properties.
Simulation of transient force and strain during thermal mechanical testing relevant to the HAZ in multi-pass welds
Authors: Gao H , Hermans M J M , Richardson I M
Published: June 2013

The transient force and strain typically experienced in the heat affected zone of multi-pass welds were simulated using an electro-thermal mechanical testing (ETMT) machine, and the measurements were compared with numerical calculations. The thermal input data for these tests was obtained from welding experiments on 16 mm thick high strength quenched and tempered structural steel. The samples were subjected to thermal cycles under different mechanical constraints to represent realistic welding conditions. Phase transformations and high temperature elasto-plastic deformation were observed, describing time dependent material response. A comparison of experimental and numerical results indicates good agreement in strain evolution, but a deviation in the force was found during fast cooling from high temperatures due to modified material properties. Our results show that ETMT offers insight into transient force and strain evolution, which is beneficial for the validation of weld models and associated material data.
Optimisation of friction-stir welding process using vibro-acoustic signal analysis
Authors: Orozco Mario Sánchez , Macías Emilio Jiménez , Roca Angel Sánchez , Fals Hipólito Carvajal , Fernández Julio Blanco
Published: June 2013

This paper presents a mathematical model to predict the tensile strength (TS) of friction-stir welded (FSW) AA1050 aluminium alloy joint. This model has been obtained from the optimisation of the parameters of models developed from vibro-acoustic signals produced during the process. The multiple response method was used to obtain the optimisation model. During experimental development, the process parameters selected to be assessed were rotation speed (RS), travel speed, and tool profile (TP). The TS of the welded joint and the root mean square (RMS) value of the vibro-acoustic signal in the frequency range of 3·2–6·4 kHz were analysed as response variables. In order to validate the model, the optimal values of the factors and responses are presented, showing their agreement with the experimental values obtained. This model can be used to develop and optimise the parameters of the automatic control of the FSW process, based on the vibro-acoustic signal generated.
The CXCR4 mutations in WHIM syndrome impair the stability of the T-cell immunologic synapse
Authors: Kallikourdis Marinos , Trovato Anna Elisa , Anselmi Fabio , Sarukhan Adelaida , Roselli Giuliana , Tassone Laura , Badolato Raffaele , Viola Antonella
Published: June 2013

Key Points

The CXCR4 mutations in WHIM syndrome impair the stability of the T cell–antigen–presenting cell immunologic synapse.
Human CD1c+ dendritic cells secrete high levels of IL-12 and potently prime cytotoxic T-cell responses
Authors: Nizzoli Giulia , Krietsch Jana , Weick Anja , Steinfelder Svenja , Facciotti Federica , Gruarin Paola , Bianco Annalisa , Steckel Bodo , Moro Monica , Crosti Mariacristina , Romagnani Chiara , Stölzel Katharina , Torretta Sara , Pignataro Lorenzo , Scheibenbogen Carmen , Neddermann Petra , De Francesco Raffaele , Abrignani Sergio , Geginat Jens
Published: June 2013

Key Points

CD1c+ DC but not BDCA-3+ DC or other antigen-presenting cells secrete high amounts of bioactive IL-12. CD1c+ DC efficiently cross-present antigens, prime CD8+ T cells, and induce the highest levels of cytotoxic molecules.
Cinema in the training of psychiatry residents: focus on helping relationships
Authors: Gramaglia Carla , Jona Amalia , Imperatori Fredrica , Torre Eugenio , Zeppegno Patrizia
Published: June 2013

Background

Medical schools are currently charged with a lack of education as far as empathic/relational skills and the meaning of being a health-care provider are concerned, thus leading to increased interest in medical humanities.

Discussion

Medical humanities can offer an insight into human illness and in a broader outlook into human condition, understanding of one self, responsibility. An empathic relation to patients might be fostered by a matching approach to humanities and sciences, which should be considered as subjects of equal relevance, complementary to one another. Recently, movies have been used in medical – especially psychiatric - trainees education, but mainly within the limits of teaching a variety of disorders. A different approach dealing with the use of cinema in the training of psychiatry residents is proposed, based on Jung and Hillman’s considerations about the relation between images and archetypes, archetypal experience and learning.

Selected full-length movies or clips can offer a priceless opportunity to face with the meaning of being involved in a care-providing, helping profession.
The cholesterol lowering efficacy of plant stanol ester yoghurt in a Turkish population: a double-blind, placebo-controlled trial
Authors: Buyuktuncer Zehra , Fisunoğlu Mehmet , Guven Gulay Sain , Unal Serhat , Besler Halit Tanju
Published: June 2013

Background

We evaluated the cholesterol lowering efficacy of low-fat spoonable yoghurt with 1.9 g/d plant stanols as esters on plasma lipid profiles of Turkish subjects with mild to moderate hypercholesterolemia.

Methods

Using a randomised, double-blind, placebo-controlled study design, intervention (n = 35) and control (n = 35) groups consumed either 115 g low-fat yoghurt with 1.9 g/d plant stanols as esters or placebo yoghurt, respectively, for 4 weeks. Seventy subjects with untreated mild to moderate hypercholesterolemia (aged 23-65 years) were recruited. Changes in the lipid profile, including lipoproteins, apolipoproteins, and triglycerides, and anthropometric measurements were monitored at screening, baseline, and at the end of the second, third, and fourth weeks of intervention. The general linear model repeated measures procedure was used to test differences in the repeated continuous variables between study groups.

Results

Serum total cholesterol (4.6%), LDL cholesterol (6.3%), and non-HDL cholesterol (6.2%) concentrations were reduced significantly from baseline in the plant stanol group compared to the control group (p = 0.007, p = 0.005 and p = 0.005, respectively). A variation in the response of serum total and LDL cholesterol between the subjects in plant stanol group was obtained. No clinically significant change in anthropometrical measurements was observed during the intervention.

Conclusions

The spoonable low-fat yoghurt with 1.9 g/d plant stanols as esters lowered total, LDL, and non-HDL cholesterol levels in Turkish subjects with mild to moderate hypercholesterolemia. Nevertheless variation in baseline cholesterol levels, genetic predisposition of the subjects and compliance may contribute to a large individual variability.
Parental education associations with children’s body composition: mediation effects of energy balance-related behaviors within the ENERGY-project
Authors: Fernández-Alvira Juan M , te Velde Saskia J , De Bourdeaudhuij Ilse , Bere Elling , Manios Yannis , Kovacs Eva , Jan Natasa , Brug Johannes , Moreno Luis A
Published: June 2013

Background

It is well known that the prevalence of overweight and obesity is considerably higher among youth from lower socio-economic families, but there is little information about the role of some energy balance-related behaviors in the association between socio-economic status and childhood overweight and obesity. The objective of this paper was to assess the possible mediation role of energy balance-related behaviors in the association between parental education and children’s body composition.

Methods

Data were obtained from the cross sectional study of the “EuropeaN Energy balance Research to prevent excessive weight Gain among Youth” (ENERGY) project. 2121 boys and 2516 girls aged 10 to 12 from Belgium, Greece, Hungary, the Netherlands, Norway, Slovenia and Spain were included in the analyses. Data were obtained via questionnaires assessing obesity related dietary, physical activity and sedentary behaviors and basic anthropometric objectively measured indicators (weight, height, waist circumference). The possible mediating effect of sugared drinks intake, breakfast consumption, active transportation to school, sports participation, TV viewing, computer use and sleep duration in the association between parental education and children’s body composition was explored via MacKinnon’s product-of-coefficients test in single and multiple mediation models. Two different body composition indicators were included in the models, namely Body Mass Index and waist circumference.

Results

The association between parental education and children’s body composition was partially mediated by breakfast consumption, sports participation, TV viewing and computer use. Additionally, a suppression effect was found for sugared drinks intake. No mediation effect was found for active transportation and sleep duration. The significant mediators explained a higher proportion of the association between parental education and waist circumference compared to the association between parental education and BMI.

Conclusions

Tailored overweight and obesity prevention strategies in low SES preadolescent populations should incorporate specific messages focusing on the importance of encouraging daily breakfast consumption, increasing sports participation and decreasing TV viewing and computer use. However, longitudinal research to support these findings is needed.
Exploring dendritic cell based vaccines targeting survivin for the treatment of head and neck cancer patients
Authors: Turksma Annelies W , Bontkes Hetty J , Ruizendaal Janneke J , Scholten Kirsten BJ , Akershoek Johanneke , Rampersad Shakila , Moesbergen Laura M , Cillessen Saskia AGM , Santegoets Saskia JAM , de Gruijl Tanja D , Leemans C René , Meijer Chris JLM , Hooijberg Erik
Published: June 2013

Background

New treatment modalities are needed for the treatment of cancers of the head and neck region (HNSCC). Survivin is important for the survival and proliferation of tumor cells and may therefore provide a target for immunotherapy. Here we focused on theex vivopresence andin vitroinduction of survivin specific T cells.

Methods

Tetramer staining and ELIspot assays were used to document the presence of survivin specific T cells in patient derived material, and to monitor the presence and persistence of survivin specific T cells after repeatedin vitrostimulation with autologous dendritic cells.

Results

Ex vivoanalysis showed the presence of survivin-specific T cells in the peripheral blood (by tetramer analysis) and in the draining lymph node (by ELIspot analysis) in a HNSCC and a locally advanced breast cancer patient respectively. However, we were unable to maintain isolated survivin specific T cells for prolonged periods of time. For thein vitrogeneration of survivin specific T cells, monocyte derived DC were electroporated with mRNA encoding full length survivin or a survivin mini-gene together with either IL21 or IL12 mRNA. Western blotting and immunohistochemical staining of dendritic cell cytospin preparations confirmed translation of the full length survivin protein. After repeated stimulation we observed an increase, followed by a decrease, of the number of survivin specific T cells. FACS sorted or limiting dilution cloned survivin specific T cells could not be maintained on feeder mix for prolonged periods of time. Protein expression analysis subsequently showed that activated, but not resting T cells contain survivin protein.

Conclusions

Here we have shown that survivin specific T cells can be detectedex vivoin patient derived material. Furthermore, survivin specific T cells can be inducedin vitrousing autologous dendritic cells with enforced expression of survivin and cytokines. However, we were unable to maintain enriched or cloned survivin specific T cells for prolonged periods of time. Endogenous expression of survivin in activated T cells and subsequent fratricide killing might explain ourin vitroobservations. We therefore conclude that survivin, although it is a universal tumor antigen, might not be the ideal target for immunotherapeutic strategies for the treatment of cancer of the head and neck.
Combined features based on MT1-MMP expression, CD11b + immunocytes density and LNR predict clinical outcomes of gastric cancer
Authors: Peng Chun-Wei , Wang Lin-Wei , Fang Min , Yang Gui-Fang , Li Yan , Pang Dai-Wen
Published: June 2013

Background

Given the complexity of tumor microenvironment, no single marker from cancer cells could adequately predict the clinical outcomes of gastric cancer (GC). The objective of this study was to evaluate the prognostic role of combined features including conventional pathology, proteinase and immune data in GC.

Methods

In addition to pathological studies, immunohistochemistry was used to assess membrane-type 1 matrix metalloproteinase (MT1-MMP) expression and CD11b + immunocytes density in three independent GC tissue microarrays containing 184 GC tissues. Separate and combined features were evaluated for their impact on overall survival (OS).

Results

We found that traditional factors including tumor size, histological grade, lymph node status, serosa invasion and TNM stage were associated with OS (P < 0.05 for all). Moreover, statistically significant differences in OS were found among lymph node ratio (LNR) subgroups (P < 0.001), MT1-MMP subgroups (P = 0.015), and CD11b + immunocytes density subgroups (P = 0.031). Most importantly, combined feature (MT1-MMP positive, low CD11b + immunocytes density and high LNR) was found by multivariate analysis to be an independent prognostic factors for OS after excluding other confounding factors (HR = 3.818 [95%CI: 2.223-6.557], P < 0.001). In addition, this combined feature had better performance in predicting clinical outcomes after surgery long before recurrence had occurred (Area under the curve: 0.689 [95%CI: 0.609-0.768], P < 0.001).

Conclusions

These findings indicate that better information on GC prognosis could be obtained from combined clinico-pathological factors, tumor cells and the tumor microenvironment.
The altered expression profile of microRNAs in cardiopulmonary bypass canine models and the effects of mir-499 on myocardial ischemic reperfusion injury
Authors: Qin Han , Chen Guang-xian , Liang Meng-ya , Rong Jian , Yao Jian-ping , Liu Hai , Wu Zhong-kai
Published: June 2013

Background

MicroRNAs were enrolled in various cardiovascular disease especially ischemic heart diseases, but the microRNA changes during myocardial ischemia reperfusion injury underwent cardiopulmonary bypass are still unknown. This study screens the microRNA differences in CPB canines and evaluates the relationship of microRNAs with myocardial ischemia reperfusion injury.

Methods

13 healthy canines received CPB with 60 minutes of aortic clamping and cardioplegic arrest, followed by 90 minutes reperfusion. Left ventricular myocardial samples, blood samples and hemodynamic data were taken at different time points. We performed microRNAs microarray experiments upon the left ventricle myocardium tissue of canines before CPB and after reperfusion for 90 minutes by pooling 3 tissue samples together and used qRT-PCR for confirmation.

Results

Statistically significant difference was found in mir-499 level before CPB and after reperfusion (T1 vs. T4, p = 0.041). We further examined the mir-499 levels by using qRT-PCR in all 13 canines at 4 different time points (T1 vs. T4, p = 0.029). Mir-499 expression was negatively correlated with cardiac troponin T (cTnT) and creatine kinase- MB (CK-MB) levels of canines in all time points samples (r = 0.469, p < 0.001 and r = 0.273, p = 0.050 respectively). Moreover, higher mir-499 expression level was associated with higher dP/dtmax at 25 minutes and 90 minutes after reperfusion.

Conclusion

Myocardial ischemic reperfusion injury with cardiopulmonary bypass results in declining level of mir-499 expression in left ventricle myocardium of canines, suggesting mir-499 would be a potential therapeutic target in cardiac protection during open heart surgery.
DNA damage strength modulates a bimodal switch of p53 dynamics for cell-fate control
Authors: Chen Xi , Chen Jia , Gan Siting , Guan Huaji , Zhou Yuan , Ouyang Qi , Shi Jue
Published: June 2013

Background

The p53 pathway is differentially activated in response to distinct DNA damage, leading to alternative phenotypic outcomes in mammalian cells. Recent evidence suggests that p53 expression dynamics play an important role in the differential regulation of cell fate, but questions remain as to how p53 dynamics and the subsequent cellular response are modulated by variable DNA damage.

Results

We identified a novel, bimodal switch of p53 dynamics modulated by DNA-damage strength that is crucial for cell-fate control. After low DNA damage, p53 underwent periodic pulsing and cells entered cell-cycle arrest. After high DNA damage, p53 underwent a strong monotonic increase and cells activated apoptosis. We found that the damage dose-dependent bimodal switch was due to differential Mdm2 upregulation, which controlled the alternative cell fates mainly by modulating the induction level and pro-apoptotic activities of p53.

Conclusions

Our findings not only uncover a new mode of regulation for p53 dynamics and cell fate, but also suggest that p53 oscillation may function as a suppressor, maintaining a low level of p53 induction and pro-apoptotic activities so as to render cell-cycle arrest that allows damage repair.
Impaired toll-like receptor 8 signaling in multiple sclerosis
Authors: Johnson Tory P , Tyagi Richa , Patel Karan , Schiess Nicoline , Calabresi Peter A , Nath Avindra
Published: June 2013

Background

The etiology and immunopathology of multiple sclerosis (MS) is not well understood. It is recognized that although autoreactive T cells are the main early mediators of disease, other cell types, including cells of the innate immune system contribute to MS pathogenesis. The objective of this study was to determine if Toll-like receptor (TLR) signaling is functionally altered in patients with MS.

Findings

Peripheral blood mononuclear cells from healthy donors and patients with relapsing remitting MS were stimulated with specific agonists of TLRs 3, 7, 8 and 9. Using quantitative polymerase chain reaction transcript levels of tumor necrosis factor-α, interferon-α and interleukin (IL)-12β were quantified from patients with MS and healthy donors. TLR8-induced production ofIL12Btranscripts and protein was functionally impaired in patients with MS as compared to healthy controls (P<0.05 andP<0.005, respectively). Patients with MS also expressed lower baseline levels of TLR8 as compared to healthy controls (P<0.05).

Conclusions

TLR8 expression and signaling is impaired in peripheral blood mononuclear cells from patients with MS. This finding suggests that loss of TLR8 signaling may be contributing to autoimmune processes in MS.
Multi-scale agent-based modeling on melanoma and its related angiogenesis analysis
Authors: Wang Jun , Zhang Le , Jing Chenyang , Ye Gang , Wu Hulin , Miao Hongyu , Wu Yukun , Zhou Xiaobo
Published: June 2013

Background

Recently, melanoma has become the most malignant and commonly occurring skin cancer. Melanoma is not only the major source (75%) of deaths related to skin cancer, but also it is hard to be treated by the conventional drugs. Recent research indicated that angiogenesis is an important factor for tumor initiation, expansion, and response to therapy. Thus, we proposed a novel multi-scale agent-based computational model that integrates the angiogenesis into tumor growth to study the response of melanoma cancer under combined drug treatment.

Results

Our multi-scale agent-based model can simulate the melanoma tumor growth with angiogenesis under combined drug treatment. The significant synergistic effects between drug Dox and drug Sunitinib demonstrated the clinical potential to interrupt the communication between melanoma cells and its related vasculatures. Also, the sensitivity analysis of the model revealed that diffusivity related to the micro-vasculatures around tumor tissues closely correlated with the spread, oscillation and destruction of the tumor.

Conclusions

Simulation results showed that the 3D model can represent key features of melanoma growth, angiogenesis, and its related micro-environment. The model can help cancer researchers understand the melanoma developmental mechanism. Drug synergism analysis suggested that interrupting the communications between melanoma cells and the related vasculatures can significantly increase the drug efficacy against tumor cells.
Quinolone prophylaxis for the prevention of BK virus infection in kidney transplantation: study protocol for a randomized controlled trial
Authors: Humar Atul , Gill John , Johnston Olwyn , Fergusson Dean , House Andrew A , Lebel Louise , Cockfield Sandra , Kim S Joseph , Zaltzman Jeff , Cantarovich Marcelo , Karpinski Martin , Ramsay Tim , Knoll Greg A
Published: June 2013

Background

BK virus infection has emerged as a major complication in kidney transplantation leading to a significant reduction in graft survival. There are currently no proven strategies to prevent or treat BK virus infection. Quinolone antibiotics, such as levofloxacin, have demonstrated activity against BK virus. We hypothesize that administration of a quinolone antibiotic, when given early post-transplantation, will prevent the establishment of BK viral replication in the urine and thus prevent systemic BK virus infection.

Methods/design

The aim of this pilot trial is to assess the efficacy, safety and feasibility of a 3-month course of levofloxacin in the kidney transplant population. This is a multicenter, randomized, double-blind, placebo-controlled trial with two parallel arms conducted in 11 Canadian kidney transplant centers. A total of 154 patients with end-stage renal disease undergoing kidney transplantation will be randomized to receive a 3-month course of levofloxacin or placebo starting in the early post-transplant period. Levofloxacin will be administered at 500 mg po daily with dose adjustments based on kidney function. The primary outcome will be the time to occurrence of BK viruria within the first year post-transplantation. Secondary outcomes include BK viremia, measures of safety (adverse events, resistant infections,Clostridium difficile-associated diarrhea), measures of feasibility (proportion of transplanted patients recruited into the trial), proportion of patients adherent to the protocol, patient drop-out and loss to follow-up,and use of quinolone antibiotics outside of the trial protocol.

Discussion

Results from this pilot study will provide vital information to design and conduct a large, multicenter trial to determine if quinolone therapy decreases clinically meaningful outcomes in kidney transplantation. If levofloxacin significantly reduces BK viruria and urine viral loads in kidney transplantation, it will provide important justification to progress to the larger trial. If the full trial shows that levofloxacin significantly reduces BK infection and improves outcomes, its use in kidney transplantation will be strongly endorsed given the lack of proven therapies for this condition.

Trial registration

This trial was funded by the Canadian Institutes of Health Research (grant number:222493) and is registered at ClinicalTrials.gov (NCT01353339).
Reduced expression of miR-22 in gastric cancer is related to clinicopathologic characteristics or patient prognosis
Authors: Wang Weibin , Li Fujun , Zhang Yong , Tu Yanyang , Yang Qi , Gao Xingchun
Published: June 2013

Objective

Involvements of microRNA-22 (miR-22) in cancer development have attracted much attention, but its role in tumorigenesis of gastric cancer is still largely unknown. Therefore, the aim of this study was to investigate the expression patterns and clinical implications of miR-22 in gastric cancer.

Methods

Quantitative RT-PCR was performed to evaluate the expression levels of miR-22 in 98 pairs of gastric cancer and normal adjacent mucosa.

Results

Compared with normal adjacent mucosa, miR-22 expression was significantly downregulated in gastric cancer tissues (P < 0.001). Of 98 patients with gastric cancer, 58 (59.2%) were placed in the low miR-22 expression group and 40 (40.8%) were placed in the high miR-22 expression group. In addition, tumors with low miR-22 expression had greater extent of lymph node metastasis (P = 0.02) and distant metastasis (P = 0.01), and were at a worse stage (P = 0.01) than the tumors with high miR-22 expression. Moreover, the gastric cancer patients with low miR-22 expression had shorter overall survival than those with high miR-22 expression (P = 0.03). MiR-22, determined by multivariate analysis, was an independent prognostic factor for patients with gastric cancer.

Conclusion

Our data offer the convincing evidence that the reduced expression of miR-22 was significantly associated with malignant development of gastric cancer and may be a novel prognostic marker of this disease. miR-22 might have potentials in the application of cancer therapy for patients with gastric cancer.
Nurr1 regulates Top IIβ and functions in axon genesis of mesencephalic dopaminergic neurons
Authors: Heng Xin , Jin Gang , Zhang Xin , Yang Dehuang , Zhu Mingzhe , Fu Shijun , Li Xuping , Le Weidong
Published: June 2013

Background

NURR1 (also named as NR4A2) is a member of the steroid/thyroid hormone receptor family, which can bind to DNA and modulate expression of target genes. Previous studies have shown that NURR1 is essential for the nigral dopaminergic neuron phenotype and function maintenance, and the defects of the gene are possibly associated with Parkinson's disease (PD).

Results

In this study, we used new bornNurr1knock-out mice combined with Affymetrix genechip technology and real time polymerase chain reaction (PCR) to identifyNurr1regulated genes, which led to the discovery of several transcripts differentially expressed in the nigro-striatal pathway ofNurr1knock-out mice. We found that an axon genesis gene calledTopoisomerase IIβ(Top IIβ) was down-regulated inNurr1knock-out mice and we identified two functional NURR1 binding sites in the proximalTop IIβpromoter. While inTop IIβnull mice, we saw a significant loss of dopaminergic neurons in the substantial nigra and lack of neurites along the nigro-striatal pathway. Using specific TOP II antagonist ICRF-193 orTop IIβsiRNA in the primary cultures of ventral mesencephalic (VM) neurons, we documented that suppression of TOP IIβ expression resulted in VM neurites shortening and growth cones collapsing. Furthermore, microinjection of ICRF-193 into the mouse medial forebrain bundle (MFB) led to the loss of nigro-striatal projection.

Conclusion

Taken together, our findings suggest thatTop IIβmight be a down-stream target ofNurr1, which might influence the processes of axon genesis in dopaminergic neurons via the regulation of TOP IIβ expression. TheNurr1-Top IIβinteraction may shed light on the pathologic role ofNurr1defect in the nigro-striatal pathway deficiency associated with PD.
American tegumentary leishmaniasis caused by Leishmania (Viannia) braziliensis: assessment of parasite genetic variability at intra- and inter-patient levels
Authors: Oliveira Fernanda S , Valete-Rosalino Cláudia M , Pacheco Sandro JB , Costa Filipe A Carvalho , Schubach Armando O , Pacheco Raquel S
Published: June 2013

Background

The genetic variability ofLeishmania(Viannia)braziliensiswas assessed at intra and interpatient levels of individuals with different clinical manifestations of American tegumentary leishmaniasis (ATL).

Methods

Fifty-two samples, of which 13 originated from cutaneous lesions and 39 from mucosal lesions, provided by 35 patients, were examined by low-stringency single-specific-primer PCR (LSSP-PCR) and phenetic analysis. Genetic variability ofL. (V.)braziliensis, in kinetoplast DNA (kDNA) signatures, was compared both from different patients and from different lesions of the same patient. Phenetic analysis was performed to evaluate the degree of heterogeneity of the kDNA minicircles. In order to evaluate inter and intrapatientL. (V.)braziliensisgenetic variability, the percentage of shared bands and analysis of the coefficients of similarity were analyzed.

Results

Different genetic profiles, representing kDNA signatures of the parasite, were obtained by LSSP-PCR analysis of each sample. Phenetic analysis grouped genetic profiles of different levels of differentiation from more similar to most divergent. The percentage of shared bands at the inter and intrapatient levels was 77% and 89%, respectively. Comparison of the average inter and intrapatient coefficients of similarity and their standard deviations were statistically significant (p < 0.001).

Conclusion

Genetic variability at the intrapatient level was less pronounced than that between different patients. A conceptual model was proposed to better understand the complexity at both levels.
Astragalus polysaccharide enhances immunity and inhibits H9N2 avian influenza virus in vitro and in vivo
Authors: Kallon Sanpha , Li Xiaorong , Ji Jun , Chen Cuiying , Xi Qianyun , Chang Shuang , Xue Chunyi , Ma Jingyun , Xie Qingmei , Zhang Youngliang
Published: June 2013

This study investigated the humoral immunization of Astragalus polysaccharide (APS) against H9N2 avian influenza virus (H9N2 AIV) infection in chickens.

The effects of APS treatment on H9N2 infection was evaluated by an MTT [3(4, 5-dimethylthiazol-2-yl)-2, 3-diphenyl tetrazolium bromide] assay and analysis of MHC and cytokine mRNA expression. The effect on lymphocyte and serum antibody titers in vivo was also investigated. IL-4, IL-6, IL-10, LITAF, IL-12 and antibody titers to H9N2 AIV were enhanced in the first week after APS treatment. The results indicated that APS treatment reduces H9N2 AIV replication and promotes early humoral immune responses in young chickens.
Peripheral regulatory cells immunophenotyping in Primary Sjögren's Syndrome: a cross-sectional study
Authors: Furuzawa-Carballeda Janette , Hernández-Molina Gabriela , Lima Guadalupe , Rivera-Vicencio Yahaira , Férez-Blando Karen , Llorente Luis
Published: June 2013

Introduction

IL-10--producing B cells, Foxp3-expressing T cells (Tregs) and the IDO-expressing dendritic cells (pDC) are able to modulate inflammatory processes, to induce immunological tolerance and, in turn, to inhibit the pathogenesis of autoimmune disease.

The aim of the study was to characterize and to enumerate peripheral IL-10--producing B cells, Tregs and pDCregs in primary Sjögren's Syndrome (pSS) patients in regard of their clinical and serologic activity.

Methods

Fifty pSS patients and 25 healthy individuals were included in the study. CD19+--expressing peripheral B lymphocytes were purified by positive selection. CD19+/CD24hi/CD38hi/IL-10--producing B cells, CD4+/CD25hi/Foxp3+ and CD8+/CD28-/Foxp3+ Tregs, as well as CCR6+/CD123+/IDO+ DCs, were quantitated by flow cytometry.

Results

Immature/transitional circulating IgA+ IL-10--producing B cells had higher levels in pSS patients versus control group, whereas CD19+/CD38hi/IgG+/IL-10+ cells had lower percentage versus control. Indeed CD19+/CD24hi/CD38hi/CD5+/IL-10+, CD19+/CD24hi/CD38hi/CD10+/IL-10+, CD19+/CD24hi/CD38hi/CD20+/IL-10+, CD19+/CD24hi/CD38hi/CD27-/IL-10+, and CD19+/CD24hi/CD38hi/CXCR7+/IL-10+ cells had higher frequency in clinical inactive pSS patients when compared with control group. Remarkably, only percentages of CD19+/CD24hi/CD38hi/CD10+/IL-10+ and CD19+/CD24hi/CD38hi/CD27-/IL-10+ subsets were increased in pSS serologic inactive versus control group (P < 0.05). The percentage of IDO-expressing pDC cells was higher in pSS patients regardless of their clinical or serologic activity. There were no statistically significant differences in the percentage of CD4+/CD25hi/Foxp3+ Tregs between patient groups versus controls. Nonetheless, a decrease in the frequency of CD8+/CD28-/Foxp3+ Tregs was found in inactive pSS patients versus controls (P < 0.05).

Conclusions

The findings of this exploratory study show that clinical inactive pSS patients have an increased frequency of IL-10--producing B cells and IDO-expressing pDC cells.
Species-specific PAMP recognition by TLR2 and evidence for species-restricted interaction with Dectin-1
Authors: Willcocks Sam , Offord Victoria , Seyfert Hans-Martin , Coffey Tracey J , Werling Dirk
Published: June 2013

TLRs mediate recognition of a wide range of microbial products, including LPS, lipoproteins, flagellin, and bacterial DNA, and signaling through TLRs leads to the production of inflammatory mediators. In addition to TLRs, many other surface receptors have been proposed to participate in innate immunity and microbial recognition, and signaling through some of these, for example, C-type lectins, is likely to cooperate with TLR signaling in defining inflammatory responses. In the present study, we examined the importance of the ECD and intracellular TIR domain of boTLR2 and huTLR2 to induce a species-specific response by creating a chimeric TLR2 protein. Our results indicate that the strength of the response to any TLR2 ligand tested was dependent on the extracellular, solenoid structure, but not the intracellular TIR domain. Furthermore, we examined whether the recognition of two PAMPs by Dectin-1, a CLR, depends on the interaction with TLR2 from the same species. TLR2 expression seemed to affect the Dectin-1-dependent production of CXCL8 to β-glucan containing zymosan as well as Listeria monocytogenes. Furthermore, the interaction of Dectin-1 with TLR2 seemed to require that both receptors are from the same species. Our data demonstrate that the differences in the TLR2 response seen between the bovine and human system depend on the ECD of TLR2 and that collaborative recognition of distinct microbial components by different classes of innate-immune receptors is crucial in orchestrating inflammatory responses.
Vertical electric source in transient marine CSEM: Effect of 3D inhomogeneities on the late time response
Authors: Singer Bension Sh. , Atramonova Svetlana
Published: June 2013

The time-domain marine controlled-source electromagnetic method, based on injection of electric currents into the sea via a vertical cable and measurements of the transient vertical electric field, is characterized by high sensitivity to resistive reservoirs and robustness with respect to distorting effects of lateral heterogeneities. This is due to the fact that a vertical electric dipole induces in a stratified medium only a transverse magnetic (TM) field. In addition, the vertical electric field is not directly contributed by the transverse electric (TE) component of the field scattered by heterogeneities. Nevertheless, a closed-form solution shows that the first order effect of a lateral heterogeneity displays itself as a parallel shift of the late time response curves. The effect is also observed in 3D responses evaluated by numerical solutions of the integral equation of the modified iterative dissipative method. Moreover, in “favorable” conditions, scattering on heterogeneities may change the law of the field decay. The parallel shift of the late time curves is caused by vertical polarization of the scatterer, while its horizontal polarization leads to an abnormally fast decay of the vertical electric field. The latter effect, observed against the background of the general decay of the free electromagnetic field, can be associated with “energy channeling from the TM to TE field.” Neither of the effects necessarily deteriorates the method sensitivity. Unlike the vertical electric field, the horizontal electromagnetic field is contributed by the scattered TE field. As a result, the abnormally fast decay of the vertical electric field is accompanied by an abnormally slow decay of the horizontal components. The transient horizontal electric field may become almost insensitive to the reservoir resistivity. In addition to unrealistically harsh requirements to the transmitter tilt, this may render accurate measurements of the horizontal electromagnetic field of a vertical electric bipole not feasible.
Collaborative stepped care v. care as usual for common mental disorders: 8-month, cluster randomised controlled trial
Authors: Oosterbaan Desiree B. , Verbraak Marc J. P. M. , Terluin Berend , Hoogendoorn Adriaan W. , Peyrot Wouter J. , Muntingh Anna , van Balkom Anton J. L. M.
Published: June 2013

Background

Thus far collaborative stepped care (CSC) studies have not incorporated self-help as a first step.

Aims

To evaluate the effectiveness of CSC in the treatment of common mental disorders.

Method

An 8-month cluster randomised controlled trial comparing CSC to care as usual (CAU) (Dutch Trial Register identifier NTR1224). The CSC consisted of a stepped care approach guided by a psychiatric nurse in primary care with the addition of antidepressants dependent on the severity of the disorder, followed by cognitive–behavioural therapy in mental healthcare.

Results

Twenty general practitioners (GPs) and 8 psychiatric nurses were randomised to provide CSC or CAU. The GPs recruited 163 patients of whom 85% completed the post-test measurements. At 4-month mid-test CSC was superior to CAU: 74.7% (n = 68) v. 50.8% (n = 31) responders (P = 0.003). At 8-month post-test and 12-month follow-up no significant differences were found as the patients in the CAU group improved as well.

Conclusions

Treatment within a CSC model resulted in an earlier treatment response compared with CAU.
Ethanol metabolism and oxidative stress are required for unfolded protein response activation and steatosis in alcoholic liver disease
Authors: Tsedensodnom Orkhontuya , Vacaru Ana M. , Howarth Deanna L. , Yin Chunyue , Sadler Kirsten C.
Published: June 2013

Secretory pathway dysfunction and lipid accumulation (steatosis) are the two most common responses of hepatocytes exposed to ethanol and are major factors in the pathophysiology of alcoholic liver disease (ALD). However, the mechanisms by which ethanol elicits these cellular responses are not fully understood. Recent data indicates that activation of the unfolded protein response (UPR) in response to secretory pathway dysfunction can cause steatosis. Here, we examined the relationship between alcohol metabolism, oxidative stress, secretory pathway stress and steatosis using zebrafish larvae. We found that ethanol was immediately internalized and metabolized by larvae, such that the internal ethanol concentration in 4 day old larvae equilibrated to 160 mM after 1 hour of exposure to 350 mM ethanol, with an average ethanol metabolism rate of 56 μmol/larva/hour over 32 hours. Blocking alcohol dehydrogenase 1 (Adh1) and cytochrome P450 2E1 (Cyp2e1), the major enzymes that metabolize ethanol, prevented alcohol-induced steatosis and reduced induction of the UPR in the liver. Thus, we conclude that ethanol metabolism causes ALD in zebrafish. Oxidative stress generated by Cyp2e1-mediated ethanol metabolism is proposed to be a major culprit in ALD pathology. We found that production of reactive oxygen species (ROS) increased in larvae exposed to ethanol, while either inhibition of the zebrafish Cyp2e1 homolog or administration of antioxidants reduced ROS levels. Importantly, these treatments also blocked ethanol-induced steatosis and reduced UPR activation, while H2O2 acted as a pro-oxidant that synergized with low doses of ethanol to induce the UPR. Collectively, these data demonstrate that ethanol metabolism and oxidative stress are conserved mechanisms required for the development of steatosis and hepatic dysfunction in ALD, and that these processes contribute to ethanol-induced UPR activation and secretory pathway stress in hepatocytes.
dEHBP1 regulates Scabrous secretion during Notch mediated lateral inhibition
Authors: Giagtzoglou Nikolaos , Li Tongchao , Yamamoto Shinya , Bellen Hugo J.
Published: June 2013

Notch signaling is an evolutionarily conserved pathway that plays a central role in numerous developmental and disease processes. The versatility of the Notch pathway relies on the activity of context dependent regulators. These include rab11, sec15, arp3 and dEHBP1, which control Notch signaling and cell fate acquisition in asymmetrically dividing mechanosensory lineages by regulating the trafficking of the ligand Delta. Here we show that dEHBP1 also controls the specification of R8 photoreceptors, as its loss results in the emergence of supernumerary R8 photoreceptors. Given the requirements for Notch signaling during lateral inhibition, we propose that dEHBP1 regulates distinct aspects of Notch signaling in different developmental contexts. We show that dEHBP1 regulates the exocytosis of Scabrous, a positive regulator of Notch signaling. In conclusion, dEHBP1 provides developmental versatility of intercellular signaling by regulating the trafficking of distinct Notch signaling components.
TIF1γ requires sumoylation to exert its repressive activity on TGFβ signaling
Authors: Fattet Laurent , Ay Anne-Sophie , Bonneau Benjamin , Jallades Laurent , Mikaelian Ivan , Treilleux Isabelle , Gillet Germain , Hesling Cédric , Rimokh Ruth
Published: June 2013

TIF1γ, a new actor of TGFβ signaling, inhibits the Smad4-mediated TGFβ response by interaction with Smad2/3 or ubiquitination of Smad4. We have shown that TIF1γ participates in TGFβ signaling as a negative regulator of Smad4 during the TGFβ-induced epithelial-to-mesenchymal transition in mammary epithelial cells and during terminal differentiation of mammary alveolar epithelial cells and lactation. We demonstrate here that TIF1γ is sumoylated and interacts with Ubc9, the only known SUMO-conjugating enzyme. Four functional sumoylation sites lie within the middle domain of TIF1γ, the Smad interaction domain. We show that a sumoylation-defective TIF1γ mutant significantly reduces TIF1γ inhibition of Smad complexes and that of the Smad-mediated TGFβ transcriptional response. Moreover, chromatin immunoprecipitation experiments indicate that TIF1γ sumoylation is required to limit Smad4 binding on the PAI-1 TGFβ target gene promoter. Ectopic expression of TIF1γ in mammary epithelial cells inhibits TGFβ-induced EMT, an effect relieved by expression of non-sumoylated TIF1γ. Taken together, our results identify a new TGFβ regulatory layer, whereby sumoylation strengthens the TIF1γ repressive action on canonical TGFβ signaling.