bluuebunny/crossref_metadata_2025 huggingface dataset:
A predicted protein, KIAA0247, is a cell cycle modulator in colorectal cancer cells under 5-FU treatment
Authors: Huang Chi-Jung , Yang Shung-Haur , Huang Shih-Ming , Lin Chih-Ming , Chien Chih-Cheng , Chen Yan-Chu , Lee Chia-Long , Wu Hao-Han , Chang Chun-Chao
Published: May 2011

Background

Colorectal cancer (CRC) is the predominant gastrointestinal malignancy and the leading cause of cancer death. The identification of genes related to CRC is important for the development of successful therapies and earlier diagnosis.

Methods

Molecular analysis of feces was evaluated as a potential method for CRC detection. Expression of a predicted protein with unknown function, KIAA0247, was found in feces evaluated using specific quantitative real-time polymerase chain reaction. Its cellular function was then analyzed using immunofluorescent staining and the changes in the cell cycle in response to 5-fluorouracil (5-FU) were assessed.

Results

Gastrointestinal tissues and peripheral blood lymphocytes ubiquitously expressed KIAA0247. 56 CRC patients fell into two group categories according to fecal KIAA0247 mRNA expression levels. The group with higher fecal KIAA0247 (n = 22; ≥ 0.4897) had a significantly greater five-year overall survival rate than the group with lower fecal KIAA0247 (n = 30; < 0.4897) (66.0 ± 11.6%; p = 0.035, log-rank test). Fecal expression of KIAA0247 inversely related to CRC tumor size (Kendall's tau-b = -0.202; p = 0.047). Immunofluorescent staining revealed that the cytoplasm of CRC cells evenly expresses KIAA0247 without 5-FU treatment, and KIAA0247 accumulates in the nucleus after 40 μM 5-FU treatment. In HCT116 p53-/- cells, which lack p53 cell cycle control, the proportion of cells in the G2/M phase was larger (13%) in KIAA0247-silent cells than in the respective shLuc control (10%) and KIAA0247-overexpressing cells (7%) after the addition of low dose (40 μM) 5-FU. Expression of three cyclin genes (cyclin A2, cyclin B1, and cyclin B2) also downregulated in the cells overexpressing KIAA0247.

Conclusions

This is the first description of a linkage between KIAA0247 and CRC. The study's data demonstrate overexpression of KIAA0247 associates with 5-FU therapeutic benefits, and also identify the clinical significance of fecal KIAA0247 in CRC.
Lytic HSV-1 infection induces the multifunctional transcription factor Early Growth Response-1 (EGR-1) in rabbit corneal cells
Authors: Bedadala Gautam R , Palem Jayavardhana R , Graham Lorna , Hill James M , McFerrin Harris E , Hsia Shao-Chung
Published: May 2011

Background

Herpes simplex virus type-1 (HSV-1) infections can cause a number of diseases ranging from simple cold sores to dangerous keratitis and lethal encephalitis. The interaction between virus and host cells, critical for viral replication, is being extensively investigated by many laboratories. In this study, we tested the hypothesis that HSV-1 lytic infection triggers the expression of important multi-functional transcription factor Egr1. The mechanisms of induction are mediated, at least in part, by signaling pathways such as NFκB and CREB.

Methods

SIRC, VERO, and 293HEK cell lines were infected with HSV-1, and the Egr-1 transcript and protein were detected by RT-PCR and Western blot, respectively. The localization and expression profile of Egr-1 were investigated further by immunofluorescence microscopy analyses. The recruitment of transcription factors to the Egr-1 promoter during infection was studied by chromatin immunoprecipitation (ChIP). Various inhibitors and dominant-negative mutant were used to assess the mechanisms of Egr-1 induction and their effects were addressed by immunofluorescence microscopy.

Results

Western blot analyses showed that Egr-1 was absent in uninfected cells; however, the protein was detected 24-72 hours post treatment, and the response was directly proportional to the titer of the virus used for infection. Using recombinant HSV-1 expressing EGFP, Egr-1 was detected only in the infected cells. ChIP assays demonstrated that NFкB and cAMP response element binding protein (CREB) were recruited to the Egr-1 promoter upon infection. Additional studies showed that inhibitors of NFкB and dominant-negative CREB repressed the Egr-1 induction by HSV-1 infection.

Conclusion

Collectively, these results demonstrate that Egr-1 is expressed rapidly upon HSV-1 infection and that this novel induction could be due to the NFкB/CREB-mediated transactivation. Egr-1 induction might play a key role in the viral gene expression, replication, inflammation, and the disease progression.
Research in advance for FMD Novel Vaccines
Authors: Zhang Liang , Zhang Jie , Chen Hao-tai , Zhou Jian-hua , ma Li-na , Ding Yao-zhong , Liu Yong-sheng
Published: June 2011

Foot-and-Mouth Disease (FMD), as a major global animal disease, affects millions of animals worldwide and remains the main sanitary barrier to the international and national trade of animals and animal products. Inactivated vaccination is the most effective measure for prevention of FMD at present, but fail to induce long-term protection and content new requires for production of FMD vaccines. As a number of Researchers hope to obtain satisfactory novel vaccines by new bio-technology, novel vaccines have been studied for more than thirty years. Here reviews the latest research progress of new vaccines, summarizes some importance and raises several suggestions for the future of FMD vaccine.
Inhibition of TRPA1 Channel Activity in Sensory Neurons by the Glial Cell Line-Derived Neurotrophic Factor Family Member, Artemin
Authors: Yoshida Naoki , Kobayashi Kimiko , Yu Lina , Wang Shenglan , Na Rengaowa , Yamamoto Satoshi , Noguchi Koichi , Dai Yi
Published: May 2011

Background:

The transient receptor potential (TRP) channel subtype A1 (TRPA1) is known to be expressed on sensory neurons and respond to changes in temperature, pH and local application of certain noxious chemicals such as allyl isothiocyanate (AITC). Artemin is a neuronal survival and differentiation factor and belongs to the glial cell line-derived neurotrophic factor (GDNF) family. Both TRPA1 and artemin have been reported to be involved in pathological pain initiation and maintenance. In the present study, using whole-cell patch clamp recording technique, in situ hybridization and behavioral analyses, we examined the functional interaction between TRPA1 and artemin.

Results:

We found that 85.8 ± 1.9% of TRPA1-expressing neurons also expressed GDNF family receptor alpha 3 (GFR α3), and 87.5 ± 4.1% of GFRα3-expressing neurons were TRPA1-positive. In whole-cell patch clamp analysis, a short-term treatment of 100 ng/ml artemin significantly suppressed the AITC-induced TRPA1 currents. A concentration-response curve of AITC resulting from the effect of artemin showed that this inhibition did not change EC50 but did lower the AITC-induced maximum response. In addition, pre-treatment of artemin significantly suppressed the number of paw lifts induced by intraplantar injection of AITC, as well as the formalin-induced pain behaviors.

Conclusions:

These findings that a short-term application of artemin inhibits the TRPA1 channel's activity and the sequential pain behaviors suggest a role of artemin in regulation of sensory neurons.
Community interventions to reduce child mortality in Dhanusha, Nepal: study protocol for a cluster randomized controlled trial
Authors: Shrestha Bhim P , Bhandari Bishnu , Manandhar Dharma S , Osrin David , Costello Anthony , Saville Naomi
Published: June 2011

Background

Neonatal mortality remains high in rural Nepal. Previous work suggests that local women's groups can effect significant improvement through community mobilisation. The possibility of identification and management of newborn infections by community-based workers has also arisen.

Methods/Design

The objective of this trial is to evaluate the effects on newborn health of two community-based interventions involving Female Community Health Volunteers.

MIRA Dhanusha community groups: a participatory intervention with women's groups. MIRA Dhanusha sepsis management: training of community volunteers in the recognition and management of neonatal sepsis.

The study design is a cluster randomized controlled trial involving 60 village development committee clusters allocated 1:1 to two interventions in a factorial design.

MIRA Dhanusha community groups: Female Community Health Volunteers (FCHVs) are supported in convening monthly women's groups. Nine groups per cluster (270 in total) work through two action research cycles in which they (i) identify local issues around maternity, newborn health and nutrition, (ii) prioritise key problems, (iii) develop strategies to address them, (iv) implement the strategies, and (v) evaluate their success. Cycle 1 focuses on maternal and newborn health and cycle 2 on nutrition in pregnancy and infancy and associated postpartum care practices.

MIRA Dhanusha sepsis management: FCHVs are trained to care for vulnerable newborn infants. They (i) identify local births, (ii) identify low birth weight infants, (iii) identify possible newborn infection, (iv) manage the process of treatment with oral antibiotics and referral to a health facility to receive parenteral gentamicin, and (v) follow up infants and support families.

Primary outcome: neonatal mortality rates. Secondary outcomes: MIRA Dhanusha community group: stillbirth, infant and under-two mortality rates, care practices and health care seeking behaviour, maternal diet, breastfeeding and complementary feeding practices, maternal and under-2 anthropometric status. MIRA Dhanusha sepsis management: identification and treatment of neonatal sepsis by community health volunteers, infection-specific neonatal mortality.

Trial Registration no

ISRCTN: ISRCTN87820538
Breast metastasis of primary colon cancer with micrometastasis in the axillary sentinel node: A metastasis that metastasized?
Authors: Perin Tiziana , Canzonieri Vincenzo , Memeo Lorenzo , Massarut Samuele
Published: May 2011

A case of single breast metastasis from colon adenocarcinoma, with omolateral axillary micrometastasis, is reported with a brief review of the pertinent literature. The originality of the oncological concept of metastasis from metastasis, through lymphatics penetration, is discussed in the setting of a rare condition of breast metastasis from a colorectal carcinoma.

The demonstration of axillary lymph node micrometastasis has been possible because fine needle aspiration cytology of the breast nodule was suspicious, but not conclusive for metastasis from colon cancer, so lumpectomy with sentinel node biopsy was planned.

Although no disseminated nodal metastases were evident on computerized tomography scan and ultrasonography before breast surgery, the patient developed brain metastases and deteriorated rapidly; she died 16 months after presenting with the breast mass.

In conclusion, solid cancers are able to further metastasize, via well-known pathways also recognized in primary cancers such as neoplastic cell invasion of peritumoral lymphatics.

Virtual Slides

The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1709104649540810.
Community capacity to acquire, assess, adapt, and apply research evidence: a survey of Ontario's HIV/AIDS sector
Authors: Wilson Michael G , Rourke Sean B , Lavis John N , Bacon Jean , Travers Robb
Published: May 2011

Background

Community-based organizations (CBOs) are important stakeholders in health systems and are increasingly called upon to use research evidence to inform their advocacy, program planning, and service delivery. To better support CBOs to find and use research evidence, we sought to assess the capacity of CBOs in the HIV/AIDS sector to acquire, assess, adapt, and apply research evidence in their work.

Methods

We invited executive directors of HIV/AIDS CBOs in Ontario, Canada (n = 51) to complete the Canadian Health Services Research Foundation's "Is Research Working for You?" survey.

Findings

Based on responses from 25 organizations that collectively provide services to approximately 32,000 clients per year with 290 full-time equivalent staff, we found organizational capacity to acquire, assess, adapt, and apply research evidence to be low. CBO strengths include supporting a culture that rewards flexibility and quality improvement, exchanging information within their organization, and ensuring that their decision-making processes have a place for research. However, CBO Executive Directors indicated that they lacked the skills, time, resources, incentives, and links with experts to acquire research, assess its quality and reliability, and summarize it in a user-friendly way.

Conclusion

Given the limited capacity to find and use research evidence, we recommend a capacity-building strategy for HIV/AIDS CBOs that focuses on providing the tools, resources, and skills needed to more consistently acquire, assess, adapt, and apply research evidence. Such a strategy may be appropriate in other sectors and jurisdictions as well given that CBO Executive Directors in the HIV/AIDS sector in Ontario report low capacity despite being in the enviable position of having stable government infrastructure in place to support them, benefiting from long-standing investment in capacity building, and being part of an active provincial network. CBOs in other sectors and jurisdictions that have fewer supports may have comparable or lower capacity. Future research should examine a larger sample of CBO Executive Directors from a range of sectors and jurisdictions.
Seatbelts and road traffic collision injuries
Authors: Abbas Alaa K , Hefny Ashraf F , Abu-Zidan Fikri M
Published: May 2011

Modification of seatbelts and their legislation played an important role in reducing morbidity and mortality of occupants in road traffic collisions. We aimed to review seatbelt development, its mechanism of action and its effects. Seatbelts reduce injury by preventing the occupant from hitting the interior parts of the vehicle or being ejected from the car. We have made a linear regression correlation between the overall seatbelt compliance and road traffic death rates in 46 high income countries to study the relationship between seatbelt use and mortality. There was a very highly significant negative correlation between the seatbelt compliance and road traffic death rates (R = - 0.77, F = 65.5, p < 0.00001). Seatbelt-related injuries include spinal, abdominal or pelvic injuries. The presence of a seatbelt sign must raise the suspicion of an intra-abdominal injury. These injuries can be reduced if seatbelts were applied correctly. Although seatbelts were recognized as an important safety measure, it still remains underused in many countries. Enforcement of seatbelt usage by law is mandatory so as to reduce the toll of death of road traffic collisions.
In vivo imaging of cell behaviors and F-actin reveals LIM-HD transcription factor regulation of peripheral versus central sensory axon development
Authors: Andersen Erica F , Asuri Namrata S , Halloran Mary C
Published: May 2011

Background

Development of specific neuronal morphology requires precise control over cell motility processes, including axon formation, outgrowth and branching. Dynamic remodeling of the filamentous actin (F-actin) cytoskeleton is critical for these processes; however, little is known about the mechanisms controlling motile axon behaviors and F-actin dynamics in vivo. Neuronal structure is specified in part by intrinsic transcription factor activity, yet the molecular and cellular steps between transcription and axon behavior are not well understood. Zebrafish Rohon-Beard (RB) sensory neurons have a unique morphology, with central axons that extend in the spinal cord and a peripheral axon that innervates the skin. LIM homeodomain (LIM-HD) transcription factor activity is required for formation of peripheral RB axons. To understand how neuronal morphogenesis is controlled in vivo and how LIM-HD transcription factor activity differentially regulates peripheral versus central axons, we used live imaging of axon behavior and F-actin distribution in vivo.

Results

We used an F-actin biosensor containing the actin-binding domain of utrophin to characterize actin rearrangements during specific developmental processes in vivo, including axon initiation, consolidation and branching. We found that peripheral axons initiate from a specific cellular compartment and that F-actin accumulation and protrusive activity precede peripheral axon initiation. Moreover, disruption of LIM-HD transcriptional activity has different effects on the motility of peripheral versus central axons; it inhibits peripheral axon initiation, growth and branching, while increasing the growth rate of central axons. Our imaging revealed that LIM-HD transcription factor activity is not required for F-actin based protrusive activity or F-actin accumulation during peripheral axon initiation, but can affect positioning of F-actin accumulation and axon formation.

Conclusion

Our ability to image the dynamics of F-actin distribution during neuronal morphogenesis in vivo is unprecedented, and our experiments provide insight into the regulation of cell motility as neurons develop in the intact embryo. We identify specific motile cell behaviors affected by LIM-HD transcription factor activity and reveal how transcription factors differentially control the formation and growth of two axons from the same neuron.
Population pharmacokinetics and pharmacodynamics of hydroxyurea in sickle cell anemia patients, a basis for optimizing the dosing regimen
Authors: Paule Ines , Sassi Hind , Habibi Anoosha , Pham Kim PD , Bachir Dora , Galactéros Frédéric , Girard Pascal , Hulin Anne , Tod Michel
Published: May 2011

Background

Hydroxyurea (HU) is the first approved pharmacological treatment of sickle cell anemia (SCA). The objectives of this study were to develop population pharmacokinetic(PK)-pharmacodynamic(PD) models for HU in order to characterize the exposure-efficacy relationships and their variability, compare two dosing regimens by simulations and develop some recommendations for monitoring the treatment.

Methods

The models were built using population modelling software NONMEM VII based on data from two clinical studies of SCA adult patients receiving 500-2000 mg of HU once daily. Fetal hemoglobin percentage (HbF%) and mean corpuscular volume (MCV) were used as biomarkers for response. A sequential modelling approach was applied. Models were evaluated using simulation-based techniques. Comparisons of two dosing regimens were performed by simulating 10000 patients in each arm during 12 months.

Results

The PK profiles were described by a bicompartmental model. The median (and interindividual coefficient of variation (CV)) of clearance was 11.6 L/h (30%), the central volume was 45.3 L (35%). PK steady-state was reached in about 35 days. For a given dosing regimen, HU exposure varied approximately fivefold among patients. The dynamics of HbF% and MCV were described by turnover models with inhibition of elimination of response. In the studied range of drug exposures, the effect of HU on HbF% was at its maximum (median Imax was 0.57, CV was 27%); the effect on MCV was close to its maximum, with median value of 0.14 and CV of 49%. Simulations showed that 95% of the steady-state levels of HbF% and MCV need 26 months and 3 months to be reached, respectively. The CV of the steady-state value of HbF% was about 7 times larger than that of MCV. Simulations with two different dosing regimens showed that continuous dosing led to a stronger HbF% increase in some patients.

Conclusions

The high variability of response to HU was related in part to pharmacokinetics and to pharmacodynamics. The steady-state value of MCV at month 3 is not predictive of the HbF% value at month 26. Hence, HbF% level may be a better biomarker for monitoring HU treatment. Continuous dosing might be more advantageous in terms of HbF% for patients who have a strong response to HU.

Trial Registration

The clinical studies whose data are analysed and reported in this work were not required to be registered in France at their time. Both studies were approved by local ethics committees (of Mondor Hospital and of Kremlin-Bicetre Hospital) and written informed consent was obtained from each patient.
Development of an ELISA for sensitive and specific detection of IgA autoantibodies against BP180 in pemphigoid diseases
Authors: Csorba Kinga , Schmidt Sabine , Florea Florina , Ishii Norito , Hashimoto Takashi , Hertl Michael , Kárpáti Sarolta , Bruckner-Tuderman Leena , Nishie Wataru , Sitaru Cassian
Published: May 2011

Background

Pemphigoids are rare diseases associated with IgG, IgE and IgA autoantibodies against collagen XVII/BP180. An entity of the pemphigoid group is the lamina lucida-type of linear IgA disease (IgA pemphigoid) characterized by IgA autoantibodies against BP180. While for the detection of IgG and IgE autoantibodies specific to collagen XVII several ELISA systems have been established, no quantitative immunoassay has been yet developed for IgA autoantibodies. Therefore, the aim of the present study was to develop an ELISA to detect IgA autoantibodies against collagen XVII in the sera of patients with pemphigoids.

Methods

We expressed a soluble recombinant form of the collagen XVII ectodomain in mammalian cells. Reactivity of IgA autoantibodies from patients with IgA pemphigoid was assessed by immunofluorescence microscopy and immunoblot analysis. ELISA test conditions were determined by chessboard titration experiments. The sensitivity, specificity and the cut-off were determined by receiver-operating characteristics analysis.

Results

The optimized assay was carried out using sera from patients with IgA pemphigoid (n = 30) and healthy donors (n = 105). By receiver operating characteristics (ROC) analysis, an area under the curve of 0.993 was calculated, indicating an excellent discriminatory capacity. Thus, a sensitivity and specificity of 83.3% and 100%, respectively, was determined for a cut-off point of 0.48. As additional control groups, sera from patients with bullous pemphigoid (n = 31) and dermatitis herpetiformis (n = 50), a disease associated with IgA autoantibodies against epidermal transglutaminase, were tested. In 26% of bullous pemphigoid patients, IgA autoantibodies recognized the ectodomain of collagen XVII. One of 50 (2%) of dermatitis herpetiformis patients sera slightly topped the cut-off value.

Conclusions

We developed the first ELISA for the specific and sensitive detection of serum IgA autoantibodies specific to collagen XVII in patients with pemphigoids. This immunoassay should prove a useful tool for clinical and translational research and should essentially improve the diagnosis and disease monitoring of patients with IgA pemphigoid. Moreover, our findings strongly suggest that IgA pemphigoid and IgG bullous pemphigoid represent two ends of the clinical spectrum of an immunological loss of tolerance against components of hemidesmosomes, which is mediated by both IgG and IgA autoantibodies.
Lack of a-disintegrin-and-metalloproteinase ADAM10 leads to intracellular accumulation and loss of shedding of the cellular prion protein in vivo
Authors: Altmeppen Hermann C , Prox Johannes , Puig Berta , Kluth Mark A , Bernreuther Christian , Thurm Dana , Jorissen Ellen , Petrowitz Bettina , Bartsch Udo , De Strooper Bart , Saftig Paul , Glatzel Markus
Published: May 2011

Background

The cellular prion protein (PrPC) fulfils several yet not completely understood physiological functions. Apart from these functions, it has the ability to misfold into a pathogenic scrapie form (PrPSc) leading to fatal transmissible spongiform encephalopathies. Proteolytic processing of PrPC generates N- and C-terminal fragments which play crucial roles both in the pathophysiology of prion diseases and in transducing physiological functions of PrPC. A-disintegrin-and-metalloproteinase 10 (ADAM10) has been proposed by cell culture experiments to be responsible for both shedding of PrPC and its α-cleavage. Here, we analyzed the role of ADAM10 in the proteolytic processing of PrPC
in vivo.

Results

Using neuron-specific Adam10 knockout mice, we show that ADAM10 is the sheddase of PrPC and that its absence in vivo leads to increased amounts and accumulation of PrPC in the early secretory pathway by affecting its posttranslational processing. Elevated PrPC levels do not induce apoptotic signalling via p53. Furthermore, we show that ADAM10 is not responsible for the α-cleavage of PrPC.

Conclusion

Our study elucidates the proteolytic processing of PrPC and proves a role of ADAM10 in shedding of PrPC
in vivo. We suggest that ADAM10 is a mediator of PrPC homeostasis at the plasma membrane and, thus, might be a regulator of the multiple functions discussed for PrPC. Furthermore, identification of ADAM10 as the sheddase of PrPC opens the avenue to devising novel approaches for therapeutic interventions against prion diseases.
Analysis of complex metabolic behavior through pathway decomposition
Authors: Ip Kuhn , Colijn Caroline , Lun Desmond S
Published: June 2011

Background

Understanding complex systems through decomposition into simple interacting components is a pervasive paradigm throughout modern science and engineering. For cellular metabolism, complexity can be reduced by decomposition into pathways with particular biochemical functions, and the concept of elementary flux modes provides a systematic way for organizing metabolic networks into such pathways. While decomposition using elementary flux modes has proven to be a powerful tool for understanding and manipulating cellular metabolism, its utility, however, is severely limited since the number of modes in a network increases exponentially with its size.

Results

Here, we present a new method for decomposition of metabolic flux distributions into elementary flux modes. Our method can easily operate on large, genome-scale networks since it does not require all relevant modes of the metabolic network to be generated. We illustrate the utility of our method for metabolic engineering of Escherichia coli and for understanding the survival of Mycobacterium tuberculosis (MTB) during infection.

Conclusions

Our method can achieve computational time improvements exceeding 2000-fold and requires only several seconds to generate elementary mode decompositions on genome-scale networks. These improvements arise from not having to generate all relevant elementary modes prior to initiating the decomposition. The decompositions from our method are useful for understanding complex flux distributions and debugging genome-scale models.
Retroperitoneal smooth muscle tumor of uncertain malignant potential after hysterectomy: a case report
Authors: Won Hye Sung , Chun Hoo Geun , Lee Kyungji
Published: May 2011

Introduction

Smooth muscle tumors of uncertain malignant potential represent a histologically heterogeneous group of uterine smooth muscle tumors that cannot be diagnosed as either benign or malignant. Smooth muscle tumors of uncertain malignant potential are usually clinically benign, but should be considered tumors of low malignant potential because they can occasionally recur or metastasize to distant sites.

Case presentation

We report the case of a 62-year-old Mongol woman diagnosed with a retroperitoneal smooth muscle tumor of uncertain malignant potential and lung metastasis, with a history of prior hysterectomy. The case was initially misdiagnosed as retroperitoneal sarcoma, and our patient received chemotherapy. However, no interval change in the size of the retroperitoneal mass and metastatic lung nodules was seen over a period of at least five years. She underwent partial resection of the retroperitoneal mass for the purposes of debulking and establishing a histopathological diagnosis. The diagnosis of the retroperitoneal mass was then confirmed as a smooth muscle tumor of uncertain malignant potential.

Conclusion

Smooth muscle tumors of uncertain malignant potential have an unpredictable clinical course, and relapses generally appear to occur after a long disease-free interval of up to several years. Therefore, patients diagnosed with smooth muscle tumors of uncertain malignant potential should receive long-term follow-up.
Comparison of analyses of the QTLMAS XIV common dataset. I: genomic selection
Authors: Pszczola Marcin , Strabel Tomasz , Wolc Anna , Mucha Sebastian , Szydlowski Maciej
Published: May 2011

Background

For the XIV QTLMAS workshop, a dataset for traits with complex genetic architecture has been simulated and released for analyses by participants. One of the tasks was to estimate direct genomic values for individuals without phenotypes. The aim of this paper was to compare results of different approaches used by the participants to calculate direct genomic values for quantitative trait (QT) and binary trait (BT).

Results

Participants applied 26 approaches for QT and 15 approaches for BT. Accuracy for QT was between 0.26 and 0.89 for males and between 0.31 and 0.89 for females, and for BT ranged from 0.27 to 0.85. For QT, percentage of lost response to selection varied from 8% to 83%, whereas for BT the loss was between 15% and 71%.

Conclusions

Bayesian model averaging methods predicted breeding values slightly better than GBLUP in a simulated data set. The methods utilizing genomic information performed better than traditional pedigree based BLUP analyses. Bivariate analyses was slightly advantageous over single trait for the same method. None of the methods estimated the non-additivity of QTL affecting the QT, which may be one of the constrains in accuracy observed in real data.
Pre-selection of markers for genomic selection
Authors: Schulz-Streeck Torben , Ogutu Joseph O , Piepho Hans-Peter
Published: May 2011

Background

Accurate prediction of genomic breeding values (GEBVs) requires numerous markers. However, predictive accuracy can be enhanced by excluding markers with no effects or with inconsistent effects among crosses that can adversely affect the prediction of GEBVs.

Methods

We present three different approaches for pre-selecting markers prior to predicting GEBVs using four different BLUP methods, including ridge regression and three spatial models. Performances of the models were evaluated using 5-fold cross-validation.

Results and conclusions

Ridge regression and the spatial models gave essentially similar fits. Pre-selecting markers was evidently beneficial since excluding markers with inconsistent effects among crosses increased the correlation between GEBVs and true breeding values of the non-phenotyped individuals from 0.607 (using all markers) to 0.625 (using pre-selected markers). Moreover, extension of the ridge regression model to allow for heterogeneous variances between the most significant subset and the complementary subset of pre-selected markers increased predictive accuracy (from 0.625 to 0.648) for the simulated dataset for the QTL-MAS 2010 workshop.
Genomic breeding value prediction and QTL mapping of QTLMAS2010 data using Bayesian Methods
Authors: Sun Xiaochen , Habier David , Fernando Rohan L , Garrick Dorian J , Dekkers Jack CM
Published: May 2011

Background

Bayesian methods allow prediction of genomic breeding values (GEBVs) using high-density single nucleotide polymorphisms (SNPs) covering the whole genome with effective shrinkage of SNP effects using appropriate priors. In this study we applied a modification of the well-known BayesA and BayesB methods to estimate the proportion of SNPs with zero effects (π) and a common variance for non-zero effects. The method, termed BayesCπ, was used to predict the GEBVs of the last generation of the QTLMAS2010 data. The accuracy of GEBVs from various methods was estimated by the correlation with phenotypes in the last generation. The methods were BayesCPi and BayesB with different π values, both with and without polygenic effects, and best linear unbiased prediction using an animal model with a genomic or numerator relationship matrix. Positions of quantitative trait loci (QTLs) were identified based on the variances of GEBVs for windows of 10 consecutive SNPs. We also proposed a novel approach to set significance thresholds for claiming QTL in this specific case by using pedigree-based simulation of genotypes. All analyses were focused on detecting and evaluating QTL with additive effects.

Results

The accuracy of GEBVs was highest for BayesCπ, but the accuracy of BayesB with π equal to 0.99 was similar to that of BayesCπ. The accuracy of BayesB dropped with a decrease in π. Including polygenic effects into the model only had marginal effects on accuracy and bias of predictions. The number of QTL identified was 15 when based on a stringent 10% chromosome-wise threshold and increased to 21 when a 20% chromosome-wise threshold was used.

Conclusions

The BayesCπ method without polygenic effects was identified to be the best method for the QTLMAS2010 dataset, because it had highest accuracy and least bias. The significance criterion based on variance of 10-SNP windows allowed detection of more than half of the QTL, with few false positives.
Small interference RNA targeting tissue factor inhibits human lung adenocarcinoma growth in vitro and in vivo
Authors: Xu Chengcheng , Gui Qi , Chen Wenshu , Wu Leiming , Sun Wei , Zhang Ni , Xu Qinzi , Wang Jianing , Fu Xiangning
Published: May 2011

Background

The human coagulation trigger tissue factor (TF) is overexpressed in several types of cancer and involved in tumor growth, vascularization, and metastasis. To explore the role of TF in biological processes of lung adenocarcinoma, we used RNA interference (RNAi) technology to silence TF in a lung adenocarcinoma cell line A549 with high-level expression of TF and evaluate its antitumor effects in vitro and in vivo.

Methods

The specific small interfering RNA (siRNA) designed for targeting human TF was transfected into A549 cells. The expression of TF was detected by reverse transcription-PCR and Western blot. Cell proliferation was measured by MTT and clonogenic assays. Cell apoptosis was assessed by flow cytometry. The metastatic potential of A549 cells was determined by wound healing, the mobility and Matrigel invasion assays. Expressions of PI3K/Akt, Erk1/2, VEGF and MMP-2/-9 in transfected cells were detected by Western blot. In vivo, the effect of TF-siRNA on the growth of A549 lung adenocarcinoma xenografts in nude mice was investigated.

Results

TF -siRNA significantly reduced the expression of TF in the mRNA and protein levels. The down-regulation of TF in A549 cells resulted in the suppression of cell proliferation, invasion and metastasis and induced cell apoptosis in dose-dependent manner. Erk MAPK, PI3K/Akt pathways as well as VEGF and MMP-2/-9 expressions were inhibited in TF-siRNA transfected cells. Moreover, intratumoral injection of siRNA targeting TF suppressed the tumor growth of A549 cells in vivo model of lung adenocarcinoma.

Conclusions

Down-regulation of TF using siRNA could provide a potential approach for gene therapy against lung adenocarcinoma, and the antitumor effects may be associated with inhibition of Erk MAPK, PI3K/Akt pathways.
Comparisons of 7- to 78-joint ultrasonography scores: all different joint combinations show equal response to adalimumab treatment in patients with rheumatoid arthritis
Authors: Hammer Hilde Berner , Kvien Tore K
Published: May 2011

Introduction

The primary objectives were to explore the associations between a comprehensive ultrasonographic (US) assessment of joints, tendons and bursae and previously described reduced joint counts (7-, 12-, 28- and 44-joint score) as well as to assess the sensitivity to change of these different US joint combinations during biological treatment.

Methods

Twenty patients with rheumatoid arthritis (RA) were examined by US (B-mode (BM) and power Doppler (PD)) with use of a semi-quantitative (0 to 3) score of 78 joints, 36 tendons/tendon groups and two bursae (hereafter described as the 78-joint score) at baseline and 1, 3, 6 and 12 months after initiating treatment with adalimumab. BM and PD scores for the different joint combinations were generated.

Results

The reduced joint scores had high correlation coefficients with the 78-joint score at all examinations (range 0.79 to 0.99 for BM and 0.77 to 0.99 for PD, each P < 0.001) and sum BM and PD scores of all the different joint combinations improved significantly during follow-up (P ≤ 0.05 to 0.001).

Conclusions

The reduced joint combinations were highly associated to the 78-joint score. Furthermore, all the joint combinations presently explored responded well to biological treatment. This indicates that an approach focusing on few joints and tendons gives equivalent information about the inflammatory activity in RA patients as a comprehensive US examination. The optimal combination of joints and tendons for a valid, reliable and feasible US measurement should be further explored to define a US score for follow-up of RA patients on biological treatment.
Videoradiographic analysis of the range of motion in unilateral experimental knee joint arthritis in rats
Authors: Boettger Michael K , Leuchtweis Johannes , Schaible Hans-Georg , Schmidt Manuela
Published: May 2011

Introduction

The translational and predictive value of animal models highly depends on the validity of respective readout parameters. In arthritis research, there has been a shift from sole threshold testing for pain-related behavior, as well as from swelling and histology assessment for inflammation, toward an analysis of joint function as indicated, for instance, by an increasing number of studies on gait abnormalities. Clinically, the range of motion (ROM) of the affected joint plays a major role in diagnosis and the assessment of treatment benefits. This parameter, however, is only insufficiently detected by currently used analytic systems in animals.

Methods

Here we used high-resolution videoradiographic analysis to assess ROM in experimental knee joint arthritis in rats. This parameter is described during the 21-day course of antigen-induced arthritis in rats. Furthermore, the therapeutic effects of antinociceptive (morphine) and anti-inflammatory (dexamethasone) treatment on ROM are documented. To obtain additional information on the implications of ROM in animal models, correlations were performed to measure pain-related behavior and inflammation.

Results

The study animals showed a significant reduction in ROM of the inflamed knee joint in the acute phase of arthritis. This was accompanied by an increase in knee joint movement on the contralateral side, indicating a compensational mechanism. Both morphine and dexamethasone treatment increased and thus normalized ROM. Changes in ROM were further stage-dependently correlated with weight bearing and joint swelling, that is, with both pain-related behavior and signs of inflammation.

Conclusions

The dynamic ROM observed in freely moving rats in our model of knee joint arthritis might serve as a parameter for global disease activity and might thus represent a promising readout parameter for preclinical assessment regarding the overall efficacy not only of antiarthritic but also of antinociceptive compounds.
Transcriptome instability in colorectal cancer identified by exon microarray analyses: Associations with splicing factor expression levels and patient survival
Authors: Sveen Anita , Ågesen Trude H , Nesbakken Arild , Rognum Torleiv O , Lothe Ragnhild A , Skotheim Rolf I
Published: May 2011

Background

Colorectal cancer (CRC) is a heterogeneous disease that, on the molecular level, can be characterized by inherent genomic instabilities; chromosome instability and microsatellite instability. In the present study we analyze genome-wide disruption of pre-mRNA splicing, and propose transcriptome instability as a characteristic that is analogous to genomic instability on the transcriptome level.

Methods

Exon microarray profiles from two independent series including a total of 160 CRCs were investigated for their relative amounts of exon usage differences. Each exon in each sample was assigned an alternative splicing score calculated by the FIRMA algorithm. Amounts of deviating exon usage per sample were derived from exons with extreme splicing scores.

Results

There was great heterogeneity within both series in terms of sample-wise amounts of deviating exon usage. This was strongly associated with the expression levels of approximately half of 280 splicing factors (54% and 48% of splicing factors were significantly correlated to deviating exon usage amounts in the two series). Samples with high or low amounts of deviating exon usage, associated with overall transcriptome instability, were almost completely separated into their respective groups by hierarchical clustering analysis of splicing factor expression levels in both sample series. Samples showing a preferential tendency towards deviating exon skipping or inclusion were associated with skewed transcriptome instability. There were significant associations between transcriptome instability and reduced patient survival in both sample series. In the test series, patients with skewed transcriptome instability showed the strongest prognostic association (P = 0.001), while a combination of the two characteristics showed the strongest association with poor survival in the validation series (P = 0.03).

Conclusions

We have described transcriptome instability as a characteristic of CRC. This transcriptome instability has associations with splicing factor expression levels and poor patient survival.
Empathetic Hardy: Bounded, Ambassadorial, and Broadcast Strategies of Narrative Empathy
Authors: Keen Suzanne
Published: June 2011

Pursuing my earlier theory of strategic narrative empathy, this essay shows Thomas Hardy's bounded strategic empathy for his fictional creations, Wessex countrymen and women; his ambassadorial strategic empathy for animals and select members of despised outgroups; and his broadcast strategic empathy for feeling humanity in an indifferent, Godless universe. Hardy's work demonstrates engagement with a variety of empathetic narrative strategies outlined in my Empathy and the Novel (2007), from the fellow-feeling of eighteenth-century moral sentimentalism, to the role-taking imagining of Romanticism, to the projection of feeling onto inanimate objects theorized by late-nineteenth-century German aesthetics as Einfühlung. Hardy's diction and notes show his knowledge of the related concepts, sympathy and altruism. At the time, sympathy (feeling for someone) was differentiated from empathy (feeling with someone); and for Hardy, altruism (nowadays seen as a consequence of empathy and sympathy) included such empathy. Hardy's strategic empathizing in his novels, in his epic poem The Dynasts, and in some of his shorter verses, I argue, links his representational strategies to his evolutionary meliorism and his belief that individual altruism might yet alleviate the painful drama of human existence. The essay details Hardy's employment of aesthetic Einfühlung to represent inanimate objects, to feel with the dead, and, paradoxically, to imagine the evolution of consciousness on the part of the unfeeling Immanent Will.
On Being Moved: Sympathy, Mobility, and Narrative Form
Authors: Burgess Miranda
Published: June 2011

This essay explores two approaches to affect in literary theory. The first of these approaches locates affect in discrete bodies and persons. The second views affect as a phenomenon anterior to the distinction of persons: a flow of energy among bodies as well as between bodies and the world. The essay argues that the first tends to function in recent theory as a stand-in for the other. Drawing a parallel with the operations of metaphor in William Wordsworth's poetics, the essay elaborates a late-eighteenth-century context for the emergence of what I argue is the similarly metaphorical relation between the two dominant conceptions of affect in theory: the development of systems of transport that seemed to threaten the autonomy of persons and feelings by putting into circulation feelings and persons from abroad; and the emergence of philosophical ideas about sympathy (Adam Smith) and aesthetic pleasure (Immanuel Kant) that reassuringly asserted, and gave priority, to the essential autonomy of the feeling self. Arguing for an understanding of metaphor as a formal enactment of displacement, for displacement as constitutive of anxiety, and thus for metaphor and displacement as the media through which late-eighteenth-century anxieties about the mobility of affect were displaced, I trace the philosophical genealogy through which this figural mode is inherited by recent theory, even in the absence of the unease that originally impelled the turn to metaphor. This essay demonstrates how narrative form may offer a conceptual alternative to figuration in affect theory, and how a model for rethinking affect may go beyond the bounded body.
Retreat and Return of the Secular in Iran
Authors: Rahnema Saeed
Published: June 2011

For nearly a century and a half, Iranian intellectuals' demands for secularism and democracy have remained unfulfilled. Needless to say, the establishment of a religious state has further exacerbated the formidable challenges in achieving their goals. Nonetheless, amid the current difficulties, there are new opportunities that were not available to previous generations of intellectuals. Thirty years of Islamic rule has made the calls for the separation of religion from the state far more widespread; despite ceaseless suppression of the opposition, a lively and vibrant civil society challenges the clerical oligarchy; the postrevolutionary secular Left and liberal intellectuals tend to be more tolerant and more independent-minded than their predecessors; and a new genre of secular Muslim intellectuals, unlike the Muslim reformers of the past, have begun challenging some basic tenets of Islam and the Islamic state. The article discusses the evolution of secularist thought in Iran and the tormented relationship among secular forces in the past. It explores the possibilities for more collaborative action among secularists of diverse persuasions, on the basis of new consensus models of secularism, with the goal of establishing a more effective counterhegemony to the clerical state.
Ideology and Political Action in the Iranian Revolution
Authors: Parsa Misagh
Published: June 2011

Scholars of the Iranian revolution have often explained the 1979 overthrow of the Pahlavi regime in terms of the rise of an Islamic movement that inspired Iranians to challenge the shah, confront the powerful army, and engage in martyrdom to bring down the monarchy. Leaders of the Islamic regime also consistently endorsed these views and claimed that the revolution was for Islam. This article analyzes the nature of the collective actions of major actors immediately before and during the revolution. Specifically, it examines the timing, demands, and claims of major collectivities and challengers that participated in the revolutionary process. It concludes that although segments of Iranian intellectuals and students fought for an Islamic government, the vast majority of the Iranian people never fought for a theocracy, established by Khomeini and his allies. The causes, processes, and outcome of the Iranian revolution were too complex to be explained by single, overarching, ideological explanations.
Focus group study of service user and carer experience of an Integrated Care Pathway
Authors: Hall Julie , Callaghan Patrick
Published: June 2011

Integrated care pathways (ICPs) are prearranged processes of care that are being increasingly used to deliver mental health services. The literature to date reveals relatively little about service user and carer experience in relation to their use. This study was completed as part of case study research and focused on the experiences of service users and carers gathered using focus groups, as a unit of analysis. The findings revealed a number of contrasts including the perspective that people did not feel that their care was individualized to them, although among them they had different perceptions of the care process. Conclusions suggest that mental health ICPs need to reflect the relationships between stakeholders, variability of illness and individual ways of living if they are to provide a framework for managing care which is responsive to the needs of people using mental health services.