bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of electrocardiogram intervals during growth of FVB/N neonate mice
Authors: Heier Christopher R , Hampton Thomas G , Wang Deli , DiDonato Christine J 
Published: August 2010

Abstract

Background
Electrocardiography remains the best diagnostic tool and therapeutic biomarker for a spectrum of pediatric diseases involving cardiac or autonomic nervous system defects. As genetic links to these disorders are established and transgenic mouse models produced in efforts to understand and treat them, there is a surprising lack of information on electrocardiograms (ECGs) and ECG abnormalities in neonate mice. This is likely due to the trauma and anaesthesia required of many legacy approaches to ECG recording in mice, exacerbated by the fragility of many mutant neonates. Here, we use a non-invasive system to characterize development of the heart rate and electrocardiogram throughout the growth of conscious neonate FVB/N mice.

Results
We examine ECG waveforms as early as two days after birth. At this point males and females demonstrate comparable heart rates that are 50% lower than adult mice. Neonatal mice exhibit very low heart rate variability. Within 12 days of birth PR, QRS and QTc interval durations are near adult values while heart rate continues to increase until weaning. Upon weaning FVB/N females quickly develop slower heart rates than males, though PR intervals are comparable between sexes until a later age. This suggests separate developmental events may contribute to these gender differences in electrocardiography.

Conclusions
We provide insight with a new level of detail to the natural course of heart rate establishment in neonate mice. ECG can now be conveniently and repeatedly used in neonatal mice. This should serve to be of broad utility, facilitating further investigations into development of a diverse group of diseases and therapeutics in preclinical mouse studies.
Identification and localization of minimal MHC-restricted CD8+ T cell epitopes within the Plasmodium falciparum AMA1 protein
Authors: Sedegah Martha , Kim Yohan , Peters Bjoern , McGrath Shannon , Ganeshan Harini , Lejano Jennylynn , Abot Esteban , Banania Glenna , Belmonte Maria , Sayo Renato , Farooq Fouzia , Doolan Denise L , Regis David , Tamminga Cindy , Chuang Ilin , Bruder Joseph T , King C Richter , Ockenhouse Christian F , Faber Bart , Remarque Edmond , Hollingdale Michael R , Richie Thomas L , Sette Alessandro 
Published: August 2010

Abstract

Background

Plasmodium falciparum apical membrane antigen-1 (AMA1) is a leading malaria vaccine candidate antigen that is expressed by sporozoite, liver and blood stage parasites. Since CD8+ T cell responses have been implicated in protection against pre-erythrocytic stage malaria, this study was designed to identify MHC class I-restricted epitopes within AMA1.

Methods
A recombinant adenovirus serotype 5 vector expressing P. falciparum AMA1 was highly immunogenic when administered to healthy, malaria-naive adult volunteers as determined by IFN-γ ELISpot responses to peptide pools containing overlapping 15-mer peptides spanning full-length AMA1. Computerized algorithms (NetMHC software) were used to predict minimal MHC-restricted 8-10-mer epitope sequences within AMA1 15-mer peptides active in ELISpot. A subset of epitopes was synthesized and tested for induction of CD8+ T cell IFN-γ responses by ELISpot depletion and ICS assays. A 3-dimensional model combining Domains I + II of P. falciparum AMA1 and Domain III of P. vivax AMA1 was used to map these epitopes.

Results
Fourteen 8-10-mer epitopes were predicted to bind to HLA supertypes A01 (3 epitopes), A02 (4 epitopes), B08 (2 epitopes) and B44 (5 epitopes). Nine of the 14 predicted epitopes were recognized in ELISpot or ELISpot and ICS assays by one or more volunteers. Depletion of T cell subsets confirmed that these epitopes were CD8+ T cell-dependent. A mixture of the 14 minimal epitopes was capable of recalling CD8+ T cell IFN-γ responses from PBMC of immunized volunteers. Thirteen of the 14 predicted epitopes were polymorphic and the majority localized to the more conserved front surface of the AMA1 model structure.

Conclusions
This study predicted 14 and confirmed nine MHC class I-restricted CD8+ T cell epitopes on AMA1 recognized in the context of seven HLA alleles. These HLA alleles belong to four HLA supertypes that have a phenotypic frequency between 23% - 100% in different human populations.
Gefitinib radiosensitizes non-small cell lung cancer cells through inhibition of ataxia telangiectasia mutated
Authors: Park Soo-Yeon , Kim Young Mee , Pyo Hongryull 
Published: August 2010

Abstract

Purpose
Inhibitors of epidermal growth factor receptor (EGFR) have shown dramatic results in a subset of patients with non-small cell lung cancer (NSCLC), and have also been shown to enhance the effect of ionizing radiation (IR). We investigated how gefitinib, an orally given EGFR inhibitor for NSCLC patients, can radiosensitize NSCLC cells.

Experimental Design and Results
In clonogenic survival assays performed in three NSCLC cell lines, gefitinib radiosensitized NCI-H460 and VMRC-LCD but not A549 cells. Gefitinib pretreatment induced multinucleated cells after IR exposure in NCI-H460 and VMRC-LCD, but not in A549 cells. Gefitinib also inhibited activation of ataxia telangiectasia mutated (ATM) after IR-exposure in NCI-H460 and VMRC-LCD, but not in A549 cells. An ATM specific inhibitor increased IR-induced multinucleated cells in both NCI-H460 and A549 cells. Gefitinib pretreatment inhibited the gradual decrease of γH2AX foci relative to time after IR exposure in NCI-H460 but not in A549 cells. Suppression of COX-2 in A549 cells induced multinucleated cells and caused radiosensitization after gefitinib+IR treatment. In contrast, COX-2 overexpression in NCI-H460 cells attenuated the induction of multinucleation and radiosensitization after the same treatment.

Conclusions
Our results suggest that gefitinib radiosensitizes NSCLC cells by inhibiting ATM activity and therefore inducing mitotic cell death, and that COX-2 overexpression in NSCLC cells inhibits this action of gefitinib.
Depletion of the oncoprotein Bcl-3 induces centrosome amplification and aneuploidy in cancer cells
Authors: Zamora Ruben , Espinosa Magali , Ceballos-Cancino Gisela , Segura Blanca , Maldonado Vilma , Melendez-Zajgla Jorge 
Published: August 2010

Abstract
Bcl-3 is an atypical member of the inhibitor of NF-kappa B family of proteins since it can function as a coactivator of transcription. Although this oncogene was described in leukemia, it is overexpressed in a number of solid tumors as well. The oncogenic potential of Bcl-3 has been associated with its capacity to increase proliferation by means of activating the cyclin D1 promoter and to its antiapoptotic role mediated by the inhibiton of p53 activity. In the course of dissecting these properties, we found that depleting Bcl-3 protein using shRNAs induce a decrease of proliferation and clonogenic survival associated with the induction of multinucleation and increased ploidy. These effects were associated with a DNA damage response, a delay in G2/M checkpoint and the induction of centrosome amplification
Expression of COX-1 and COX-2 in the endometrium of cyclic, pregnant and in a model of pseudopregnant rats and their regulation by sex steroids
Authors: St-Louis Isabelle , Singh Mohan , Brasseur Kevin , Leblanc Valérie , Parent Sophie , Asselin Eric 
Published: August 2010

Abstract

Background
Cyclooxygenases (COXs) are the rate limiting enzymes in the process of prostaglandins (PGs) synthesis, which are critical regulators of a number of reproductive processes, including ovulation, implantation, decidualization and parturition. The aim of the present study was to investigate the expression and regulation of COX-1 and COX-2 and levels of prostaglandins during rat pregnancy, in a model of pseudopregnancy and estrous cycle.

Methods
Uteri were collected from the cyclic rats on each day of estrous cycle, after every two days for pregnant (days 2 to 22) and pseudopregnant rats (days 1 to 9). In vitro primary endometrial stromal cells were cultured in the presence of steroid hormones and their respective inhibitors for the possible modulation of COX-1 and COX-2. Endometrial protein extracts were used for western blot analysis and tissue sections were prepared for protein localization using immunofluorescence. Measurements of PGF2alpha and PGE2 metabolites in serum were performed by enzyme immunoassay (EIA).

Results
COX-1 expression was found to be elevated during implantation and parturition, however, the levels of COX-1 decreased during decidualization periods. COX-2 was detected during early pregnancy from day 2 to 5, increased during decidual regression, and was also expressed at the time of parturition. COX-2 protein expression was found to be increased at estrus phase in cyclic rats. Both enzymes were found to be modulated in the endometrium of pseudopregnant rats, suggesting that they are regulated by 17beta-estradiol and progesterone. A significant increase in PGE2 metabolite levels was observed on day 10, 12 and 14 of pregnancy. However, an increase in PGF2alpha metabolite levels was observed only on day 14. The concentration of both these metabolites changed during pseudopregnancy and maximum levels were observed at day 7. Significant increase in PGE2 metabolite was observed at proestrus phase, on the other hand, PGF2alpha metabolite was significantly increased at proestrus and metestrus phase. COX-2 protein was regulated by 17beta-estradiol in cultured endometrial stromal cells which was blocked in the presence of ICI-182,780.

Conclusions
Taken together, these results suggest that COX-1 and COX-2 could be differentially regulated by steroid hormones and might be the key factors involved in embryo implantation, decidualization, decidua basalis regression and parturition in rats.
An N-terminally truncated envelope protein encoded by a human endogenous retrovirus W locus on chromosome Xq22.3
Authors: Roebke Christina , Wahl Silke , Laufer Georg , Stadelmann Christine , Sauter Marlies , Mueller-Lantzsch Nikolaus , Mayer Jens , Ruprecht Klemens 
Published: August 2010

AbstractBackgroundWe previously showed that the envelope (env) sequence of a human endogenous retrovirus (HERV)-W locus on chromosome Xq22.3 is transcribed in human peripheral blood mononuclear cells. Theenvopen reading frame (ORF) of this locus is interrupted by a premature stop at codon 39, but otherwise harbors a long ORF for an N-terminally truncated 475 amino acid Env protein, starting at an in-frame ATG at codon 68. We set out to characterize the protein encoded by that ORF.ResultsTransient expression of the 475 amino acid Xq22.3 HERV-WenvORF produced an N-terminally truncated HERV-W Env protein, as detected by the monoclonal anti-HERV-W Env antibodies 6A2B2 and 13H5A5. Remarkably, reversion of the stop at codon 39 in Xq22.3 HERV-Wenvreconstituted a full-length HERV-W Xq22.3 Env protein. Similar to the full-length HERV-W Env protein Syncytin-1, reconstituted full-length Xq22.3 HERV-W Env is glycosylated, forms oligomers, and is expressed at the cell surface. In contrast, Xq22.3 HERV-W Env is unglycosylated, does not form oligomers, and is located intracellularly, probably due to lack of a signal peptide. Finally, we reconfirm by immunohistochemistry that monoclonal antibody 6A2B2 detects an antigen expressed in placenta and multiple sclerosis brain lesions.ConclusionsA partially defective HERV-Wenvgene located on chromosome Xq22.3, which we propose to designate ERVWE2, has retained coding capacity and can produceex vivoan N-terminally truncated Env protein, named N-Trenv. Detection of an antigen by 6A2B2 in placenta and multiple sclerosis lesions opens the possibility that N-Trenv could be expressedin vivo. More generally, our findings are compatible with the idea that defective HERV elements may be capable of producing incomplete HERV proteins that, speculatively, may exert functions in human physiology or pathology.
What are possible barriers and facilitators to implementation of a Participatory Ergonomics programme?
Authors: Driessen Maurice T , Groenewoud Karin , Proper Karin I , Anema Johannes R , Bongers Paulien M , van der Beek Allard J 
Published: August 2010

Abstract

Background
Low back pain (LBP) and neck pain (NP) are common among workers. Participatory Ergonomics (PE) is used as an implementation strategy to prevent these symptoms. By following the steps of PE, working groups composed and prioritised ergonomic measures, and developed an implementation plan. Working group members were responsible to implement the ergonomic measures in their departments. Little is known about factors that hamper (barriers) or enhance (facilitators) the implementation of ergonomic measures. This study aimed to identify and understand the possible barriers and facilitators that were perceived during implementation.

Methods
This study is embedded in a cluster randomised controlled trial that investigated the effectiveness of PE to prevent LBP and NP among workers. For the purpose of the current study, questionnaires were sent to 81 working group members. Their answers were used to make a first inventory of possible barriers and facilitators to implementation. Based on the questionnaire information, 15 semi-structured interviews were held to explore the barriers and facilitators in more detail. All interviews were audio taped, transcribed verbatim, and analysed according to a systematic approach.

Results
All possible barriers and facilitators were obtained from questionnaire data, indicating that the semi-structured interviews did not yield information about new factors. Various barriers and facilitators were experienced. The presence of implementation plans for ergonomic measures that were already approved by the management facilitated implementation before the working group meeting. In these cases, PE served as a strategy to improve the implementation of the approved measures. Furthermore, the findings showed that the composition of a working group (i.e., including decision makers and a worker who led the implementation process) was important. Moreover, stakeholder involvement and collaboration were reported to considerably improve implementation.

Conclusions
This study showed that the working group as well as stakeholder involvement and collaboration were important facilitating factors. Moreover, PE was used as a strategy to improve the implementation of existing ergonomic measures. The results can be used to improve PE programmes, and thereby may contribute to the prevention of LBP and NP.

Trial registration number
ISRCTN27472278
Nolz1 promotes striatal neurogenesis through the regulation of retinoic acid signaling
Authors: Urbán Noelia , Martín-Ibáñez Raquel , Herranz Cristina , Esgleas Miriam , Crespo Empar , Pardo Monica , Crespo-Enríquez Ivan , Méndez-Gómez Héctor R , Waclaw Ronald , Chatzi Christina , Álvarez Susana , Álvarez Rosana , Duester Gregg , Campbell Kenneth , de Lera Angel R , Vicario-Abejón Carlos , Martinez Salvador , Alberch Jordi , Canals Josep M 
Published: August 2010

Abstract
Background
Nolz1 is a zinc finger transcription factor whose expression is enriched in the lateral ganglionic eminence (LGE), although its function is still unknown.

Results
Here we analyze the role of Nolz1 during LGE development. We show that Nolz1 expression is high in proliferating neural progenitor cells (NPCs) of the LGE subventricular zone. In addition, low levels of Nolz1 are detected in the mantle zone, as well as in the adult striatum. Similarly, Nolz1 is highly expressed in proliferating LGE-derived NPC cultures, but its levels rapidly decrease upon cell differentiation, pointing to a role of Nolz1 in the control of NPC proliferation and/or differentiation. In agreement with this hypothesis, we find that Nolz1 over-expression promotes cell cycle exit of NPCs in neurosphere cultures and negatively regulates proliferation in telencephalic organotypic cultures. Within LGE primary cultures, Nolz1 over-expression promotes the acquisition of a neuronal phenotype, since it increases the number of β-III tubulin (Tuj1)- and microtubule-associated protein (MAP)2-positive neurons, and inhibits astrocyte generation and/or differentiation. Retinoic acid (RA) is one of the most important morphogens involved in striatal neurogenesis, and regulates Nolz1 expression in different systems. Here we show that Nolz1 also responds to this morphogen in E12.5 LGE-derived cell cultures. However, Nolz1 expression is not regulated by RA in E14.5 LGE-derived cell cultures, nor is it affected during LGE development in mouse models that present decreased RA levels. Interestingly, we find that Gsx2, which is necessary for normal RA signaling during LGE development, is also required for Nolz1 expression, which is lost in Gsx2 knockout mice. These findings suggest that Nolz1 might act downstream of Gsx2 to regulate RA-induced neurogenesis. Keeping with this hypothesis, we show that Nolz1 induces the selective expression of the RA receptor (RAR)β without altering RARα or RARγ. In addition, Nozl1 over-expression increases RA signaling since it stimulates the RA response element. This RA signaling is essential for Nolz1-induced neurogenesis, which is impaired in a RA-free environment or in the presence of a RAR inverse agonist. It has been proposed that Drosophila Gsx2 and Nolz1 homologues could cooperate with the transcriptional co-repressors Groucho-TLE to regulate cell proliferation. In agreement with this view, we show that Nolz1 could act in collaboration with TLE-4, as they are expressed at the same time in NPC cultures and during mouse development.

Conclusions
Nolz1 promotes RA signaling in the LGE, contributing to the striatal neurogenesis during development.
Immunological response to highly active antiretroviral therapy following treatment for prevention of mother to child transmission of HIV‐1: a study in Côte d'Ivoire
Authors: Ekouevi Didier K , Coffie Patrick A , Chaix Marie‐Laure , Tonwe‐Gold Besigin , Amani‐Bosse Clarisse , Leroy Valériane , Abrams Elaine J , Dabis François 
Published: August 2010

BackgroundInformation is currently limited on the long‐term follow up of HIV‐1 infected women who are on highly active antiretroviral therapy (HAART) that contains nevirapine and lamivudine and who were previously exposed to antiretroviral drugs for the prevention of mother to child transmission (PMTCT) of HIV.MethodsWe studied the 36‐month immunological response to HAART in HIV‐1 infected women in Côte d'Ivoire. The women were previously exposed to antiretroviral drug regimens for PMTCT, including single‐dose nevirapine and/or short‐course zidovudine with or without lamivudine. All HAART regimens included a non‐nucleoside reverse transcriptase inhibitor.ResultsAt 36 months: the median absolute increase in CD4+ T cell count was +359 cells/mm3 (IQR: 210‐466) in 200 women who had undergone 36‐month follow‐up visits; +359 cells/mm3 (IQR: 222‐491) in 88 women not exposed to PMTCT antiretrovirals; and +363 cells/mm3 (IQR: 200‐464) in 112 women exposed to at least one antiretroviral PMTCT regimen. Overall, 49 (19.8%) of the 247 women who initiated HAART met the immunological failure criteria at least once during follow up. The overall probability of immunological failure was 0.08 (95% CI: 0.12‐0.15) at 12 months, and 0.21 (95% CI: 0.16‐0.27) at 36 months. No difference was observed according to the presence or absence of resistance mutations to nevirapine or lamivudine in women tested at four weeks postpartum. In addition, at 36 months, 23% of women were lost to follow up, dead or had stopped their treatment.ConclusionsA non‐nucleoside reverse transcriptase inhibitor‐based antiretroviral regimen, initiated a year or more after PMTCT exposure and that includes nevirapine, remains a good option for at least the first 36 months of treatment.
Phase I/II Clinical Study of Tosedostat, an Inhibitor of Aminopeptidases, in Patients With Acute Myeloid Leukemia and Myelodysplasia
Authors: Löwenberg Bob , Morgan Gareth , Ossenkoppele Gert J. , Burnett Alan K. , Zachée Pierre , Dührsen Ulrich , Dierickx Daan , Müller-Tidow Carsten , Sonneveld Pieter , Krug Utz , Bone Elisabeth , Flores Nicolas , Richardson Alison F. , Hooftman Leon , Jenkins Chris , Zweegman Sonja , Davies Faith 
Published: August 2010

Purpose To identify the maximum-tolerated dose (MTD) and to evaluate the antileukemic activity of tosedostat (formerly CHR-2797), an orally bioavailable aminopeptidase inhibitor. Patients and Methods In phase I, the MTD of once daily oral doses of tosedostat in hematologic malignancies was defined. In phase II, the therapeutic activity of the maximum-acceptable dose (MAD) of tosedostat was evaluated in elderly and/or relapsing patients with acute myeloid leukemia (AML) or myelodysplastic syndrome. Results In phase I, 16 patients were treated in four cohorts with tosedostat (60 mg to 180 mg) for 28 days. Three patients reported dose-limiting toxicities: two with reversible thrombocytopenia (> 75% reduction in platelet count) at 180 mg (MTD) and one with a Common Toxicity Criteria (CTC) grade 3 ALT elevation at 130 mg (MAD). In phase II, 41 patients were treated with 130 mg tosedostat. In phases I and II, the most common severe (CTC grades 3 to 5) adverse event was a reduction in the platelet count. Of the 51 AML patients in this study, seven reached complete marrow response (< 5% marrow blasts), with three achieving complete remission, and a further seven patients reaching a partial marrow response (between 5% and 15% marrow blasts). The overall response rate was therefore 27%. All responders were age > 60 years, and 79% had either relapsed or refractory AML. Conclusion This phase I/II study demonstrates that oral once daily dosing with 130 mg tosedostat is well tolerated and has significant antileukemic activity. The favorable risk-benefit profile suggests that further clinical trials are warranted.
Expanding the Criteria for BRCA Mutation Testing in Breast Cancer Survivors
Authors: Kwon Janice S. , Gutierrez-Barrera Angelica M. , Young Diana , Sun Charlotte C. , Daniels Molly S. , Lu Karen H. , Arun Banu 
Published: August 2010

Purpose Every year approximately 25% of women diagnosed with breast cancer are younger than 50 years of age, and almost 10% of them have a BRCA mutation. Not all potential carriers are identified by existing criteria for BRCA testing. We estimated the costs and benefits of different BRCA testing criteria for women with breast cancer younger than 50 years. Methods We developed a Markov Monte Carlo simulation to compare six criteria for BRCA mutation testing: (1) no testing (reference); (2) medullary breast cancer in patients younger than 50 years; (3) any breast cancer in patients younger than 40 years; (4) triple negative (TN) breast cancer in patients younger than 40 years; (5) TN breast cancer in patients younger than 50 years; (6) any breast cancer in patients younger than 50 years. Net health benefits were life expectancy and quality-adjusted life expectancy, and primary outcome was the incremental cost-effectiveness ratio (ICER). The model estimated the number of new breast and ovarian cancer cases. Results BRCA mutation testing for all women with breast cancer who were younger than 50 years could prevent the highest number of breast and ovarian cancer cases, but with unfavorable ICERs. Testing women with TN breast cancers who were younger than 50 years was cost-effective with an ICER of $8,027 per year of life gained ($9,084 per quality-adjusted life-year), and could reduce subsequent breast and ovarian cancer risks by 23% and 41%, respectively, compared with the reference strategy. Conclusion Testing women with TN breast cancers who were younger than 50 years for BRCA mutations is a cost-effective strategy and should be adopted into current guidelines for genetic testing.