bluuebunny/crossref_metadata_2025 huggingface dataset:
Deterioration of traditional dietary custom increases the risk of lifestyle-related diseases in young male Africans
Authors: Hamada Atsumi , Mori Mari , Mori Hideki , Muhihi Alfa , Njelekela Marina , Masesa Zablon , Mtabaji Jacob , Yamori Yukio
Published: August 2010

Background

Prevalence of metabolic syndrome (MS) is rapidly increasing worldwide. To investigate the spread of MS risks and its relationship with eating habits including fish intake, we carried out a health examination for young and middle-aged men.

Methods

The subjects were 97 healthy men (20 to 50 years) living in Mwanza, located on the shore of Lake Victoria in Tanzania. The health examination was conducted according to the basic protocol of WHO-CARDIAC (Car diovascular Di seases and A limentary C omparison) Study. This survey included anthropometric measurements, a dietary questionnaire, blood pressure measurement, and blood and 24-hour urine (24U) collection. Excretions of sodium, potassium and taurine (Tau) in 24U were estimated as the biomarkers of salt, vegetable and fish product intakes respectively.

Results

In this survey, 62.5 % of the young and 63.3% of the middle-aged adults had MS risks. The most prevalent MS risk factor was increased blood pressure (50.0% of young adults and 53.1% of the middle-aged). Tau excretions in 24U and n-3 fatty acid levels in plasma were significantly lower in young adults than those in the middle-aged (both P < 0.05). The eating frequencies of non-traditional foods such as donuts and ice cream showed negative correlations with age (r = -0.282, P < 0.01 and r = -0.246, P < 0.05), while salt intake positively correlated with age (r = 0.236, P < 0.05). Tau excretion in 24U was inversely correlated with atherosclerosis index (r = -0.306, P < 0.01) and fasting blood glucose (r = -0.284, P < 0.05).

Conclusions

Young adults in Mwanza had a decreased frequency of eating habit of fish products compared with the middle-aged as indicated by Tau excretion in 24U and n-3 fatty acid level in the plasma, and over half of young adults had one or more MS risks just as the middle-aged. The change in food habit of lowered fish intake and raised exotic food intake might be concluded to increase MS risks in young men.
Transcriptome responses to aluminum stress in roots of aspen (Populus tremula)
Authors: Grisel Nadine , Zoller Stefan , Künzli-Gontarczyk Marzanna , Lampart Thomas , Münsterkötter Martin , Brunner Ivano , Bovet Lucien , Métraux Jean-Pierre , Sperisen Christoph
Published: August 2010

Background

Ionic aluminum (mainly Al3+) is rhizotoxic and can be present in acid soils at concentrations high enough to inhibit root growth. Many forest tree species grow naturally in acid soils and often tolerate high concentrations of Al. Previously, we have shown that aspen (Populus tremula) releases citrate and oxalate from roots in response to Al exposure. To obtain further insights into the root responses of aspen to Al, we investigated root gene expression at Al conditions that inhibit root growth.

Results

Treatment of the aspen roots with 500 μM Al induced a strong inhibition of root growth within 6 h of exposure time. The root growth subsequently recovered, reaching growth rates comparable to that of control plants. Changes in gene expression were determined after 6 h, 2 d, and 10 d of Al exposure. Replicated transcriptome analyses using the Affymetrix poplar genome array revealed a total of 175 significantly up-regulated and 69 down-regulated genes, of which 70% could be annotated based on Arabidopsis genome resources. Between 6 h and 2 d, the number of responsive genes strongly decreased from 202 to 26, and then the number of changes remained low. The responses after 6 h were characterized by genes involved in cell wall modification, ion transport, and oxidative stress. Two genes with prolonged induction were closely related to the Arabidopsis Al tolerance genes ALS3 (for Al sensitive 3) and MATE (for multidrug and toxin efflux protein, mediating citrate efflux). Patterns of expression in different plant organs and in response to Al indicated that the two aspen genes are homologs of the Arabidopsis ALS3 and MATE.

Conclusion

Exposure of aspen roots to Al results in a rapid inhibition of root growth and a large change in root gene expression. The subsequent root growth recovery and the concomitant reduction in the number of responsive genes presumably reflect the success of the roots in activating Al tolerance mechanisms. The aspen genes ALS3 and MATE may be important components of these mechanisms.
Fucoidan present in brown algae induces apoptosis of human colon cancer cells
Authors: Kim Eun Ji , Park So Young , Lee Jae-Yong , Park Jung Han Yoon
Published: August 2010

Background

Fucoidan is a sulfated polysaccharide found in brown algae; it has been shown to exhibit a number of biological effects, including anti-tumor effects. In this study, we evaluated the effects of fucoidan on apoptosis in HT-29 and HCT116 human colon cancer cells.

Methods

HT-29 and HCT116 cells were cultured with various concentrations of fucoidan (0 - 20 μg/mL). Apoptosis was assayed via Hoechst staining and Annexin V staining followed by flow cytometric analysis. Western blot analyses and JC-1 staining were conducted to determine the levels of apoptosis-regulating proteins and mitochondrial membrane permeability, respectively.

Results

Fucoidan induced substantial reductions in viable cell numbers and apoptosis of HT-29 and HCT116 cells in a dose-dependent manner. In HT-29 cells, fucoidan also increased the levels of cleaved caspases-8, -9, -7, and -3, and cleaved poly (ADP-ribose) polymerase (PARP) levels. The levels of the X-linked inhibitor of apoptosis protein and survivin were attenuated in the fucoidan-treated cells. Fucoidan was also shown to enhance mitochondrial membrane permeability, as well as the cytochrome c and Smac/Diablo release from the mitochondria. Fucoidan increased the levels of the Bak and truncated Bid proteins, but reduced the levels of Mcl-1. Additionally, fucoidan increased the levels of the tumor necrosis factor-related apoptosis-inducing ligand, Fas and death receptor 5 proteins. The caspase-8 and -9 inhibitors Z-IETD-FMK and Z-LEHD-FMK induced a reduction in fucoidan-mediated apoptosis. Caspase-8 inhibitor inhibited the fucoidan-induced cleavage of Bid, caspases-9 and -3, and PARP.

Conclusion

The findings of this study indicate that fucoidan induces apoptosis in HT-29 and HCT116 human colon cancer cells, and that this phenomenon is mediated via both the death receptor-mediated and mitochondria-mediated apoptotic pathways. These results suggest that fucoidan may prove useful in the development of a colon cancer-preventive protocol.
The increase of alpha-melanocyte-stimulating hormone in the plasma of chronic fatigue syndrome patients
Authors: Shishioh-Ikejima Nobue , Ogawa Tokiko , Yamaguti Kouzi , Watanabe Yasuyoshi , Kuratsune Hirohiko , Kiyama Hiroshi
Published: August 2010

Background

Despite extensive research, no reliable biological marker for chronic fatigue syndrome (CFS) has yet been identified. However, hyperactivation of melanotrophs in the pituitary gland and increased levels of plasma alpha-melanocyte-stimulating hormone (α-MSH) have recently been detected in an animal model of chronic stress. Because CFS is considered to be caused partly by chronic stress events, increased α-MSH plasma levels may also occur in CFS patients. We therefore examined α-MSH levels in CFS patients.

Methods

Fifty-five CFS patients, who were previously diagnosed within 10 years of with the disease, were enrolled in this study. Thirty healthy volunteers were studied as controls. Fasting bloods samples were collected in the morning and evaluated for their plasma levels of α-MSH, adrenocorticotropic hormone (ACTH), serum cortisol and dehydroepiandrosterone sulfate (DHEA-S). Mean levels of α-MSH were compared between the CFS and control groups using Welch'sttest.

Results

The mean plasma α-MSH concentration in the CFS group (17.9 ± 1.0 pg/mL) was significantly higher than that in healthy controls (14.5 ± 1.0 pg/mL, p = 0.02). However, there was a wide range of values in the CFS group. The factors correlated with the plasma α-MSH values were analyzed using Spearman's rank correlation. A negative correlation was found between the duration of the CFS and the plasma α-MSH values (p = 0.04, rs= -0.28), but no correlations with ACTH, cortisol or DHEA-S levels were identified (p = 0.55, 0.26, 0.33, respectively). The CFS patients were divided into two groups: patients diagnosed for ≤ 5 years' duration, and those diagnosed for 5-10 years' duration. They were compared with the healthy controls using one-way ANOVA and Tukey-Kramer multiple comparison tests. The mean α-MSH concentration in the ≤ 5 years group was 20.8 ± 1.2 pg/mL, which was significantly higher than that in the healthy controls (p < 0.01). There was no significant difference between the 5-10 year group (15.6 ± 1.4 pg/mL) and the healthy controls.

Conclusions

CFS patients with a disease duration of ≤ 5 years had significantly higher levels of α-MSH in their peripheral blood. α-MSH could be a potent biological marker for the diagnosis of CFS, at least during the first 5 years after onset of the disease.
Characterization of single chain antibody targets through yeast two hybrid
Authors: Vielemeyer Ole , Nizak Clément , Jimenez Ana Joaquina , Echard Arnaud , Goud Bruno , Camonis Jacques , Rain Jean-Christophe , Perez Franck
Published: August 2010

Background

Due to their unique ability to bind their targets with high fidelity, antibodies are used widely not only in biomedical research, but also in many clinical applications. Recombinant antibodies, including single chain variable fragments (scFv), are gaining momentum because they allow powerful in vitro selection and manipulation without loss of function. Regardless of the ultimate application or type of antibody used, precise understanding of the interaction between the antibody's binding site and its specific target epitope(s) is of great importance. However, such data is frequently difficult to obtain.

Results

We describe an approach that allows detailed characterization of a given antibody's target(s) using the yeast two-hybrid system. Several recombinant scFv were used as bait and screened against highly complex cDNA libraries. Systematic sequencing of all retained clones and statistical analysis allowed efficient ranking of the prey fragments. Multiple alignment of the obtained cDNA fragments provided a selected interacting domain (SID), efficiently narrowing the epitope-containing region.

Interactions between antibodies and their respective targets were characterized for several scFv. For AA2 and ROF7, two conformation-specific sensors that exclusively bind the activated forms of the small GTPases Rab6 and Rab1 respectively, only fragments expressing the entire target protein's core region were retained. This strongly suggested interaction with a non-linear epitope. For two other scFv, TA10 and SF9, which recognize the large proteins giantin and non-muscle myosin IIA, respectively, precise antibody-binding regions within the target were defined. Finally, for some antibodies, secondary targets within and across species could be revealed.

Conclusions

Our method, utilizing the yeast two-hybrid technology and scFv as bait, is a simple yet powerful approach for the detailed characterization of antibody targets. It allows precise domain mapping for linear epitopes, confirmation of non-linear epitopes for conformational sensors, and detection of secondary binding partners. This approach may thus prove to be an elegant and rapid method for the target characterization of newly obtained scFv antibodies. It may be considered prior to any research application and particularly before any use of such recombinant antibodies in clinical medicine.
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

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

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

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

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

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

Background

We 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.

Results

Transient 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.

Conclusions

A 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

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

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

Background

Information 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.

Methods

We 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.

Results

At 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.

Conclusions

A 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.
Phase IIB Trial of Oral Midostaurin (PKC412), the FMS-Like Tyrosine Kinase 3 Receptor (FLT3) and Multi-Targeted Kinase Inhibitor, in Patients With Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome With Either Wild-Type or Mutated FLT3
Authors: Fischer Thomas , Stone Richard M. , DeAngelo Daniel J. , Galinsky Ilene , Estey Elihu , Lanza Carlo , Fox Edward , Ehninger Gerhard , Feldman Eric J. , Schiller Gary J. , Klimek Virginia M. , Nimer Stephen D. , Gilliland D. Gary , Dutreix Catherine , Huntsman-Labed Alice , Virkus Jodi , Giles Francis J.
Published: August 2010

Purpose

Mutations leading to constitutive activation of the FMS-like tyrosine kinase 3 receptor (FLT3) occur in blasts of 30% of patients with acute myeloid leukemia (AML). Midostaurin (PKC412; N-benzoylstaurosporin) is a multitargeted tyrosine kinase inhibitor, with demonstrated activity in patients with AML/myelodysplastic syndrome (MDS) with FLT3 mutations.

Patients and Methods

Ninety-five patients with AML or MDS with either wild-type (n = 60) or mutated (n = 35) FLT3 were randomly assigned to receive oral midostaurin at 50 or 100 mg twice daily. The drug was discontinued in the absence of response at 2 months, disease progression, or unacceptable toxicity. Response was defined as complete response, partial response (PR), hematologic improvement, or reduction in peripheral blood or bone marrow blasts by ≥ 50% (BR).

Results

The rate of BR for the population in whom efficacy could be assessed (n = 92) was 71% in patients with FLT3-mutant and 42% in patients with FLT3 wild-type. One PR occurred in a patient with FLT3-mutant receiving the 100-mg dose regimen. Both doses were well-tolerated; there were no differences in toxicity or response rate according to the dose of midostaurin.

Conclusion

These results suggest that midostaurin has hematologic activity in both patients with FLT3-mutant and wild-type. The degree of clinical activity observed supports additional studies that combine midostaurin and other agents such as chemotherapy especially in FLT3-mutant AML.
Riding the Boom: Labour Market Experiences of New Generation Youth from Visible Minority Immigrant Families
Authors: Yan Miu Chung , Lauer Sean , Jhangiani Surita
Published: August 2010

With changes in the source of origin of immigrants, a new cohort of new generation youth from visible minority immigrant families has begun to be established and become the key replacement of the aging Canadian labour force. Based on existing research, being young, being visible, and coming from an immigrant family are possible disadvantages in the labour market. Research on this new generation youth, however, is limited. This paper reports findings of two qualitative studies examining how this new generation youth, with or without a university degree, found work and what kinds of resources they used in their job search. The economic boom in British Columbia has offered easy access to the labour market. Coming from an immigrant family, however, visible minority youth benefit very little from their social ties and those of their family. Une nouvelle cohorte de jeunes provenant de nouveaux pays d'émigration et dont les familles appartiennent à des minorités visibles ont commencé à s'établir au Canada et à devenir la clé du remplacement de la population active vieillissante. Selon la recherche existante, être jeune, être visible et issu d'une famille d'immigrants peuvent être des inconvénients sur le marché du travail. La recherche sur cette nouvelle génération de jeunes, cependant, est limitée. Ce document présente les résultats de deux études qualitatives en examinant comment cette nouvelle génération de jeunes trouve du travail et les types de ressources qu'ils utilisent dans leur recherche d'emploi, avec ou sans un diplôme universitaire. Le boom économique en Colombie-Britannique a offert un accès facile au marché du travail. Cependant, venant d'une famille d'immigrants, les jeunes des minorités visibles bénéficient très peu de leurs liens sociaux et de ceux de leur famille.
Religion and Ethnicity among Sri Lankan Tamil Youth in Ontario
Authors: Amarasingam Amarnath
Published: August 2010

The paper presents survey and interview data from twenty-five Sri Lankan Tamil youth in Ontario, specifically dealing with the interaction between religion and ethnicity, the experience and expression of religion, the importance of religion, as well as the importance of the Tamil language for religious and ethnic identity. Herbert Gans's ideas about "symbolic ethnicity" and "symbolic religiosity" are used to explore the ways in which Tamil youth in Ontario interact with their ethnic and religious heritage. Many express their ethnicity through seemingly mundane acts such as wearing a sari to a family gathering, eating with their hands, and watching Tamil movies. Many are losing their proficiency in the Tamil language, but see it as essential for their ethnic identity. Many only attend a Hindu temple three to five times per year, but see it as essential for passing on their cultural heritage to their children. In other words, much of their ethnic and religious identity is constructed through a symbolic transnationalism. The research, although preliminary, begins to fill gaps in scholarship on the Sri Lankan Tamil population in Canada, as well as the role of religion in the lives of immigrant youth. Cet article présente les résultats d'une enquête et d'entrevues faites auprès de vingt-cinq jeunes Tamouls sri-lankais en Ontario, et portant particulièrement sur l'interaction entre la religion et l'ethnicité, à savoir : l'expérience et l'expression de la religion ainsi que son importance, tout comme celle de la langue tamoule concernant l'identité religieuse et ethnique. Nous nous appuyons sur les notions d'«ethnicité symbolique» et de «religiosité symbolique» d'Herbert Gans pour explorer la manière dont les jeunes Tamouls ontariens composent avec leur héritage ethnique et religieux. Plusieurs d'entre eux expriment leur ethnicité de manière banale, comme de porter un sari à une réunion de famille, de manger avec la main ou de regarder des films tamouls. D'autres perdent leur capacité de parler couramment le tamoul, mais voient dans leur langue un facteur essentiel de leur identité ethnique. D'autres encore n'iront que trois ou quatre fois par an au temple hindou, mais y voient un élément fondamental du passage de leur héritage culturel à leurs enfants. En d'autres mots, ces jeunes construisent la plus grande partie de leur identité ethnique et religieuse à travers un transnationalisme symbolique. Bien que ce travail ne soit que préliminaire, il commence à combler les lacunes de la recherche universitaire en ce qui concerne la population tamoule au Canada ainsi que le rôle de la religion dans la vie des jeunes immigrants.
The Violence Intervention and Prevention Team (VIP): Results of an Action Research Evaluation
Authors: Rothman Emily F. , Ireland Carol , Curry Lori , Polanco Andres , Baughman Allyson , Thompson Donald
Published: August 2010

Background/Objectives: This paper describes a school-based youth violence prevention program and challenges encountered during efforts to evaluate it. Members of a community partnership team helped to shape the quantitative and qualitative data collection and to interpret results. Methods: 48 youth participants in the violence prevention program completed a survey soliciting information about violence-related risk and protective factors, including employment readiness, school connectedness, association with delinquent peers, and violence-related attitudes, intentions, and behaviors. Fourteen youth also participated in two focus groups about their satisfaction with the violence prevention program. Lessons Learned: Through the preliminary data collection process, we learned three key lessons. (1) Institutional Review Boards (IRBs) new to community-based research may need to build capacity to evaluate the human subjects implications of this type of research. (2) The identification of control or comparison groups for school-based youth violence programs may be challenging and costly. (3) Methods for reducing loss-to-follow-up with high-risk youth are needed.
Achieving Public Health Impact in Youth Violence Prevention Through Community–Research Partnerships
Authors: Massetti Greta M. , Vivolo Alana M.
Published: August 2010

Problem: Violence is a leading cause of death and disability for U.S. youth. The U.S. Centers for Disease Control and Prevention (CDC)'s Division of Violence Prevention (DVP) is committed to developing communities' capacity to engage in evidence-based youth violence (YV) prevention. Purpose: We discuss the characteristics of communities that exert influence on the development and epidemiology of YV, and discuss opportunities for how community–research partnerships can enhance efforts to prevent violence in communities. Key Points: The needs for YV prevention are unique; the nature and phenomenology of violence are community specific. Communities also vary widely in infrastructure and systems to support coordinated, evidence-based YV prevention strategies. These conditions highlight the need for community–research partnerships to enhance community capacity, employ local resources, and engage community members in the research process. Conclusion: DVP is committed to working towards creating communities in which youth are safe from violence. Approaches to YV prevention that emphasize community–research partnerships to build capacity and implement evidence-based prevention strategies can provide a supportive context for achieving that goal.
A Community-Based Approach to Preventing Youth Violence: What Can We Learn From the Playground?
Authors: Drabick Deborah A. G. , Baugh David
Published: August 2010

Background: Aggression, bullying, and victimization represent tremendous public health concerns among youth. These behaviors occur frequently in unstructured settings, such as the playground. Direct observations of the playground permit examination of these peer processes and are readily accomplished using community-based participatory research (CBPR). Objectives: To present alternative viewpoints regarding the use of playground observations to evaluate peer aggression, bullying, and victimization. Methods: We used a (1) child-specific observational coding system and (2) naturalistic observation of the playground to examine playground behaviors. Results: Peer–child processes have differential associations with conduct disorder (CD) and depression symptoms. Group-based observations suggested a number of strengths and some areas that would be amenable to intervention. Conclusion: A CBPR framework is useful for identifying youth involved in bullying and victimization; providing immediate support, interventions, and problem-solving strategies; and predicting potential negative outcomes, which can inform violence prevention and intervention efforts.
The Intriguing History and Silences of Of Woman Born: Rereading Adrienne Rich Rhetorically to Better Understand the Contemporary Context
Authors: O'Brien Hallstein D. Lynn
Published: August 2010

Adrienne Rich's text Of Woman Born: Motherhood as Experience and Institution (1986) is a canonical text in Women's Studies generally and specifically for contemporary feminist maternal scholars. From its inception to the present day, both the response to and use of Of Woman Born have been intriguing and permeated by different kinds of silences about mothering. Rereading Of Woman Born within its larger historical situation and within the white second-wave's relationship to motherhood reveals, externally, that the text was situated within a demonizing discourse that positioned the book as "anti-motherhood," and, internally, that the text emerged from within a sisterly feminist subject-position that was founded on "matrophobia"—the fear of becoming like our mothers. Both the external demonization and the internal matrophobia begin to explain both the intriguing history and curious silences on mothering. Thus, contemporary feminist maternal scholars must understand our past and present use of Rich's text to conceive a feminist subject-position that accounts for and anticipates the ongoing external and internal rhetorical situations of contemporary culture and, finally, purges past and lingering matrophobia.