Observational epidemiological study to identify the clinical profile of naïve patients starting antiretroviral (ARV) therapy in Spain

Purpose of the study: To identify the proportion of patients starting ARV treatment with NNRTIs or with a PI/r and to explore and compare their clinical profile establishing different factors whereby physicians select the initial ARV treatment in a Spanish clinical setting. Methods: An observational study was conducted in two different phases. In Phase I a cross-sectional registration was conducted for patients who initiated ARV treatment in a 6-month period in 65 Spanish hospitals. In Phase II clinical and social-demographic features were collected retrospectively of patients who visited HIV clinics between August and November 2010 who had started ARV treatment containing an NNRTIs or a PI/r in Phase I. Summary of results: In Phase I, 1,687 subjects who initiated ARV treatment were registered, of which 53% started with an NNRTI-based regimen whereas 42% started with a PI/r-based regimen. Two percent of the treatment initiations occurred in a clinical trial. In Phase II, 642 patients were paired consecutively and retrospectively. The group of patients was composed of predominantly male subjects (81% vs 19%). The median time between diagnosis and the start of ARV treatment was 3.6±5.3 years. At the initiation of treatment, 72% of patients had a CD4 count below 350 cells/µl. Although treatment based on NNRTIs in naïve patients is the most frequent option in Spain, the analysis of clinical profiles shows that PI/r-based therapy is more often used than NNRTIs with statistical significance in patients with high viral load, Fig. A (≥100.000 copies/ml) (58% vs 42%; OR:1,75; 95% CI: 1,26–2,43; p<0,01), with CD4 cell counts <200 cells/µl, Fig. B (68% vs 31%; OR: 2,92; 95% CI: 1,99–4,27; p<0,01), and in patients at CDC stage C (65% vs 35%; OR: 2,05; CI: 1,27–3,31; p<0,01). Conclusions: In Spain, HIV is still diagnosed late (as measured by CD4 count<350 cells/µl). Treatment based on NNRTIs are more frequently used in naïve patients, although PIs/r-based regimens play an important role being the preferred option in patients with high viral load (≥100.000 copies/ml) and low CD4 cell count (<200 cells/µl)

Propiedades psicométricas del cuestionario de percepción de justicia en la lectura de la prensa deportiva

Introducción. El presente estudio analiza las propiedades psico- métricas del cuestionario de percepción de justicia en la lectura de la pren- sa deportiva. Apoyados en la teoría organizacional del ámbito del trabajo (Greenberg, 1987) y en el cuestionario de percepción de justicia de Colquitt (2001), se adaptaron los conceptos al ámbito de la prensa deportiva, dado que no existen instrumentos que midan la inuencia de la lectura de la prensa deportiva sobre la percepción de justicia de los lectores. Método. La muestra se compuso de 220 participantes, 166 hombres y 54 mujeres, con edades de 20,72 ± 3,08 años (18-41 años). Se realizaron análisis factoriales exploratorio y conrmatorio para analizar la estructura factorial del cues- tionario con dos submuestras divididas aleatoriamente. Resultados. Los resultados mostraron la viabilidad y adecuación de una estructura con tres factores (justicia informacional, justicia interpersonal, justicia distributiva) con adecuados índices de ajuste de validez y abilidad, mostrando eviden- cias consistentes de la estructura factorial obtenida. Discusión. Disponer de un instrumento válido para medir la percepción de justicia que origina la lectura de la prensa deportiva en los lectores podrá en el futuro originar lí- neas de investigación de gran interés social y cientíco. Estas líneas podrán abrir nuevos conocimientos en la psicología del deporte que nos permitan actuar de modo más adecuado en el tratamiento de los eventos deportivos mediáticos.

ERBB4 confers metastatic capacity in Ewing sarcoma.

Metastatic spread is the single-most powerful predictor of poor outcome in Ewing sarcoma (ES). Therefore targeting pathways that drive metastasis has tremendous potential to reduce the burden of disease in ES. We previously showed that activation of the ERBB4 tyrosine kinase suppresses anoikis, or detachment-induced cell death, and induces chemoresistance in ES cell lines in vitro. We now show that ERBB4 is transcriptionally overexpressed in ES cell lines derived from chemoresistant or metastatic ES tumours. ERBB4 activates the PI3K-Akt cascade and focal adhesion kinase (FAK), and both pathways contribute to ERBB4-mediated activation of the Rac1 GTPase in vitro and in vivo. ERBB4 augments tumour invasion and metastasis in vivo, and these effects are blocked by ERBB4 knockdown. ERBB4 expression correlates significantly with reduced disease-free survival, and increased expression is observed in metastatic compared to primary patient-matched ES biopsies. Our findings identify a novel ERBB4-PI3K-Akt-FAK-Rac1 pathway associated with aggressive disease in ES. These results predict that therapeutic targeting of ERBB4, alone or in combination with cytotoxic agents, may suppress the metastatic phenotype in ES

A comprehensive RNA-Seq-based gene expression atlas of the summer squash (Cucurbita pepo) provides insights into fruit morphology and ripening mechanisms

Background: Summer squash (Cucurbita pepo: Cucurbitaceae) are a popular horticultural crop for which there is insufficient genomic and transcriptomic information. Gene expression atlases are crucial for the identification of genes expressed in different tissues at various plant developmental stages. Here, we present the first comprehensive gene expression atlas for a summer squash cultivar, including transcripts obtained from seeds, shoots, leaf stem, young and developed leaves, male and female flowers, fruits of seven developmental stages, as well as primary and lateral roots. Results: In total, 27,868 genes and 2352 novel transcripts were annotated from these 16 tissues, with over 18,000 genes common to all tissue groups. Of these, 3812 were identified as housekeeping genes, half of which assigned to known gene ontologies. Flowers, seeds, and young fruits had the largest number of specific genes, whilst intermediate-age fruits the fewest. There also were genes that were differentially expressed in the various tissues, the male flower being the tissue with the most differentially expressed genes in pair-wise comparisons with the remaining tissues, and the leaf stem the least. The largest expression change during fruit development was early on, from female flower to fruit two days after pollination. A weighted correlation network analysis performed on the global gene expression dataset assigned 25,413 genes to 24 coexpression groups, and some of these groups exhibited strong tissue specificity. Conclusions: These findings enrich our understanding about the transcriptomic events associated with summer squash development and ripening. This comprehensive gene expression atlas is expected not only to provide a global view of gene expression patterns in all major tissues in C. pepo but to also serve as a valuable resource for functional genomics and gene discovery in Cucurbitaceae

Differential responses to doxorubicin-induced phosphorylation and activation of Akt in human breast cancer cells

INTRODUCTION: We have shown previously that overexpression of constitutively active Akt or activation of Akt caused by constitutively active Ras or human epidermal growth factor receptor-2 (HER2) confers on breast cancer cells resistance to chemotherapy or radiotherapy. As an expanded study we here report differential responses in terms of phosphorylation and activation of Akt as a result of treatment with doxorubicin in a panel of breast cancer cell lines. METHODS: The levels of Akt phosphorylation and activity were measured by Western blot analysis with an anti-Ser473-phosphorylated Akt antibody and by in vitro Akt kinase assay using glycogen synthase kinase-3 as a substrate. RESULTS: Within 24 hours after exposure to doxorubicin, MCF7, MDA468 and T47D cells showed a drug-dose-dependent increase in the levels of phosphorylated Akt; in contrast, SKBR3 and MDA231 cells showed a decrease in the levels of phosphorylated Akt, and minimal or no changes were detected in MDA361, MDA157 and BT474 cells. The doxorubicin-induced Akt phosphorylation was correlated with increased kinase activity and was dependent on phosphoinositide 3-kinase (PI3-K). An increased baseline level of Akt was also found in MCF7 cells treated with ionizing radiation. The cellular responses to doxorubicin-induced Akt phosphorylation were potentiated after the expression of Akt upstream activators including HER2, HER3 and focal adhesion kinase. CONCLUSION: Taken together with our recent published results showing that constitutive Akt mediates resistance to chemotherapy or radiotherapy, our present data suggest that the doxorubicin-induced phosphorylation and activation of Akt might reflect a cellular defensive mechanism of cancer cells to overcome doxorubicin-induced cytotoxic effects, which further supports the current efforts of targeting PI3-K/Akt for enhancing the therapeutic responses of breast cancer cells to chemotherapy and radiotherapy

KRAS, BRAF and PIK3CA Mutations and the Loss of PTEN Expression in Chinese Patients with Colorectal Cancer

Background: To investigate the frequency and relationship of the KRAS, BRAF and PIK3CA mutations and the loss of PTEN expression in Chinese patients with colorectal cancer (CRC). Methodology/Principal Findings: Genomic DNA was extracted from the formalin-fixed paraffin-embedded (FFPE) tissues of 69 patients with histologically confirmed CRC. Automated sequencing analysis was conducted to detect mutations in the KRAS (codons 12, 13, and 14), BRAF (codon 600) and PIK3CA (codons 542, 545 and 1047). PTEN protein expression was evaluated by immunohistochemistry on 3 mm FFPE tissue sections. Statistical analysis was carried out using SPSS 16.0 software. The frequency of KRAS, BRAF and PIK3CA mutations and loss of PTEN expression was 43.9 % (25/57), 25.4 % (15/59), 8.2 % (5/61) and 47.8 % (33/69), respectively. The most frequent mutation in KRAS, BRAF and PIK3CA was V14G (26.7 % of all mutations), V600E (40.0 % of all mutations) and V600L (40.0 % of all mutations), and H1047L (80.0 % of all mutations), respectivly. Six KRAS mutatant patients (24.0%) harbored BRAF mutations. BRAF and PIK3CA mutations were mutually exclusive. No significant correlation was observed between the four biomarkers and patients ’ characteristics. Conclusions/Significance: BRAF mutation rate is much higher in this study than in other studies, and overlap a lot with KRAS mutations. Besides, the specific types of KRAS and PIK3CA mutations in Chinese patients could be quite different from that of patients in other countries. Further studies are warranted to examine their impact on prognosis and response to targete

Human Adenovirus Type 36 Enhances Glucose Uptake in Diabetic and Nondiabetic Human Skeletal Muscle Cells Independent of Insulin Signaling

OBJECTIVE—Human adenovirus type 36 (Ad-36) increases adiposity but improves insulin sensitivity in experimentally infected animals. We determined the ability of Ad-36 to increase glucose uptake by human primary skeletal muscle (HSKM) cells

First RNA-seq approach to study fruit set and parthenocarpy in zucchini (Cucurbita pepo L.)

[EN] Background: Zucchini fruit set can be limited due to unfavourable environmental conditions in off-seasons crops that caused ineffective pollination/fertilization. Parthenocarpy, the natural or artificial fruit development without fertilization, has been recognized as an important trait to avoid this problem, and is related to auxin signalling. Nevertheless, differences found in transcriptome analysis during early fruit development of zucchini suggest that other complementary pathways could regulate fruit formation in parthenocarpic cultivars of this species. The development of next-generation sequencing technologies (NGS) as RNA-sequencing (RNA-seq) opens a new horizon for mapping and quantifying transcriptome to understand the molecular basis of pathways that could regulate parthenocarpy in this species. The aim of the current study was to analyze fruit transcriptome of two cultivars of zucchini, a non-parthenocarpic cultivar and a parthenocarpic cultivar, in an attempt to identify key genes involved in parthenocarpy. Results: RNA-seq analysis of six libraries (unpollinated, pollinated and auxin treated fruit in a non-parthenocarpic and parthenocarpic cultivar) was performed mapping to a new version of C. pepo transcriptome, with a mean of 92% success rate of mapping. In the non-parthenocarpic cultivar, 6479 and 2186 genes were differentially expressed (DEGs) in pollinated fruit and auxin treated fruit, respectively. In the parthenocarpic cultivar, 10,497 in pollinated fruit and 5718 in auxin treated fruit. A comparison between transcriptome of the unpollinated fruit for each cultivar has been performed determining that 6120 genes were differentially expressed. Annotation analysis of these DEGs revealed that cell cycle, regulation of transcription, carbohydrate metabolism and coordination between auxin, ethylene and gibberellin were enriched biological processes during pollinated and parthenocarpic fruit set. Conclusion: This analysis revealed the important role of hormones during fruit set, establishing the activating role of auxins and gibberellins against the inhibitory role of ethylene and different candidate genes that could be useful as markers for parthenocarpic selection in the current breeding programs of zucchini.Research worked is supported by the project RTA2014-00078 from the Spanish Institute of Agronomy Research INIA (Instituto Nacional de Investigacion y Tecnologia Agraria y Alimentaria) and also PP.AVA.AVA201601.7, FEDER y FSE (Programa Operativo FSE de Andalucia 2007-2013 "Andalucia se mueve con Europa"). TPV is supported by a FPI scholarship from RTA2011-00044-C02-01/02 project of INIA. 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Tumor Suppressor RASSF1A Promoter: p53 Binding and Methylation

Oncogenes and tumor suppressors work in concert to regulate cell growth or death, which is a pair of antagonist factors for regulation of tumorigenesis. Here we show promoter characteristic of tumor suppressor RASSF1A, which revealed a p53 binding site in the distal and a GC-rich region in the proximal promoter region of RASSF1A, in despite of TATA box-less. The GC-rich region, which is ∼300 bp upstream from the RASSF1A ATG, showed the strongest promoter activity in an assay of RASSF1A-driving GFP expression. Methylation analysis of the CpG island showed that 78.57% of the GC sties were methylated in testis tumor samples compared with methylation-less in normal testis. Hypermethylation of the GC-rich region is associated with RASSF1A silencing in human testis tumors. In addition, electrophoretic mobility shift assay indicated that p53 protein bound to the RASSF1A promoter. Further chromatin immunoprecipitation confirmed p53 binding to the RASSF1A. Moreover, p53 binding to the promoter down-regulated RASSF1A expression. These results suggest that p53 protein specifically binds to the RASSF1A promoter and inhibits its expression. Our results provide new insight into the mechanism of action of tumor suppressors and may be a starting point for development of new approaches to cancer treatment