Signatures of Selection in Fusion Transcripts Resulting From Chromosomal Translocations in Human Cancer

BACKGROUND: The recurrence and non-random distribution of translocation breakpoints in human tumors are usually attributed to local sequence features present in the vicinity of the breakpoints. However, it has also been suggested that functional constraints might contribute to delimit the position of translocation breakpoints within the genes involved, but a quantitative analysis of such contribution has been lacking. METHODOLOGY: We have analyzed two well-known signatures of functional selection, such as reading-frame compatibility and non-random combinations of protein domains, on an extensive dataset of fusion proteins resulting from chromosomal translocations in cancer. CONCLUSIONS: Our data provide strong experimental support for the concept that the position of translocation breakpoints in the genome of cancer cells is determined, to a large extent, by the need to combine certain protein domains and to keep an intact reading frame in fusion transcripts. Additionally, the information that we have assembled affords a global view of the oncogenic mechanisms and domain architectures that are used by fusion proteins. This can be used to assess the functional impact of novel chromosomal translocations and to predict the position of breakpoints in the genes involved

Measurement of the inclusive and dijet cross-sections of b-jets in pp collisions at sqrt(s) = 7 TeV with the ATLAS detector

The inclusive and dijet production cross-sections have been measured for jets containing b-hadrons (b-jets) in proton-proton collisions at a centre-of-mass energy of sqrt(s) = 7 TeV, using the ATLAS detector at the LHC. The measurements use data corresponding to an integrated luminosity of 34 pb^-1. The b-jets are identified using either a lifetime-based method, where secondary decay vertices of b-hadrons in jets are reconstructed using information from the tracking detectors, or a muon-based method where the presence of a muon is used to identify semileptonic decays of b-hadrons inside jets. The inclusive b-jet cross-section is measured as a function of transverse momentum in the range 20 < pT < 400 GeV and rapidity in the range |y| < 2.1. The bbbar-dijet cross-section is measured as a function of the dijet invariant mass in the range 110 < m_jj < 760 GeV, the azimuthal angle difference between the two jets and the angular variable chi in two dijet mass regions. The results are compared with next-to-leading-order QCD predictions. Good agreement is observed between the measured cross-sections and the predictions obtained using POWHEG + Pythia. MC@NLO + Herwig shows good agreement with the measured bbbar-dijet cross-section. However, it does not reproduce the measured inclusive cross-section well, particularly for central b-jets with large transverse momenta.Comment: 10 pages plus author list (21 pages total), 8 figures, 1 table, final version published in European Physical Journal

Androgen-Regulated Transcriptional Control of Sialyltransferases in Prostate Cancer Cells

The expression of gangliosides is often associated with cancer progression. Sialyltransferases have received much attention in terms of their relationship with cancer because they modulate the expression of gangliosides. We previously demonstrated that GD1a production was high in castration-resistant prostate cancer cell lines, PC3 and DU145, mainly due to their high expression of β-galactoside α2,3-sialyltransferase (ST3Gal) II (not ST3Gal I), and the expression of both ST3Gals was regulated by NF-κB, mainly by RelB. We herein demonstrate that GD1a was produced in abundance in cancerous tissue samples from human patients with hormone-sensitive prostate cancers as well as castration-resistant prostate cancers. The expression of ST3Gal II was constitutively activated in castration-resistant prostate cancer cell lines, PC3 and DU145, because of the hypomethylation of CpG island in its promoter. However, in androgen-depleted LNCap cells, a hormone-sensitive prostate cancer cell line, the expression of ST3Gal II was silenced because of the hypermethylation of the promoter region. The expression of ST3Gal II in LNCap cells increased with testosterone treatment because of the demethylation of the CpG sites. This testosterone-dependent ST3Gal II expression was suppressed by RelB siRNA, indicating that RelB activated ST3Gal II transcription in the testosterone-induced demethylated promoter. Therefore, in hormone-sensitive prostate cancers, the production of GD1a may be regulated by androgen. This is the first report indicating that the expression of a sialyltransferase is transcriptionally regulated by androgen-dependent demethylation of the CpG sites in its gene promoter

Phlebotomine sand fly survey in the focus of leishmaniasis in Madrid, Spain (2012-2014): seasonal dynamics, Leishmania infantum infection rates and blood meal preferences

BACKGROUND: An unusual increase of human leishmaniasis cases due to Leishmania infantum is occurring in an urban area of southwestern Madrid, Spain, since 2010. Entomological surveys have shown that Phlebotomus perniciosus is the only potential vector. Direct xenodiagnosis in hares (Lepus granatensis) and rabbits (Oryctolagus cuniculus) collected in the focus area proved that they can transmit parasites to colonized P. perniciosus. Isolates were characterized as L. infantum. The aim of the present work was to conduct a comprehensive study of sand flies in the outbreak area, with special emphasis on P. perniciosus. METHODS: Entomological surveys were done from June to October 2012-2014 in 4 stations located close to the affected area. Twenty sticky traps (ST) and two CDC light traps (LT) were monthly placed during two consecutive days in every station. LT were replaced every morning. Sand fly infection rates were determined by dissecting females collected with LT. Molecular procedures applied to study blood meal preferences and to detect L. infantum were performed for a better understanding of the epidemiology of the outbreak. RESULTS: A total of 45,127 specimens belonging to 4 sand fly species were collected: P. perniciosus (75.34%), Sergentomyia minuta (24.65%), Phlebotomus sergenti (0.005%) and Phlebotomus papatasi (0.005%). No Phlebotomus ariasi were captured. From 3203 P. perniciosus female dissected, 117 were infected with flagellates (3.7%). Furthermore, 13.31% and 7.78% of blood-fed and unfed female sand flies, respectively, were found infected with L. infantum by PCR. The highest rates of infected P. perniciosus were detected at the end of the transmission periods. Regarding to blood meal preferences, hares and rabbits were preferred, although human, cat and dog blood were also found. CONCLUSIONS: This entomological study highlights the exceptional nature of the Leishmania outbreak occurring in southwestern Madrid, Spain. It is confirmed that P. perniciosus is the only vector in the affected area, with high densities and infection rates. Rabbits and hares were the main blood meal sources of this species. These results reinforce the need for an extensive and permanent surveillance in this region, and others of similar characteristics, in order to control the vector and regulate the populations of wild reservoirs.This study was partially sponsored and funded by: Dirección General de Salud Pública, Consejería de Sanidad, Comunidad de Madrid; Colegio de Veterinarios de Madrid; Colegio de Biólogos de Madrid and EU grant FP7-261504 EDENext (http://www.edenext.eu).S

DNA vaccination for prostate cancer: key concepts and considerations

While locally confined prostate cancer is associated with a low five year mortality rate, advanced or metastatic disease remains a major challenge for healthcare professionals to treat and is usually terminal. As such, there is a need for the development of new, efficacious therapies for prostate cancer. Immunotherapy represents a promising approach where the host’s immune system is harnessed to mount an anti-tumour effect, and the licensing of the first prostate cancer specific immunotherapy in 2010 has opened the door for other immunotherapies to gain regulatory approval. Among these strategies DNA vaccines are an attractive option in terms of their ability to elicit a highly specific, potent and wide-sweeping immune response. Several DNA vaccines have been tested for prostate cancer and while they have demonstrated a good safety profile they have faced problems with low efficacy and immunogenicity compared to other immunotherapeutic approaches. This review focuses on the positive aspects of DNA vaccines for prostate cancer that have been assessed in preclinical and clinical trials thus far and examines the key considerations that must be employed to improve the efficacy and immunogenicity of these vaccines

Algorithm for the use of biochemical markers of bone turnover in the diagnosis, assessment and follow-up of treatment for osteoporosis

Introduction Increased biochemical bone turnover markers (BTMs) measured in serum are associated with bone loss, increased fracture risk and poor treatment adherence, but their role in clinical practice is presently unclear. The aim of this consensus group report is to provide guidance to clinicians on how to use BTMs in patient evaluation in postmenopausal osteoporosis, in fracture risk prediction and in the monitoring of treatment efficacy and adherence to osteoporosis medication. Methods A working group with clinical scientists and osteoporosis specialists was invited by the Scientific Advisory Board of European Society on Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO). Results Serum bone formation marker PINP and resorption marker βCTX-I are the preferred markers for evaluating bone turnover in the clinical setting due to their specificity to bone, performance in clinical studies, wide use and relatively low analytical variability. BTMs cannot be used to diagnose osteoporosis because of low sensitivity and specificity, but can be of value in patient evaluation where high values may indicate the need to investigate some causes of secondary osteoporosis. Assessing serum levels of βCTX-I and PINP can improve fracture prediction slightly, with a gradient of risk of about 1.2 per SD increase in the bone marker in addition to clinical risk factors and bone mineral density. For an individual patient, BTMs are not useful in projecting bone loss or treatment efficacy, but it is recommended that serum PINP and βCTX-I be used to monitor adherence to oral bisphosphonate treatment. Suppression of the BTMs greater than the least significant change or to levels in the lower half of the reference interval in young and healthy premenopausal women is closely related to treatment adherence. Conclusion In conclusion, the currently available evidence indicates that the principal clinical utility of BTMs is for monitoring oral bisphosphonate therapy