Minimising Immunohistochemical False Negative ER Classification Using a Complementary 23 Gene Expression Signature of ER Status

BACKGROUND: Expression of the oestrogen receptor (ER) in breast cancer predicts benefit from endocrine therapy. Minimising the frequency of false negative ER status classification is essential to identify all patients with ER positive breast cancers who should be offered endocrine therapies in order to improve clinical outcome. In routine oncological practice ER status is determined by semi-quantitative methods such as immunohistochemistry (IHC) or other immunoassays in which the ER expression level is compared to an empirical threshold. The clinical relevance of gene expression-based ER subtypes as compared to IHC-based determination has not been systematically evaluated. Here we attempt to reduce the frequency of false negative ER status classification using two gene expression approaches and compare these methods to IHC based ER status in terms of predictive and prognostic concordance with clinical outcome. METHODOLOGY/PRINCIPAL FINDINGS: Firstly, ER status was discriminated by fitting the bimodal expression of ESR1 to a mixed Gaussian model. The discriminative power of ESR1 suggested bimodal expression as an efficient way to stratify breast cancer; therefore we identified a set of genes whose expression was both strongly bimodal, mimicking ESR expression status, and highly expressed in breast epithelial cell lines, to derive a 23-gene ER expression signature-based classifier. We assessed our classifiers in seven published breast cancer cohorts by comparing the gene expression-based ER status to IHC-based ER status as a predictor of clinical outcome in both untreated and tamoxifen treated cohorts. In untreated breast cancer cohorts, the 23 gene signature-based ER status provided significantly improved prognostic power compared to IHC-based ER status (P = 0.006). In tamoxifen-treated cohorts, the 23 gene ER expression signature predicted clinical outcome (HR = 2.20, P = 0.00035). These complementary ER signature-based strategies estimated that between 15.1% and 21.8% patients of IHC-based negative ER status would be classified with ER positive breast cancer. CONCLUSION/SIGNIFICANCE: Expression-based ER status classification may complement IHC to minimise false negative ER status classification and optimise patient stratification for endocrine therapies

Pediatric Measles Vaccine Expressing a Dengue Antigen Induces Durable Serotype-specific Neutralizing Antibodies to Dengue Virus

Dengue disease is an increasing global health problem that threatens one-third of the world's population. Despite decades of efforts, no licensed vaccine against dengue is available. With the aim to develop an affordable vaccine that could be used in young populations living in tropical areas, we evaluated a new strategy based on the expression of a minimal dengue antigen by a vector derived from pediatric live-attenuated Schwarz measles vaccine (MV). As a proof-of-concept, we inserted into the MV vector a sequence encoding a minimal combined dengue antigen composed of the envelope domain III (EDIII) fused to the ectodomain of the membrane protein (ectoM) from DV serotype-1. Immunization of mice susceptible to MV resulted in a long-term production of DV1 serotype-specific neutralizing antibodies. The presence of ectoM was critical to the immunogenicity of inserted EDIII. The adjuvant capacity of ectoM correlated with its ability to promote the maturation of dendritic cells and the secretion of proinflammatory and antiviral cytokines and chemokines involved in adaptive immunity. The protective efficacy of this vaccine should be studied in non-human primates. A combined measles–dengue vaccine might provide a one-shot approach to immunize children against both diseases where they co-exist

Cell-Type Independent MYC Target Genes Reveal a Primordial Signature Involved in Biomass Accumulation

The functions of key oncogenic transcription factors independent of context have not been fully delineated despite our richer understanding of the genetic alterations in human cancers. The MYC oncogene, which produces the Myc transcription factor, is frequently altered in human cancer and is a major regulatory hub for many cancers. In this regard, we sought to unravel the primordial signature of Myc function by using high-throughput genomic approaches to identify the cell-type independent core Myc target gene signature. Using a model of human B lymphoma cells bearing inducible MYC, we identified a stringent set of direct Myc target genes via chromatin immunoprecipitation (ChIP), global nuclear run-on assay, and changes in mRNA levels. We also identified direct Myc targets in human embryonic stem cells (ESCs). We further document that a Myc core signature (MCS) set of target genes is shared in mouse and human ESCs as well as in four other human cancer cell types. Remarkably, the expression of the MCS correlates with MYC expression in a cell-type independent manner across 8,129 microarray samples, which include 312 cell and tissue types. Furthermore, the expression of the MCS is elevated in vivo in Eμ-Myc transgenic murine lymphoma cells as compared with premalignant or normal B lymphocytes. Expression of the MCS in human B cell lymphomas, acute leukemia, lung cancers or Ewing sarcomas has the highest correlation with MYC expression. Annotation of this gene signature reveals Myc's primordial function in RNA processing, ribosome biogenesis and biomass accumulation as its key roles in cancer and stem cells

Temporal Dynamics of Host Molecular Responses Differentiate Symptomatic and Asymptomatic Influenza A Infection

Exposure to influenza viruses is necessary, but not sufficient, for healthy human hosts to develop symptomatic illness. The host response is an important determinant of disease progression. In order to delineate host molecular responses that differentiate symptomatic and asymptomatic Influenza A infection, we inoculated 17 healthy adults with live influenza (H3N2/Wisconsin) and examined changes in host peripheral blood gene expression at 16 timepoints over 132 hours. Here we present distinct transcriptional dynamics of host responses unique to asymptomatic and symptomatic infections. We show that symptomatic hosts invoke, simultaneously, multiple pattern recognition receptors-mediated antiviral and inflammatory responses that may relate to virus-induced oxidative stress. In contrast, asymptomatic subjects tightly regulate these responses and exhibit elevated expression of genes that function in antioxidant responses and cell-mediated responses. We reveal an ab initio molecular signature that strongly correlates to symptomatic clinical disease and biomarkers whose expression patterns best discriminate early from late phases of infection. Our results establish a temporal pattern of host molecular responses that differentiates symptomatic from asymptomatic infections and reveals an asymptomatic host-unique non-passive response signature, suggesting novel putative molecular targets for both prognostic assessment and ameliorative therapeutic intervention in seasonal and pandemic influenza

Rapport IV.7a. Mécanismes de la pollution des eaux souterraines et aménagement de l’environnement. Détermination quantitative d’une source de pollution des eaux souterraines par des produits pétroliers

Pollution mechanisms of underground waters due to mineral oil products begin at the level of impregnation bodg bg the exchange between non-miscible liquids in contact within a bearing-water stratum, develops by the dissolved hydrocarbons traces dispersion and is submitted to bio-chemical processes effect. The report presents a study of hydrocarbons transfer in the water, from usual mineral oil products and pure materials, carried out in a laboratory on porous matrixes. The first results obtained put on the wrong the exchange constante concept that was used until now for characterizing a pollution source. A new definition of initial conditions relating to pollution materials flow is introduced. With the hypotheses put forward, the authors show that, practically, the extent of the field polluated by mechanical dispersion does not depend on the water flowing velocity ; then, the natural bio-degradation effects may be noted more especially as this velocity is small.Le mécanisme de pollution de l’eau souterraine par un produit pétrolier débute au niveau du corps d’imprégnation par l’échange entre les liquides non miscibles en contact dans l’aquifère. Il se développe par la dispersion des traces d’hydrocarbures dissoutes et subit l’influence de processus biochimiques de dégradation. Dans ce rapport est présentée une étude du transfert d’hydrocarbures dans l’eau, à partir de produits pétroliers usuels et de corps purs, sur matrices poreuses au laboratoire. Les premiers résultats obtenus mettent en défaut le concept de «constante d’échange» utilisé jusqu’alors pour caractériser la source de pollution. On introduit une nouvelle définition des conditions initiales relative au flux de polluant. Avec les hypothèses avancées, on montre que l’étendue du domaine contaminé par dispersion mécanique ne dépend pratiquement pas de la vitesse d’écoulement de l’eau ; les effets de la biodégradation naturelle se font alors sentir d’autant plus que cette vitesse est faible.Zilliox L., Muntzer Paul. Rapport IV.7a. Mécanismes de la pollution des eaux souterraines et aménagement de l’environnement. Détermination quantitative d’une source de pollution des eaux souterraines par des produits pétroliers. In: La mécanique des fluides et l'environnement. Prévision et maîtrise de la qualité de l'eau et de l'air. Compte rendu des quatorzièmes journées de l'hydraulique. Paris, 7-9 septembre 1976. Tome 2, 1977

Maintaining efficacy in the treatment of diabetic peripheral neuropathic pain: role of duloxetine

Lindsay Zilliox1, James W Russell1,21Department of Neurology, Neuromuscular Division, The University of Maryland School of Medicine, 2VA Maryland Health Care System, Baltimore, MD, USAIntroduction: Neuropathy is one of the most frequent complications of diabetes. Of all the symptoms associated with diabetic neuropathy, pain has the largest impact on sleep and quality of life. In the past few years further medications have been added to the available therapies for neuropathic pain. One of these medications, duloxetine hydrochloride (duloxetine), is a balanced and potent selective serotonin and norepinephrine reuptake inhibitor.Methods: Medline was searched from January 2005 to September 2009 using the key words duloxetine and peripheral neuropathy for clinical trials limited to human research published in English and duloxetine and pharmacology in the nervous system.Results: Duloxetine has been shown to effectively reduce diabetic peripheral neuropathic pain compared to placebo at doses of 60 mg/day and 120 mg/day with minimal to moderate side effects. This effect is seen with minimal effects on glycemic control and without any clinically relevant effects on lipid control, or cardiovascular parameters. In addition, its efficacy and tolerability is comparable to other medications commonly used in the management of neuropathic pain. Furthermore, duloxetine performs favorably both in terms of quality of life and in cost utility analyses.Discussion and conclusion: This article reviewed the issues related to management of diabetic peripheral neuropathic pain, the pharmacology and rationale for use of duloxetine, efficacy studies, and the safety and tolerability of treatment with duloxetine. Duloxetine is an acceptable initial or alternative treatment for patients with diabetic neuropathic pain.Keywords: duloxetine, diabetic neuropathy, neuropathic pai