Breast Cancer Biomarker Discovery in the Functional Genomic Age: A Systematic Review of 42 Gene Expression Signatures

In this review we provide a systematic analysis of transcriptomic signatures derived from 42 breast cancer gene expression studies, in an effort to identify the most relevant breast cancer biomarkers using a meta-analysis method. Meta-data revealed a set of 117 genes that were the most commonly affected ranging from 12% to 36% of overlap among breast cancer gene expression studies. Data mining analysis of transcripts and protein-protein interactions of these commonly modulated genes indicate three functional modules significantly affected among signatures, one module related with the response to steroid hormone stimulus, and two modules related to the cell cycle. Analysis of a publicly available gene expression data showed that the obtained meta-signature is capable of predicting overall survival (P < 0.0001) and relapse-free survival (P < 0.0001) in patients with early-stage breast carcinomas. In addition, the identified meta-signature improves breast cancer patient stratification independently of traditional prognostic factors in a multivariate Cox proportional-hazards analysis

Antimicrobial activities of secondary metabolites of endophytic fungi isolated from Catharanthus roseus

Introduction: Recently, several endophytes have been shown to possess the potentials to synthesize novel bioactive compounds that have found use for drug discovery. We isolated endophytic fungi associated with Catharanthus roseus collected from the river banks of Amassoma in Southern Nigeria, and identified some of their bioactive secondary metabolites. Methods: The fungi were subjected to solid-state fermentation on rice medium and the metabolites were extracted using ethyl acetate. The fungal crude extracts were screened for antimicrobial activity and were also subjected to high-performance liquid chromatography-diode-array detection (HPLC-DAD) analysis for the identification of the bioactive compounds. Results: The fungal extracts showed both antibacterial and antifungal activities with minimum inhibitory concentrations ranging from 0.0625 to 1 mg/mL. The HPLC-DAD analysis of the extracts suggested the presence of citreoisocoumarin, citreoisocoumarinol, questinol, hydroxyemodin, acropyrone, methyl 2-(4-hydroxyphenyl) acetate, nigricinol, and cladosporin. Conclusion: The results of this study suggest that endophytic fungi associated with C. roseus could be a promising source of novel bioactive compounds with pharmaceutical and industrial importance

Rhomboid domain containing 2 (RHBDD2): A novel cancer-related gene over-expressed in breast cancer

In the course of breast cancer global gene expression studies, we identified an uncharacterized gene known as RHBDD2 (Rhomboid domain containing 2) to be markedly over-expressed in primary tumors from patients with recurrent disease. In this study, we identified RHBDD2 mRNA and protein expression significantly elevated in breast carcinomas compared with normal breast samples as analyzed by SAGE (n=46) and immunohistochemistry (n=213). Interestingly, specimens displaying RHBDD2 over-expression were predominantly advanced stage III breast carcinomas (p=0.001). Western-blot, RT-PCR and cDNA sequencing analyses allowed us to identify two RHBDD2 alternatively spliced mRNA isoforms expressed in breast cancer cell lines. We further investigated the occurrence and frequency of gene amplification and over-expression affecting RHBDD2 in 131 breast samples. RHBDD2 gene amplification was detected in 21% of 98 invasive breast carcinomas analyzed. However, no RHBDD2 amplification was detected in normal breast tissues (n=17) or breast benign lesions (n=16) (p=0.014). Interestingly, siRNA mediated silencing of RHBDD2 expression results in a decrease of MCF7 breast cancer cells proliferation compared with the corresponding controls (p=0.001). In addition, analysis of publicly available gene expression data showed a strong association between high RHBDD2 expression and decreased overall survival (p=0.0023), relapsefree survival (p= 0.0013), and metastasis-free interval (p=0.006) in patients with primary ERnegative breast carcinomas. In conclusion, our findings suggest that RHBDD2 over-expression behaves as an indicator of poor prognosis and may play a role facilitating breast cancer progression

DMBA induced mouse mammary tumors display high incidence of activating Pik3caH1047 and loss of function Pten mutations

Controversy always existed on the utility of chemically induced mouse mammary carcinogenesis models as valid equivalents for the study of human breast cancer. Here, we performed whole exome and RNA sequencing on long latency mammary tumors (218 ± 27 days) induced by the carcinogen 7,12-Dimethylbenzathracene (DMBA) and short latency tumors (65 ± 11 days) induced by the progestin Medroxyprogesterone Acetate (MPA) plus DMBA in CD2F1 mice. Long latency tumors displayed a high frequency of Pi3kca and/or Pten mutations detected in 11 of 13 (85%) long latency cases (14/22, 64% overall). Eighty-two percent (9/11) of tumors carried the Pik3ca H1047L/R hot-spot mutation, as frequently found in human breast cancer. These tumors were luminal-like and mostly ER/PR+, as in humans. Transcriptome profiling indicated a significant activation of the PI3K-Akt pathway (p=3.82e-6). On the other hand MPA+DMBA induced short latency tumors displayed mutations in cancer drivers not commonly found mutated in human breast cancer (e.g. Hras and Apc). These tumors were mostly basal-like and MPA exposure led to Rankl overexpression (60 fold induction) and immunosuppressive gene expression signatures. In summary, long latency DMBA induced mouse mammary tumors reproduce the molecular profile of human luminal breast carcinomas representing an excellent preclinical model for the testing of PIK3CA/Akt/mTOR pathway inhibitory therapies and a good platform for the developing of additional preclinical tools such as syngeneic transplants in immunocompetent hosts

Strategic engagement and librarians

The future of the academic book is a strategic engagement issue for librarians. Books might not be stored in or purchased for university libraries; they might not even exist in a physical form. How will academic books be organised and accessed in the future, if they are not in libraries? How will librarians at universities engage academic researchers in strategic conversations about the future of their academic books? This chapter argues that conversations between librarians and academic book authors about the future are more important than ever. It puts the current challenges in context, using data from the Research Excellence Framework and the University of Nottingham library catalogue, identifying the strategic role of librarians in shaping the future of the academic book through strategic engagement

WWOX at the crossroads of cancer, metabolic syndrome related traits and CNS pathologies

WWOX was cloned as a putative tumor suppressor gene mapping to chromosomal fragile site FRA16D. Deletions affecting WWOX accompanied by loss of expression are frequent in various epithelial cancers. Translocations and deletions affecting WWOX are also common in multiple myeloma and are associated with worse prognosis. Metanalysis of gene expression datasets demonstrates that low WWOX expression is significantly associated with shorter relapse-free survival in ovarian and breast cancer patients. Although somatic mutations affecting WWOX are not frequent, analysis of TCGA tumor datasets led to identifying 44 novel mutations in various tumor types. The highest frequencies of mutations were found in head and neck cancers and uterine and gastric adenocarcinomas. Mouse models of gene ablation led us to conclude that Wwox does not behave as a highly penetrant, classical tumor suppressor gene since its deletion is not tumorigenic in most models and its role is more likely to be of relevance in tumor progression rather than in initiation. Analysis of signaling pathways associated with WWOX expression confirmed previous in vivo and in vitro observations linking WWOX function with the TGFβ/SMAD and WNT signaling pathways and with specific metabolic processes. Supporting these conclusions recently we demonstrated that indeed WWOX behaves as a modulator of TGFβ/SMAD signaling by binding and sequestering SMAD3 in the cytoplasmic compartment. As a consequence progressive loss of WWOX expression in advanced breast cancer would contribute to the pro-metastatic effects resulting from TGFβ/SMAD3 hyperactive signaling in breast cancer.Recently, GWAS and resequencing studies have linked the WWOX locus with familial dyslipidemias and metabolic syndrome related traits. Indeed, gene expression studies in liver conditional KO mice confirmed an association between WWOX expression and lipid metabolism.Finally, very recently the first human pedigrees with probands carrying homozygous germline loss of function WWOX mutations have been identified. These patients are characterized by severe CNS related pathology that includes epilepsy, ataxia and mental retardation. In summary, WWOX is a highly conserved and tightly regulated gene throughout evolution and when defective or deregulated the consequences are important and deleterious as demonstrated by its association not only with poor prognosis in cancer but also with other important human pathologies such as metabolic syndrome and CNS related pathologic conditions.Centro de Investigaciones Inmunológicas Básicas y Aplicada

B1 B cells acquire a proliferative and anti-inflammatory profile during pregnancy in mice

B1 B cells are a distinct subpopulation of B cells characterized by their unique capacity of self-renewal and the ability to secrete IgM without foreign antigen exposure (natural antibodies). In addition, upon activation, B1 B cells produce large quantities of the potent anti-inflammatory cytokine IL-10. Though the mechanisms that control natural antibodies production are not fully elucidated, it was recently associated with a down-regulation of CD1d expression in B1 B cells. Taking into account that both, IL-10 and natural antibodies are known to be fundamental components in pregnancy wellbeing, the aim of this study was to evaluate proliferation status as well as CD1d expression and IL-10 production by B1 B cells during pregnancy. Flow cytometry analysis, on splenic B1 B cells from pregnant (P) and non-pregnant (NP) mice was performed to evaluate ki-67 (proliferation marker) and CD1d expression as well as IL-10 production upon LPS stimulation. We observed significantly higher expression levels of Ki-67 in splenic B1 B cells from P compared to NP (Unpaired t-test p<0,0001; n=3) mice which was mirrored by higher percentages of B1 B cells in the spleen of P mice (Unpaired t-test p=0,0095; n=11). In addition, B1 B cells from P mice expressed lower levels of CD1d as compared to NP mice (Unpaired t-test p<0,0001; n=3). Furthermore, LPS-stimulated B1 B cells from P mice produced significantly higher levels of IL-10 compared to NP mice in vitro (Unpaired t-test p=0,015; n=5).Overall, our results demonstrate that not only B1 B cells are expanded in the spleen during pregnancy but they also seem to acquire the capacity to produce higher levels of natural antibodies and IL-10 during this period, suggesting their critical role in the intricate process of pregnancy tolerance.Fil: Valeff, Natalin Jimena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Abba, Martin C.. Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Inmunológicas Básicas y Aplicadas; ArgentinaFil: Jensen, Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaLXVI Reunión anual de la Sociedad Argentina de Investigación Clínica; LXIX Reunión Anual de la Sociedad Argentina de Inmunología; LIII Reunión Anual de la Asociación Argentina de Farmacología Experimental y XI Reunión Anual de la Asociación Argentina de NanomedicinasBuenos AiresArgentinaSociedad Argentina de Investigación ClínicaSociedad Argentina de InmunologíaAsociación Argentina de Farmacología ExperimentalAsociación Argentina de Nanomedicina

An Evidence-Based Survey on Full-Scale Membrane Biological Reactors: Main Technical Features and Operational Aspects

This paper presents the results of a survey on full-scale membrane biological reactors (MBRs) wastewater treatment plants (WWTPs) in Italy. Alongside the main technical characteristics of the Italian MBR plants, the opinions of the plant managers on the operational advantages and disadvantages are described. As reported by the MBR technology suppliers, approximately 290 MBR municipal or industrial WWTPs are in operation in Italy, out of which 242 were studied in this survey. Data from more than one hundred municipal WWTPs were collected; these account for a total capacity of about 2,000,000 population equivalent (PE), which corresponds to 3% of the total organic load treated by the Italian WWTPs with secondary and advanced treatment. Usually, small installations adopt the flat-sheet rather than hollow-fiber membrane configuration. The main reasons why the MBR technology has been preferred to other options are its potential to be used for increasing the treatment capacity of existing plants and its compactness. Moreover, the followed operational advantages have been highlighted: easiness to comply with the discharge limits, removal of pathogens without specific disinfection units, possibility of internal reuse of the effluent, and process automation. Membrane fouling and plant shutdown have been recorded as the most relevant troubles, the last one indeed occurring only occasionally or rarely

Antimicrobial drugs for persistent diarrhoea of unknown or non-specific cause in children under six in low and middle income countries: systematic review of randomized controlled trials

Background A high proportion of children with persistent diarrhoea in middle and low income countries die. The best treatment is not clear. We conducted a systematic review to evaluate the effectiveness of antimicrobial drug treatment for persistent diarrhoea of unknown or non-specific cause. Methods We included randomized comparisons of antimicrobial drugs for the treatment of persistent diarrhoea of unknown or non-specific cause in children under the age of six years in low and middle income countries. We searched the electronic databases MEDLINE, EMBASE, LILACS, WEB OF SCIENCE, and the Cochrane Central Register of Controlled Trials (CENTRAL) to May 2008 for relevant randomized or quasi randomized controlled trials. We summarised the characteristics of the eligible trials, assessed their quality using standard criteria, and extracted relevant outcomes data. Where appropriate, we combined the results of different trials. Results Three trials from South East Asia and one from Guatemala were included, all were small, and three had adequate allocation concealment. Two were in patients with diarrhoea of unknown cause, and two were in patients in whom known bacterial or parasitological causes of diarrhoea had been excluded. No difference was demonstrated for oral gentamicin compared with placebo (presence of diarrhoea at 6 or 7 days; 2 trials, n = 151); and for metronidazole compared with placebo (presence of diarrhoea at 3, 5 and 7 days; 1 trial, n = 99). In one small trial, sulphamethoxazole-trimethoprim appeared better than placebo in relation to diarrhoea at seven days and total stool volume (n = 55). Conclusion There is little evidence as to whether or not antimicrobials help treat persistent diarrhoea in young children in low and middle income countries

Secure and Differentially Private Detection of Net Neutrality Violations by Means of Crowdsourced Measurements

Evaluating Network Neutrality requires comparing the quality of service experienced by multiple users served by different Internet Service Providers. Consequently, the issue of guaranteeing privacy-friendly network measurements has recently gained increasing interest. In this paper we propose a system which gathers throughput measurements from users of various applications and Internet services and stores it in a crowdsourced database, which can be queried by the users themselves to verify if their submitted measurements are compliant with the hypothesis of a neutral network. Since the crowdsourced data may disclose sensitive information about users and their habits, thus leading to potential privacy leakages, we adopt a privacy-preserving method based on randomized sampling and suppression of small clusters. Numerical results show that the proposed solution ensures a good trade-off between usefulness of the system, in terms of precision and recall of discriminated users, and privacy, in terms of differential privacy