Hormone Receptor and ERBB2 Status in Gene Expression Profiles of Human Breast Tumor Samples

The occurrence of large publically available repositories of human breast tumor gene expression profiles provides an important resource to discover new breast cancer biomarkers and therapeutic targets. For example, knowledge of the expression of the estrogen and progesterone hormone receptors (ER and PR), and that of the ERBB2 in breast tumor samples enables choice of therapies for the breast cancer patients that express these proteins. Identifying new biomarkers and therapeutic agents affecting the activity of signaling pathways regulated by the hormone receptors or ERBB2 might be accelerated by knowledge of their expression levels in large gene expression profiling data sets. Unfortunately, the status of these receptors is not invariably reported in public databases of breast tumor gene expression profiles. Attempts have been made to employ a single probe set to identify ER, PR and ERBB2 status, but the specificity or sensitivity of their prediction is low. We enquired whether estimation of ER, PR and ERBB2 status of profiled tumor samples could be improved by using multiple probe sets representing these three genes and others with related expression

A target based approach identifies genomic predictors of breast cancer patient response to chemotherapy

BACKGROUND: The efficacy of chemotherapy regimens in breast cancer patients is variable and unpredictable. Whether individual patients either achieve long-term remission or suffer recurrence after therapy may be dictated by intrinsic properties of their breast tumors including genetic lesions and consequent aberrant transcriptional programs. Global gene expression profiling provides a powerful tool to identify such tumor-intrinsic transcriptional programs, whose analyses provide insight into the underlying biology of individual patient tumors. For example, multi-gene expression signatures have been identified that can predict the likelihood of disease reccurrence, and thus guide patient prognosis. Whereas such prognostic signatures are being introduced in the clinical setting, similar signatures that predict sensitivity or resistance to chemotherapy are not currently clinically available. METHODS: We used gene expression profiling to identify genes that were co-expressed with genes whose transcripts encode the protein targets of commonly used chemotherapeutic agents. RESULTS: Here, we present target based expression indices that predict breast tumor response to anthracycline and taxane based chemotherapy. Indeed, these signatures were independently predictive of chemotherapy response after adjusting for standard clinic-pathological variables such as age, grade, and estrogen receptor status in a cohort of 488 breast cancer patients treated with adriamycin and taxotere/taxol. CONCLUSIONS: Importantly, our findings suggest the practicality of developing target based indices that predict response to therapeutics, as well as highlight the possibility of using gene signatures to guide the use of chemotherapy during treatment of breast cancer patients

Evaluating The Importance Of Competencies Within Accounting Information Systems Curricula

In International Education Guideline No. 11, the International Federation of Accountants identified the essential information technology (IT) competencies, knowledge, and skills required for entry-level accounting positions. These IT competencies are classified into three categories:  (1) IT concepts for business systems (nine competencies), (2) internal control in computer-based business systems (six competencies), and (3) the roles of the professional accountant in information systems (18 competencies classified into three subcategories). In this exploratory study, we surveyed accounting information systems educators about the relative importance of the IFAC competencies to prepare undergraduate students for entry-level accounting positions. The results provide accounting educators with an understanding of current practice regarding the relative emphasis placed on IT competencies in AIS courses.  Using this information, the results may be used to guide the allocation of resources within the AIS curriculum

Hepatocyte growth factor and MET support mouse enteric nervous system development, the peristaltic response, and intestinal epithelial proliferation in response to injury

UNLABELLED: Factors providing trophic support to diverse enteric neuron subtypes remain poorly understood. We tested the hypothesis that hepatocyte growth factor (HGF) and the HGF receptor MET might support some types of enteric neurons. HGF and MET are expressed in fetal and adult enteric nervous system. In vitro, HGF increased enteric neuron differentiation and neurite length, but only if vanishingly small amounts (1 pg/ml) of glial cell line-derived neurotrophic factor were included in culture media. HGF effects were blocked by phosphatidylinositol-3 kinase inhibitor and by MET-blocking antibody. Both of these inhibitors and MEK inhibition reduced neurite length. In adult mice, MET was restricted to a subset of calcitonin gene-related peptide-immunoreactive (IR) myenteric plexus neurons thought to be intrinsic primary afferent neurons (IPANs). Conditional MET kinase domain inactivation (Met(fl/fl); Wnt1Cre+) caused a dramatic loss of myenteric plexus MET-IR neurites and 1-1\u27-dioctodecyl-3,3,3\u27,3\u27-tetramethylindocarbocyamine perchlorate (DiI) labeling suggested reduced MET-IR neurite length. In vitro, Met(fl/fl); Wnt1Cre+ mouse bowel had markedly reduced peristalsis in response to mucosal deformation, but normal response to radial muscle stretch. However, whole-bowel transit, small-bowel transit, and colonic-bead expulsion were normal in Met(fl/fl); Wnt1Cre+ mice. Finally, Met(fl/fl); Wnt1Cre+ mice had more bowel injury and reduced epithelial cell proliferation compared with WT animals after dextran sodium sulfate treatment. These results suggest that HGF/MET signaling is important for development and function of a subset IPANs and that these cells regulate intestinal motility and epithelial cell proliferation in response to bowel injury. SIGNIFICANCE STATEMENT: The enteric nervous system has many neuronal subtypes that coordinate and control intestinal activity. Trophic factors that support these neuron types and enhance neurite growth after fetal development are not well understood. We show that a subset of adult calcitonin gene-related peptide (CGRP)-expressing myenteric neurons produce MET, the receptor for hepatocyte growth factor, and that loss of MET activity affects peristalsis in response to mucosal stroking, reduces MET-immunoreactive neurites, and increases susceptibility to dextran sodium sulfate-induced bowel injury. These observations may be relevant for understanding and treating intestinal motility disorders and also suggest that enhancing the activity of MET-expressing CGRP neurons might be a useful strategy to reduce bowel inflammation

Pea3 Transcription Factors and Wnt1-Induced Mouse Mammary Neoplasia

The role of the PEA3 subfamily of Ets transcription factors in breast neoplasia is controversial. Although overexpression of PEA3 (E1AF/ETV4), and of the related factors ERM (ETV5) and ER81 (ETV1), have been observed in human and mouse breast tumors, PEA3 factors have also been ascribed a tumor suppressor function. Here, we utilized the MMTV/Wnt1 mouse strain to further interrogate the role of PEA3 transcription factors in mammary tumorigenesis based on our previous observation that Pea3 is highly expressed in MMTV/Wnt1 mammary tumors. Pea3 expression in mouse mammary tissues was visualized using a Pea3NLSlacZ reporter strain. In normal mammary glands, Pea3 expression is predominantly confined to myoepithelial cells. Wnt1 transgene expression induced marked amplification of this cell compartment in nontumorous mammary glands, accompanied by an apparent increase in Pea3 expression. The pattern of Pea3 expression in MMTV/Wnt1 mammary glands recapitulated the cellular profile of activated β-catenin/TCF signaling, which was visualized using both β-catenin immunohistochemistry and the β-catenin/TCF-responsive reporter Axin2NLSlacZ. To test the requirement for PEA3 factors in Wnt1-induced tumorigenesis, we employed a mammary-targeted dominant negative PEA3 transgene, ΔNPEA3En. Expression of ΔNPEA3En delayed early-onset tumor formation in MMTV/Wnt1 virgin females (P = 0.03), suggesting a requirement for PEA3 factor function for Wnt1-driven tumor formation. Consistent with this observation, expression of the ΔNPEA3En transgene was profoundly reduced in mammary tumors compared to nontumorous mammary glands from bigenic MMTV/Wnt1, MMTV/ΔNPEA3En mice (P = 0.01). Our data provide the first description of Wnt1-mediated expansion of the Pea3-expressing myoepithelial compartment in nontumorous mammary glands. Consistent with this observation, mammary myoepithelium was selectively responsive to Wnt1. Together these data suggest the MMTV/Wnt1 strain as a potential model of basal breast cancer. Furthermore, this study provides evidence for a protumorigenic role of PEA3 factors in breast neoplasia, and supports targeting the PEA3 transcription factor family in breast cancer

E2F1 and KIAA0191 expression predicts breast cancer patient survival

<p>Abstract</p> <p>Background</p> <p>Gene expression profiling of human breast tumors has uncovered several molecular signatures that can divide breast cancer patients into good and poor outcome groups. However, these signatures typically comprise many genes (~50-100), and the prognostic tests associated with identifying these signatures in patient tumor specimens require complicated methods, which are not routinely available in most hospital pathology laboratories, thus limiting their use. Hence, there is a need for more practical methods to predict patient survival.</p> <p>Methods</p> <p>We modified a feature selection algorithm and used survival analysis to derive a 2-gene signature that accurately predicts breast cancer patient survival.</p> <p>Results</p> <p>We developed a tree based decision method that segregated patients into various risk groups using <it>KIAA0191 </it>expression in the context of <it>E2F1 </it>expression levels. This approach led to highly accurate survival predictions in a large cohort of breast cancer patients using only a 2-gene signature.</p> <p>Conclusions</p> <p>Our observations suggest a possible relationship between <it>E2F1 </it>and <it>KIAA0191 </it>expression that is relevant to the pathogenesis of breast cancer. Furthermore, our findings raise the prospect that the practicality of patient prognosis methods may be improved by reducing the number of genes required for analysis. Indeed, our <it>E2F1/KIAA0191 </it>2-gene signature would be highly amenable for an immunohistochemistry based test, which is commonly used in hospital laboratories.</p

Genomic epidemiology of Escherichia coli:Antimicrobial resistance through a One Health lens in sympatric humans, livestock and peri-domestic wildlife in Nairobi, Kenya

BackgroundLivestock systems have been proposed as a reservoir for antimicrobial-resistant (AMR) bacteria and AMR genetic determinants that may infect or colonise humans, yet quantitative evidence regarding their epidemiological role remains lacking. Here, we used a combination of genomics, epidemiology and ecology to investigate patterns of AMR gene carriage in Escherichia coli, regarded as a sentinel organism.MethodsWe conducted a structured epidemiological survey of 99 households across Nairobi, Kenya, and whole genome sequenced E. coli isolates from 311 human, 606 livestock and 399 wildlife faecal samples. We used statistical models to investigate the prevalence of AMR carriage and characterise AMR gene diversity and structure of AMR genes in different host populations across the city. We also investigated household-level risk factors for the exchange of AMR genes between sympatric humans and livestock.ResultsWe detected 56 unique acquired genes along with 13 point mutations present in variable proportions in human and animal isolates, known to confer resistance to nine antibiotic classes. We find that AMR gene community composition is not associated with host species, but AMR genes were frequently co-located, potentially enabling the acquisition and dispersal of multi-drug resistance in a single step. We find that whilst keeping livestock had no influence on human AMR gene carriage, the potential for AMR transmission across human-livestock interfaces is greatest when manure is poorly disposed of and in larger households.ConclusionsFindings of widespread carriage of AMR bacteria in human and animal populations, including in long-distance wildlife species, in community settings highlight the value of evidence-based surveillance to address antimicrobial resistance on a global scale. Our genomic analysis provided an in-depth understanding of AMR determinants at the interfaces of One Health sectors that will inform AMR prevention and control