Expression of the Aldo-Ketoreductases AKR1B1 and AKR1B10 in Human Cancers

The American Cancer Society estimates that there will be more than 1.5 million new cases of cancer in 2011, underscoring the need for identification of new therapeutic targets and development of novel cancer therapies. Previous studies have implicated the human aldo-ketoreductases AKR1B1 and AKR1B10 in cancer, and therefore we examined AKR1B1 and AKR1B10 expression across all major human cancer types using the Oncomine cancer gene expression database (Compendia Biosciences, www.oncomine.com). Using this database, we found that expression of AKR1B1 and AKR1B10 varies greatly by cancer type and tissue of origin, including agreement with previous reports that AKR1B10 is significantly over-expressed in cancers of the lungs and liver. AKR1B1 is more broadly over-expressed in human cancers than AKR1B10, albeit at a generally lower magnitude. AKR1B1 over-expression was found to be associated with shortened patient survival in acute myelogenous leukemias and multiple myelomas. High AKR1B10 expression tends to predict less aggressive clinical course generally, notably within lung cancers, where it tends to be highly over-expressed compared to normal tissue. These findings suggest that AKR1B1 inhibitors in particular hold great potential as novel cancer therapeutics

Regulation of epithelial-mesenchymal transition and DNA damage responses by singleminded-2s

Virtually all signaling pathways that play key roles in development such as the transfroming growth factor (TGF)-beta, notch, and wnt pathways also influence tumor formation, implying that cancer is in a sense development gone awry. Therefore, identification and elucidation of developmental pathways has great potential for generating new diagnostic tools and molecular therapy targets. Singleminded-2s (SIM2s), a splice variant of the basic helilx-loop-helix / PER-ARNT-SIM (bHLH/PAS) transcriptional repressor Singleminded-2, is lost or repressed in approximately 70% of human breast tumors and has a profound influence on normal mammary development. In order to gain a better understanding of the mechanisms by which SIM2s restricts malignant transformation and progression in breast cancer, we depleted SIM2 RNA in MCF-7 cells using a retroviral shRNA system and examined gene expression and functional abilities of the SIM2-depleted MCF-7 cells (SIM2i) relative to a control MCF line expressing a non-specific “scrambled” shRNA (SCR). Depletion of SIM2 resulted in an epithelial-mesenchymal transition (EMT)-like effect characterized by increased migration and invasion, altered morphology, and loss of epithelial markers concomitant with gain of mesenchymal markers. The root of this effect may be loss of SIM2- mediated repression of the E-cadherin repressor slug, as SIM2 is able to bind and repress transcription from the slug promoter, and slug expression is dramatically elevated in SIM2i MCF-7 cells. Consistent with the previously established role of slug in resistance to various cancer therapies, SIM2i cells are resistant to the radiomimetic doxorubicin and appear to have elevated self-renewal capacity under certain conditions. Intriguingly, SIM2 protein levels are elevated by treatment with DNA damaging agents, and SIM2 interacts with the p53 complex via co-regulation of specific p53- target gene such as p21/WAF1/CIP1. These results provide a plausible mechanism for the tumor suppressor activity of SIM2, and provide insight into a novel tumor suppressive transcriptional circuit that may have utility as a therapeutic target

What Aboriginal and Torres Strait Islander Students in North Queensland say about effective teaching practices: measuring teacher cultural competence

The study presents the outcomes of the first two phases of a four phase Australian-based research initiative which seeks to support a better understanding of classroom practices that have value in learning for Aboriginal students. The questions guiding the research are: (1) What do Indigenous students and their parents identify as the pedagogical practices influencing their (child's) learning? (2) What are the statistically validated factors that are identified as composites of a culturally competent teacher, and to what extent are these represented in classrooms? The presentation concludes by presenting a statistically validated Effective Teaching Profile that is currently being applied in the participant schools to determine if there are teaching practices salient to fostering learning for Indigenous students

What Aboriginal and Torres Strait Islander students in North Queensland say about effective teaching practices: measuring teacher pedagogical cultural competence

Similar to most Indigenous peoples, the Aboriginal and Torres Strait (Indigenous Australians) people of northern Queensland presently participate in a school system that has been drawn from the predominantly white Australian culture. Although Indigenous staff work in schools, especially elementary schools, the majority of teachers, principals, and school operations administrators are non-Aboriginal and the curricula and pedagogy of classrooms are based on models derived from the dominant culture. Because of this, school practices such as the content of curricula and pedagogical practices have both intentionally and unintentionally denied the inclusion of those aspects of culture that have value and are important to children (Bishop, 1996). With the imperative to address issues of inequity in terms of Indigenous student achievement in education, Catholic Education has established an imperative to move towards an educational system grounded in culturebased intentions to address inequity in student achievement and validate community practice and aspiration. The study described here presents the outcomes of all phases of a four phase research initiative which arose in response to this cultural denial to support a move towards a better understanding of classroom practices that have value in the learning of Indigenous students. The following questions guide the four phases of our research: (1) What do Indigenous students and their parents identify as the pedagogical practices influencing their (child’s) learning? (2) What are the statistically validated factors that are identified as composites of a culturally competent teacher for Indigenous students in this context, and to what extent are these represented in Catholic Education classrooms? (3) What teaching behaviours are identified as statistically significant in influencing Indigenous students’ learning and (4) What teacher thinking processes are influential in promoting teaching practice shifts towards cultural competence

Quality Teaching Practices as Reported by Aboriginal Parents, Students and their Teachers: Comparisons and Contrasts

This paper summarizes the findings from the first phase of a three-part project which, overall, investigates what Aboriginal1 students perceive as the qualities and actions of effective teachers and subsequently seeks to determine the impact of the enactment of these identified qualities on educational outcomes. This first phase of the research was centered on gathering accounts of quality teachers and teaching practice from students, parents and their teachers from phenomenologically aligned interviews. Similar and contrasting themes among these three groups are presented, with the intention of exposing potential mismatch in perception of the construct of ‘quality’ teaching. Finally, we present implications of this research in light of the more recent development of professional standards for Australian teachers that seek to define and evaluate high quality teaching

Loss of Singleminded-2s in the Mouse Mammary Gland Induces an Epithelial-Mesenchymal Transition Associated with Up-Regulation of Slug and Matrix Metalloprotease 2

The short splice variant of the basic helix-loop-helix Per-Arnt-Sim transcription factor Singleminded-2, SIM2s, has been implicated in development and is frequently lost or reduced in primary breast tumors. Here, we show that loss of Sim2s causes aberrant mouse mammary gland ductal development with features suggestive of malignant transformation, including increased proliferation, loss of polarity, down-regulation of E-cadherin, and invasion of the surrounding stroma. Additionally, knockdown of SIM2s in MCF-7 breast cancer cells contributed to an epithelial-mesenchymal transition (EMT) and increased tumorigenesis. In both Sim2(−/−) mammary glands and SIM2s-depleted MCF7 cells, these changes were associated with increased SLUG and MMP2 levels. SIM2s protein was detectable on the SLUG promoter, and overexpression of SIM2s repressed expression from a SLUG-controlled reporter in a dose-dependent manner. To our knowledge, SIM2s is the first protein shown to bind and repress the SLUG promoter, providing a plausible explanation for the development role and breast tumor-suppressive activity of SIM2s. Together, our results suggest that SIM2s is a key regulator of mammary-ductal development and that loss of SIM2s expression is associated with an invasive, EMT-like phenotype

Mitochondrial ATP fuels ABC transporter-mediated drug efflux in cancer chemoresistance

Chemotherapy remains the standard of care for most cancers worldwide, however development of chemoresistance due to the presence of the drug-effluxing ATP binding cassette (ABC) transporters remains a significant problem. The development of safe and effective means to overcome chemoresistance is critical for achieving durable remissions in many cancer patients. We have investigated the energetic demands of ABC transporters in the context of the metabolic adaptations of chemoresistant cancer cells. Here we show that ABC transporters use mitochondrial-derived ATP as a source of energy to efflux drugs out of cancer cells. We further demonstrate that the loss of methylation-controlled J protein (MCJ) (also named DnaJC15), an endogenous negative regulator of mitochondrial respiration, in chemoresistant cancer cells boosts their ability to produce ATP from mitochondria and fuel ABC transporters. We have developed MCJ mimetics that can attenuate mitochondrial respiration and safely overcome chemoresistance in vitro and in vivo. Administration of MCJ mimetics in combination with standard chemotherapeutic drugs could therefore become an alternative strategy for treatment of multiple cancers

High-throughput gene discovery in the rat

The rat is an important animal model for human diseases and is widely used in physiology. In this article we present a new strategy for gene discovery based on the production of ESTs from serially subtracted and normalized cDNA libraries, and we describe its application for the development of a comprehensive nonredundant collection of rat ESTs. Our new strategy appears to yield substantially more EST clusters per ESTs sequenced than do previous approaches that did not use serial subtraction. However, multiple rounds of library subtraction resulted in high frequencies of otherwise rare internally primed cDNAs, defining the limits of this powerful approach. To date, we have generated >200,000 3′ ESTs from >100 cDNA libraries representing a wide range of tissues and developmental stages of the laboratory rat. Most importantly, we have contributed to ∼50,000 rat UniGene clusters. We have identified, arrayed, and derived 5′ ESTs from >30,000 unique rat cDNA clones. Complete information, including radiation hybrid mapping data, is also maintained locally at http://genome.uiowa.edu/clcg.html. All of the sequences described in this article have been submitted to the dbEST division of the NCBI

What Aboriginal and Torres Strait Islander students in North Queensland say about effective teaching practices: measuring teacher pedagogical cultural competence

Similar to most Indigenous peoples, the Aboriginal and Torres Strait (Indigenous Australians) people of northern Queensland presently participate in a school system that has been drawn from the predominantly white Australian culture. Although Indigenous staff work in schools, especially elementary schools, the majority of teachers, principals, and school operations administrators are non-Aboriginal and the curricula and pedagogy of classrooms are based on models derived from the dominant culture. Because of this, school practices such as the content of curricula and pedagogical practices have both intentionally and unintentionally denied the inclusion of those aspects of culture that have value and are important to children (Bishop, 1996). With the imperative to address issues of inequity in terms of Indigenous student achievement in education, Catholic Education has established an imperative to move towards an educational system grounded in culturebased intentions to address inequity in student achievement and validate community practice and aspiration. The study described here presents the outcomes of all phases of a four phase research initiative which arose in response to this cultural denial to support a move towards a better understanding of classroom practices that have value in the learning of Indigenous students. The following questions guide the four phases of our research: (1) What do Indigenous students and their parents identify as the pedagogical practices influencing their (child’s) learning? (2) What are the statistically validated factors that are identified as composites of a culturally competent teacher for Indigenous students in this context, and to what extent are these represented in Catholic Education classrooms? (3) What teaching behaviours are identified as statistically significant in influencing Indigenous students’ learning and (4) What teacher thinking processes are influential in promoting teaching practice shifts towards cultural competence

What Queensland Indigenous students and parents say about effective teaching practices: a Catholic Education intiative

Despite the often quoted characteristics of Culturally Responsive Pedagogy and the plethora of untested 'good ideas' in the Australian literature, no systematic and empirically-based research provides any conclusive indication of ‘what works' in influencing Indigenous students' learning (Price & Hughes, 2009). As Rowe (2003) laments, there is a growing uneasiness related to how little is known about teacher quality from Indigenous students' own perspectives. This is echoed by Price and Hughes (2009) who claim that there is [still] astoundingly little known about what Aboriginal and Torres Strait Islander students see as the qualities of effective teachers, and the impact this has on educational outcomes. Considering the significant contribution in Canada and New Zealand made by government-funded, evidence-based studies in culturally responsive teaching grounded in Indigenous communities and their students' voiced identification of influences upon their learning (for example, Lewthwaite et al in Canada and Bishop et al in Aotearoa-New Zealand), it is disturbing that no similar empirically-based research exists in the Australian context. As Craven asserts (2007, p. 4) "there is astoundingly little known about what Aboriginal students see as the qualities of effective teachers and the impact this has on educational outcomes." As well, she states, "There is a need to critically validate the generalisability of the commonly cited claims [for example, by Hattie and Rowe] to Aboriginal students to tease out facets of quality teaching that are salient to Aboriginal students; elucidate their perspectives of teacher quality; and test the influence of specific facets of quality teaching on academic outcomes and the consequences of the findings for developing interventions for Aboriginal school students." The research described herewith focuses on addressing this imperative. This study presents the outcomes of the first phase of a three phase Australian Research Council research initiative which focuses on identifying through the voices of Aboriginal students, teachers and community members, the teaching practices that influence Aboriginal student engagement and learning. The study is associated with the Diocese of Townsville Catholic Education schools in northern Queensland, primarily in the Mount Isa area, a small rural city in northern Queensland, Australia. Through phenomenological aligned interviews, students, teachers and community members express their views of the characteristics of effective teachers and effective teaching. Considering that the national discourse in Australia is monopolised by discussion on teaching quality, we problematize this discourse based upon what the Aboriginal community asserts as characteristics of such practice