IL-23R is epigenetically regulated and modulated by chemotherapy in non-small cell lung cancer

The Interleukin-23 (IL-23)/IL-23R signaling axis is an important inflammatory pathway, involved in the stimulation and regulation of the T helper (Th) 17 lymphocytes, resulting in the production of IL-17. Aside from auto-immunity, this cytokine has also been linked to carcinogenesis and polymorphisms in the IL-23R gene are associated with an increased risk for the development of a number of different cancers. Activation of the IL-23 pathway results in the up-regulation of STAT3 and it is thought that the pathological consequences associated with this are in part due to the production of IL-17. We have previously identified IL-23A as pro-proliferative and epigenetically regulated in non-small cell lung cancer (NSCLC). The current study aims to evaluate IL-23R in greater detail in NSCLC. We demonstrate that IL-23R is expressed and epigenetically regulated in NSCLC through histone post-translation modifications and CpG island methylation. In addition, Gemcitabine treatment, a chemotherapy drug used in the treatment of NSCLC, resulted in the up-regulation of the IL-23R. Furthermore, Apilimod (STA 5326), a small molecule which blocks the expression of IL-23 and IL-12, reduced the proliferative capacity of NSCLC cells, particularly in the adenocarcinoma (A549) sub-type. Apilimod is currently undergoing investigation in a number of clinical trials for the treatment of auto-immune conditions such as Crohn's disease and Rheumatoid Arthritis. Our results may have implications for treating NSCLC patients with Gemcitabine or epigenetic targeted therapies. However, Apilimod may possibly provide a new treatment avenue for NSCLC patients. Work is currently ongoing to further delineate the IL-23/IL-23R axis in this disease.

Epigenetic regulation of chemokine/chemokine receptor expression

Epigenetic regulation of gene expression is an important event for normal cellular homeostasis. Gene expression may be "switched" on or "turned" off via epigenetic means through adjustments in DNA architecture. These structural alterations result from changes to the DNA methylation status in addition to histone posttranslational modifications such as acetylation and methylation. Drugs which can alter the status of these epigenetic markers are currently undergoing clinical trials in a wide variety of diseases, including cancer.We illustrate the treatment of cell lines with histone deacetylase (HDi) and DNA methyltransferase inhibitors and the subsequent RNA isolation and reverse transcriptase polymerase chain reaction for several members of the CXC (ELR(+)) chemokine family. In addition we describe a chromatin immunoprecipitation assay to determine the association between chromatin transcription markers and DNA following pretreatment of cell cultures with an HDi, Trichostatin A (TSA). This assay allows us to determine whether treatment with TSA dynamically remodels the promoter region of our selected genes, as judged by the differences in the PCR product between our treated and untreated samples.

Narratives of healing: a case study of a young Liberian refugee settled in Australia

The Tree of Life group program is a narrative-based expressive arts intervention, designed to target the psychological difficulties faced by young people from refugee backgrounds. This study utilised a case study methodology to investigate the experience of a single adolescent from a Liberian background resettled in Australia, who participated in a manualised version of the Tree of Life program. The case study aimed to identify the underlying therapeutic processes that enabled the participant to adopt a preferred self-narrative. The participant was observed to demonstrate positive gains as a result of program participation. Five therapeutic factors were identified as particularly salient to the program’s success: the exploration of alternative stories of self; the fostering of group cohesion; the provision of corrective emotional experiences; the experience of outsider witnesses; and the instillation of hope. These factors were discussed in relation to working with young people from refugee backgrounds. Recommendations for future implementation of the Tree of Life program are provided.

The role of the Eph and ephrin proteins in prostate cancer

Prostate cancer is the most commonly diagnosed malignancy and the second leading cause of cancer related deaths in Australian men. Treatment in the early stages of the disease involves surgery, radiation and/or hormone therapy. However, in late stages of the disease these treatments are no longer effective and only palliative care is available. Therefore, there is a focus on exploration of novel therapies to increase survival and treatment efficacy. Advanced prostate cancer is characterised by bone or other distant metastasis. Spreading of the primary tumour to a secondary location is a complex process requiring an initial loss in cell-cell adhesion followed by increased cell migration and invasion. One gene family that has been known to affect cell-to-cell contact in other model systems are the Eph receptor tyrosine kinases. They are the largest family of receptor tyrosine kinases made up of 14 vertebrate Eph receptors that bind to nine cell membrane bound ephrin ligands. Eph-ephrin interaction is crucial in regulating cell behaviour in developmental processes and it is now thought that the underlying mechanisms involved in development may also be involved in cancer. Aberrant expression has been reported in many human malignancies including prostate cancer. Furthermore, expression has been linked with metastasis and poor prognosis in other tumour models. This study explores the potential role of the Eph receptor family in prostate cancer, in particular the roles of EphA2, EphA3 and ephrin-A5. Gene expression profiles were established for the Eph family in a series of prostate cancer cell lines using quantitative real time RT-PCR. A smaller subset of the most prominently expressed genes was chosen to screen a cohort of clinical samples. Elevated levels of EphA2, EphA3 and their ligands, ephrin-A1 and ephrin-A5 were observed in individual cell lines. Interestingly high EphA3 expression was observed in the androgen responsive cell lines while EphA2 was more prominent in the androgen independent cell lines. However, studies using 5-dihydrotestosterone suggest that EphA3 expression in not regulated by androgen. Cells expressing EphA2 showed a greater ability for migration and invasion while cells expressing EphA3 showed poor migration and invasion. Forced expression of EphA2 in the LNCaP cell line resulted in a more invasive phenotype while forced expression of EphA3 in the PC-3 cell line suggests a possible negative effect for EphA3 on cell migration and invasion. Cell signalling studies show activation of EphA2 decreases activity of proteins thought to be involved in pathways regulating cell movement including Akt, Src and FAK. Changes to the activation status of Rho family members, including RhoA and Rac1, associated with reorganisation of the actin cytoskeleton, an important part of cell migration was also observed. As a result, activation of EphA2 in PC-3 cells resulted in a less invasive phenotype. A novel finding in this study was the discovery of a combination of two EphA2 Mabs able to activate EphA2. Preliminary results show a potential for this antibody combination to reduce prostate cancer invasion in vitro. A unique aspect of Eph-ephrin interaction is the resulting bi-directional signalling that occurs through both the receptor and ligand. In this study a potential role for ephrin-A5 mediated signalling in prostate cancer was observed. LNCaP cells express high levels of EphA3 and its high affinity ligand ephrin-A5. In stripe assays, used to study guidance cues, LNCaP cells show strong attraction/migration to EphA3-Fc stripes but not ephrin-A5-Fc stripes suggesting ephrin-A5 mediated reverse cell signalling is involved. Knockdown of ephrin-A5 using shRNA resulted in a decrease in attraction/migration to EphA3-Fc stripes. Furthermore a reduction in proliferation was also observed in vitro. A subcutaneous xenograft model using ephrin-A5 shRNA cells versus controls showed a decrease in tumour formation. This study demonstrates a difference in EphA2 and EphA3 function in prostate cancer migration/invasion and a potential role for ephrin-A5 in prostate cancer cell adhesion and growth.

Optimization of an integrated model for automatic reduction and expansion of long queries

A long query provides more useful hints for searching relevant documents, but it is likely to introduce noise which affects retrieval performance. In order to smooth such adverse effect, it is important to reduce noisy terms, introduce and boost additional relevant terms. This paper presents a comprehensive framework, called Aspect Hidden Markov Model (AHMM), which integrates query reduction and expansion, for retrieval with long queries. It optimizes the probability distribution of query terms by utilizing intra-query term dependencies as well as the relationships between query terms and words observed in relevance feedback documents. Empirical evaluation on three large-scale TREC collections demonstrates that our approach, which is automatic, achieves salient improvements over various strong baselines, and also reaches a comparable performance to a state of the art method based on user’s interactive query term reduction and expansion.

The consultative process used in outreach : a narrative account

Aim The aim of this paper was to provide a narrative account of the communication skills used in an effective outreach consultation utilizing Neighbour’s consultative model. Other consultation models were considered; however, because of their overly comprehensive approach or emphasis on behaviour modification, these were deemed inappropriate. Background The nursing profession has endured significant changes of late and as a result is developing more autonomous roles in both the community and the acute health care settings. In the past, the term consultancy was used within the medical context; nowadays, there are advance nurse practitioners for whom consultancy is an integral part of their role. Although every nursing interaction is in essence a consultation, the fact that nurses are taking up on new advanced roles highlights the necessity for nurses to develop their consultation skills even further. Therefore, it makes sense to explore what aspects of that consultancy role needs special consideration in order to ensure that positive outcomes are achieved. Conclusions This paper has used a narrative account to uncover those salient skills needed to enhance the therapeutic relationship with a patient requiring the services of outreach. Furthermore, the application of a recognized consultation model was used to elucidate the underpinning knowledge of systematic history taking and assessment as well as demonstrating the communication skills and strategies needed to increase the patient’s participation and empowerment throughout the consultation. Relevance to clinical practice Effective communication skills encompassed in a consultative model are integral to the success in safeguarding the well-being of patients requiring advanced levels of care. Prejudging or pre-empting information being conveyed can be detrimental to patient safety and may prolong or complicate treatment plans.

The value of political connections : evidence from Korean chaebols

This thesis examines the value of political connections for business groups by constructing a unique dataset that allows us to identify the form and extent of the connections. Results show firms' membership to family-controlled business groups (South Korean chaebol) play a key role in determining the value of political connections. Politically connected chaebol firms experience substantial price increases following the establishment of the connection than other firms, but the reverse is found for other (non-family-controlled) connected business groups.

Temporal and functional changes in glycosaminoglycan expression during osteogenesis

Heparan sulfate proteoglycans (HSPGs) are complex and labile macromolecular moieties on the surfaces of cells that control the activities of a range of extracellular proteins, particularly those driving growth and regeneration. Here, we examine the biosynthesis of heparan sulfate (HS) sugars produced by cultured MC3T3-E1 mouse calvarial pre-osteoblast cells in order to explore the idea that changes in HS activity in turn drive phenotypic development during osteogenesis. Cells grown for 5 days under proliferating conditions were compared to cells grown for 20 days under mineralizing conditions with respect to their phenotype, the forms of HS core protein produced, and their HS sulfotransferase biosynthetic enzyme levels. RQ-PCR data was supported by the results from the purification of day 5 and day 20 HS forms by anionic exchange chromatography. The data show that cells in active growth phases produce more complex forms of sugar than cells that have become relatively quiescent during active mineralization, and that these in turn can differentially influence rates of cell growth when added exogenously back to preosteoblasts.

The osteogenic transcription factor Runx2 regulates components of the fibroblast growth factor/proteoglycan signaling axis in osteoblasts

Heparan sulfate proteoglycans cooperate with basic fibroblast growth factor (bFGF/FGF2) signaling to control osteoblast growth and differentiation, as well as metabolic functions of osteoblasts. FGF2 signaling modulates the expression and activity of Runt-related transcription factor 2 (Runx2/Cbfa1), a key regulator of osteoblast proliferation and maturation. Here, we have characterized novel Runx2 target genes in osteoprogenitors under conditions that promote growth arrest while not yet permitting sustained phenotypic maturation. Runx2 enhances expression of genes related to proteoglycan-mediated signaling, including FGF receptors (e.g., FGFR2 and FGFR3) and proteoglycans (e.g., syndecans [Sdc1, Sdc2, Sdc3], glypicans [Gpc1], versican [Vcan]). Runx2 increases expression of the glycosyltransferase Exostosin-1 (Ext1) and heparanase, as well as alters the relative expression of N-linked sulfotransferases (Ndst1 = Ndst2 > Ndst3) and enzymes mediating O-linked sulfation of heparan sulfate (Hs2st > Hs6st) or chondroitin sulfate (Cs4st > Cs6st). Runx2 cooperates with FGF2 to induce expression of Sdc4 and the sulfatase Galns, but Runx2 and FGF2 suppress Gpc6, thus suggesting intricate Runx2 and FGF2 dependent changes in proteoglycan utilization. One functional consequence of Runx2 mediated modulations in proteoglycan-related gene expression is a change in the responsiveness of bone markers to FGF2 stimulation. Runx2 and FGF2 synergistically enhance osteopontin expression (>100 fold), while FGF2 blocks Runx2 induction of alkaline phosphatase. Our data suggest that Runx2 and the FGF/proteoglycan axis may form an extracellular matrix (ECM)-related regulatory feed-back loop that controls osteoblast proliferation and execution of the osteogenic program.

Built to last or meant to end : intertemporal choice in strategic alliance portfolios

A salient but rarely explicitly studied characteristic of interfirm relationships is that they can intentionally be formed for finite periods of time. What determines firms' intertemporal choices between different alliance time horizons? Shadow of the future theorists suggest that when an alliance has an explicitly set short-term time frame, there is an increased risk that partners may behave opportunistically. This does not readily explain the high incidence of time-bound alliances being formed. Reconciling insights from the shadow of the future perspective with nascent research on the flexibility of temporary organizations, and shifting the focus from the level of individual transactions to that of strategic alliance portfolios, we argue that firms may be willing to accept a higher risk of opportunism when there are offsetting gains in strategic flexibility in managing their strategic alliance portfolio. Consequently, we hypothesize that environmental factors that increase the need for strategic flexibility—namely, dynamism and complexity in the environment—are likely to increase the relative share of time-bound alliances in strategic alliance portfolios. Our analysis of longitudinal data on the intertemporal alliance choices of a large sample of small and medium-sized enterprises provides support for this argument. Our findings fill an important gap in theory about time horizons in interfirm relationships and temporary organizations and show the importance of separating planned terminations from duration-based performance measures.

Pilot plant studies of ion exchange for desalination of coal seam gas produced water

This paper reports a study of ion exchange (IX) as an alternative CSG water treatment to the widely used reverse osmosis (RO) desalination process. An IX pilot plant facility has been constructed and operated using both synthetic and real CSG water samples. Application of appropriate synthetic resin technology has proved the effectiveness of IX processes.

Analysis of steel structures for first- and second-order element (displacement and force) solutions

Finite element method (FEM) relies on an approximate function to fit into a governing equation and minimizes the residual error in the integral sense in order to generate solutions for the boundary value problems (nodal solutions). Because of this FEM does not show simultaneous capacities for accurate displacement and force solutions at node and along an element, especially when under the element loads, which is of much ubiquity. If the displacement and force solutions are strictly confined to an element’s or member’s ends (nodal response), the structural safety along an element (member) is inevitably ignored, which can definitely hinder the design of a structure for both serviceability and ultimate limit states. Although the continuous element deflection and force solutions can be transformed into the discrete nodal solutions by mesh refinement of an element (member), this setback can also hinder the effective and efficient structural assessment as well as the whole-domain accuracy for structural safety of a structure. To this end, this paper presents an effective, robust, applicable and innovative approach to generate accurate nodal and element solutions in both fields of displacement and force, in which the salient and unique features embodies its versatility in applications for the structures to account for the accurate linear and second-order elastic displacement and force solutions along an element continuously as well as at its nodes. The significance of this paper is on shifting the nodal responses (robust global system analysis) into both nodal and element responses (sophisticated element formulation).

Recursive pathways to marginal likelihood estimation with prior-sensitivity analysis

We investigate the utility to computational Bayesian analyses of a particular family of recursive marginal likelihood estimators characterized by the (equivalent) algorithms known as "biased sampling" or "reverse logistic regression" in the statistics literature and "the density of states" in physics. Through a pair of numerical examples (including mixture modeling of the well-known galaxy dataset) we highlight the remarkable diversity of sampling schemes amenable to such recursive normalization, as well as the notable efficiency of the resulting pseudo-mixture distributions for gauging prior-sensitivity in the Bayesian model selection context. Our key theoretical contributions are to introduce a novel heuristic ("thermodynamic integration via importance sampling") for qualifying the role of the bridging sequence in this procedure, and to reveal various connections between these recursive estimators and the nested sampling technique.

Structural abstraction of process specifications

Software engineers constantly deal with problems of designing, analyzing, and improving process specifications, e.g., source code, service compositions, or process models. Process specifications are abstractions of behavior observed or intended to be implemented in reality which result from creative engineering practice. Usually, process specifications are formalized as directed graphs in which edges capture temporal relations between decisions, synchronization points, and work activities. Every process specification is a compromise between two points: On the one hand engineers strive to operate with less modeling constructs which conceal irrelevant details, while on the other hand the details are required to achieve the desired level of customization for envisioned process scenarios. In our research, we approach the problem of varying abstraction levels of process specifications. Formally, developed abstraction mechanisms exploit the structure of a process specification and allow the generalization of low-level details into concepts of a higher abstraction level. The reverse procedure can be addressed as process specialization.