Genetic basis for the increased expression of vacuolar H+ translocating ATPase genes upon imatinib treatment in human lymphoblastoid cells

Purpose The role of v-ATPases in cancer biology is being increasingly recognized. Yeast studies indicate that the tyrosine kinase inhibitor imatinib may interact with the v-ATPase genes and alter the course of cancer progression. Data from humans in this regard are lacking.

Methods We constructed 55 lymphoblastoid cell lines from pedigreed, cancer-free human subjects and treated them with IC20 concentration of imatinib mesylate. Using these cell lines, we (i) estimated the heritability and differential expression of 19 genes encoding several subunits of the v-ATPase protein in response to imatinib treatment; (ii) estimated the genetic similarity among these genes; and (iii) conducted a high-density scan to find cis-regulating genetic variation associated with differential expression of these genes.

Results We found that the imatinib response of the genes encoding v-ATPase subunits is significantly heritable and can be clustered to identify novel drug targets in imatinib therapy. Further, five of these genes were significantly cis-regulated and together represented nearly half-log fold change in response to imatinib (p = 0.0107) that was homogenous (p = 0.2598).

Conclusions Our results proffer support to the growing view that personalized regimens using proton pump inhibitors or v-ATPase inhibitors may improve outcomes of imatinib therapy in various cancers.

Training postgraduate psychology students to deliver psychological services online

Information and communication technologies are increasingly being used to remotely deliver psychological services. This delivery method confers clear advantages to both client and therapist, including the accessibility of services by otherwise unserved populations and cost-effective treatment. Remote services can be delivered in a real-time or delayed manner, providing clients with a wealth of therapy options not previously available. The proliferation of these services has outstripped the development and implementation of all but the most rudimentary of regulatory frameworks, potentially exposing clients to substandard psychological services. Integrating mandatory training on the delivery of online psychological services into accredited postgraduate psychology courses would aid in addressing this issue. The purpose of this article is to outline issues of consideration in the development and implementation of such a training programme. An online etherapy training programme developed by Swinburne University's National eTherapy Centre will be used as an example throughout.

The more things change, the more they stay the same : the 2012 alternative film/video festival

The Alternative Film/Video Festival in Belgrade has historically been one of a triumvirate of critical festivals, with Pula’s MAFAF (1965-1990) and Zagreb’s initiating GEFF (1963-70), servicing experimental, exploratory, avant-garde, personal film in the former Yugoslavia, at Belgrade’s Academic Film Center (AFC) within the Student City Cultural Centre (DKSG). Initiated in 1982 it was resurrected in 2003 with a dual regional and international focus after a hiatus due to the collapse of the socialist states of the former Yugoslavia. As well as a series of curated and retrospective programs each competition program is now split into international and regional halves, selected by Greg de Cuir and Zoran Saveski with production support by Milan Milosavljević. Two film workshops were also available. One on scratch film by Ivan Ladislav Galeta, the other on filming and processing led by Vassily Bourakis. Initiated by de Cuir the first Alternative Film/Video Research Forum was part of the festival this year bringing together research on alternative/ experimental/ avant-garde/ underground film and video. Although I participated in this side-bar I will concentrate here more on discussions from the festival roundtable and contextualise a small number of films, a couple from competition but mainly regional work that I would find difficult to encounter without attendance here.

Direct observation of the intergallery expansion of polystyrene–montmorillonite nanocomposites

The intergallery expansion development of a series of differently modified montmorillonite polystyrene nanocomposites was directly observed with time-resolved in situ small-angle X-ray scattering (SAXS) using synchrotron radiation. The results indicated that the interlayer expansion varied depending on the clay modification and the chemical compatibility of the clay modifiers with the styrene monomer. The influence of the differently modified clays on the free radical polymerization was also investigated, particularly the effect on the conversion of styrene and molecular weight evolution of the polymer. On the basis of the kinetic study of the polymerization of styrene in the presence of varied modified clay particles, the intergallery expansion mechanism was postulated and discussed for different composite morphologies. Such studies provide an important guideline for the design of clay modifiers and development of clay–polymer nanocomposites.

Implementation salvage experiences from the Melbourne diabetes prevention study

Background Many public health interventions based on apparently sound evidence from randomised controlled trials encounter difficulties when being scaled up within health systems. Even under the best of circumstances, implementation is exceedingly difficult. In this paper we will describe the implementation salvage experiences from the Melbourne Diabetes Prevention Study, which is a randomised controlled trial of the effectiveness and cost-effectiveness nested in the state-wide Life! Taking Action on Diabetes program in Victoria, Australia.

Discussion The Melbourne Diabetes Prevention Study sits within an evolving larger scale implementation project, the Life! program. Changes that occurred during the roll-out of that program had a direct impact on the process of conducting this trial. The issues and methods of recovery the study team encountered were conceptualised using an implementation salvage strategies framework. The specific issues the study team came across included continuity of the state funding for Life! program and structural changes to the Life! program which consisted of adjustments to eligibility criteria, referral processes, structure and content, as well as alternative program delivery for different population groups. Staff turnover, recruitment problems, setting and venue concerns, availability of potential participants and participant characteristics were also identified as evaluation roadblocks. Each issue and corresponding salvage strategy is presented.

Summary The experiences of conducting such a novel trial as the preliminary Melbourne Diabetes Prevention Study have been invaluable. The lessons learnt and knowledge gained will inform the future execution of this trial in the coming years. We anticipate that these results will also be beneficial to other researchers conducting similar trials in the public health field. We recommend that researchers openly share their experiences, barriers and challenges when conducting randomised controlled trials and implementation research. We encourage them to describe the factors that may have inhibited or enhanced the desired outcomes so that the academic community can learn and expand the research foundation of implementation salvage.

The role of lipogenesis in the development of obesity and diabetes in Israeli sand rats (Psammomys obesus)

Obesity and diabetes in Israeli sand rats, Psammomys obesus, occur with the sequential transition of animals from normal insulin sensitivity to impaired insulin sensitivity, accompanied by increased adiposity, prior to insulin resistance and obesity, in a manner similar to susceptible human populations. The current study was designed to examine the role of de novo lipid synthesis in the development of excessive weight gain in P. obesus. Sand rats were classified at 12 wk of age into three groups: A, normoglycemic normoinsulinemic; B, normoglycemic hyperinsulinemic; C, hyperglycemic hyperinsulinemic, based on glucose and insulin responses in fed sand rats. Body weight, liver weight, white adipose tissue (WAT) mass and food intake were significantly elevated in Group C compared to Group A (P < 0.05). Lipogenic rate was measured by the amount of 3H incorporated into subscapular brown adipose tissue (BAT), epidiymal WAT and liver per hour, from sand rats with and without access to food. No difference in lipogenic rate was found between the groups in BAT, indicating that this tissue is of minor importance in whole body lipogenesis in P. obesus. In the WAT there was a greater lipogenic rate with the development of obesity and hyperinsulinemia (Group B vs. Group A) but no difference in the liver. However, the onset of hyperglycemia (Group C) further stimulated WAT lipogenesis and initiated increased hepatic lipogenesis, both of which contributed to the pre-existing obesity. This study suggests that elevated lipogenesis is not the primary cause of obesity in P. obesus, as lipogenic rate only markedly increases after obesity is already present in hyperglycemic animals.

Leptin and the development of obesity and diabetes in Psammomys obesus

The recently discovered ob gene and its circulating product, leptin, may be critical factors in the control of energy balance. Recent studies in ob/ob mice, which lack circulating leptin, have shown dramatic reductions in food intake and bodyweight after leptin treatment. In addition, studies in both humans with obesity and animal models of obesity have demonstrated hyperleptinemia. Here, we report a longitudinal study examining changes in circulating leptin during the development of obesity and diabetes in Psammomys obesus. Over the 8 weeks of the study, lean animals increased their bodyweight by 154% and leptin levels remained essentially unchanged. In contrast, animals that developed obesity (223 % increase in bodyweight), hyperglycemia, and hyperinsulinemia also developed hyperleptinemia between 4 weeks and 8 weeks of age. These results demonstrate that the development of hyperleptinemia is associated with the development of obesity and subsequent metabolic abnormalities.

Cigarette smoke-induced changes to alveolar macrophage phenotype and function are improved by treatment with procysteine

Defective efferocytosis may perpetuate inflammation in smokers with or without chronic obstructive pulmonary disease (COPD). Macrophages may phenotypically polarize to classically activated M1 (proinflammatory; regulation of antigen presentation) or alternatively activated M2 (poor antigen presentation; improved efferocytosis) markers. In bronchoalveolar lavage (BAL)–derived macrophages from control subjects and smoker/ex-smoker COPD subjects, we investigated M1 markers (antigen-presenting major histocompatibility complex [MHC] Classes I and II), complement receptors (CRs), the high-affinity Fc receptor involved with immunoglobulin binding for phagocytosis (Fc-gamma receptor, FcγR1), M2 markers (dendritic cell–specific intercellular adhesion molecule-grabbing nonintegrin [DC-SIGN] and arginase), and macrophage function (efferocytosis and proinflammatory cytokine production in response to LPS). The availability of glutathione (GSH) in BAL was assessed, because GSH is essential for both M1 function and efferocytosis. We used a murine model to investigate macrophage phenotype/function further in response to cigarette smoke. In lung tissue (disaggregated) and BAL, we investigated CRs, the available GSH, arginase, and efferocytosis. We further investigated the therapeutic effects of an oral administration of a GSH precursor, cysteine l-2-oxothiazolidine-4-carboxylic acid (procysteine). Significantly decreased efferocytosis, available GSH, and M1 antigen–presenting molecules were evident in both COPD groups, with increased DC-SIGN and production of proinflammatory cytokines. Increased CR-3 was evident in the current-smoker COPD group. In smoke-exposed mice, we found decreased efferocytosis (BAL and tissue) and available GSH, and increased arginase, CR-3, and CR-4. Treatment with procysteine significantly increased GSH, efferocytosis (BAL: control group, 26.2%; smoke-exposed group, 17.66%; procysteine + smoke-exposed group, 27.8%; tissue: control group, 35.9%; smoke-exposed group, 21.6%; procysteine + smoke-exposed group, 34.5%), and decreased CR-4 in lung tissue. Macrophages in COPD are of a mixed phenotype and function. The increased efferocytosis and availability of GSH in response to procysteine indicates that this treatment may be useful as adjunct therapy for improving macrophage function in COPD and in susceptible smokers.

Offshoring of IT services : survey of literature and research agenda

Although international outsourcing or offshoring of information technology services by advanced industrialised countries from less developed countries is a relatively new phenomenon, a plethora of research exists on the subject. And, given the multidisciplinary nature of the subject, the literature on offshoring is often disparate and subject to confusion. This paper surveys the developments in the empirical literature on offshoring over the 1992-2007 period and identifies potential areas for future research. The main findings are that while the intensity of research on the subject has increased rapidly over a short period of time, research efforts to date have focussed mostly on offshoring decision and offshoring management particularly from the perspective of the offshorer. Future research opportunities exist in the area of offshoring strategy and performance relationship, the behaviour and performance of offshore service providers particularly within the context of firms from less developed countries competing globally, and the nature of competition among offshore service providers both within and among countries.