Housing supply chain model for innovation: research report

The aim of this research is to undertake a case study analysis of successful delivery of an innovation to the Australian housing construction industry. This study is conducted on the “innovator group”; that is, the group that created the idea of an innovation for the housing sector and then were intimately involved in creation, development and diffusion. It is apparent that there were key players involved in this process which are representative of various organisations along the supply chain – designer, developer, subcontractor and supplier. Much rhetoric states that integration of the supply chain actors will solve construction problems, however, in reality we know little beyond this in the Australian context as there has been little research conducted previously. This study will examine in detail the process undertaken by this particular group to deliver an innovation to the housing sector which required an integrated construction supply chain model. This report was published by the Australian Housing Supply Chain Alliance and written by Professor Kerry London, School of Property, Construction and Project Management, RMIT University with Research Fellow, Jessica Siva

Client managment on house projects : faciliating client learning for successful architect-client relationships

This paper reports the findings of a study which examined architect-client relationships on house projects with a focus on the supportive role of architects in helping clients deal with project issues. Habitus theory explains that the nature of architecture as a specialised activity places architects within an architectural habitus, distinguishing them from clients who are not trained in the field, which is at the heart of the problematic architect-client relationship. An underlying premise was that habitus shock, that is, a mismatch between the architect and client\u27s habituses Occurs as they enter into a relationship on the house project. Using the qualitative approach underpinned by the constructivist perspective for data collection and analysis, eight in-depth interviews were conducted across five case studies of successful architect-client relationships. The narrative inquiry approach was used to establish the extent to which habitus shock occurred and to describe the stages involved in the client\u27s adjustment process during habitus shock. The findings indicate that habitus shock occurred on all five case studies, which resulted in client learning, enabling clients to function with competency in the unfamiliar environment. Client learning achieved during habitus shock was directly linked to the amount of difficulty experienced. This study has refined our understanding of the architect-client relationship on house projects by exploring more deeply client behaviour and the ways in which clients successfully deal with difficulties on house projects rather than simply identifying the uncertainties and conflicts that occur on projects. The findings demonstrate that client learning during habitus shock is a characteristic of successful relationships. One of the most significant outcomes of thi s study is that it demonstrated the potential to facilitate client learning during habitus shock to contribute to the development of successful architect-client relationships.<br /

Habitus shock : a model for architect-client relationships on house projects based on sociological and psychological perspectives

The widening gap between architects and clients and the associated problems in the management of their relationship have long been recognised by practitioners and researchers alike. An emerging trend in recent studies is to develop descriptive models to describe behavioural characteristics of relationships based on observations of \u27 real world\u27 practice, indicating the significance of understanding the complexities of the social environment in which the architect-client relationship is within. This research built upon the work of past descriptive models by exploring the architect-client relationship on house projects with a focus on the client\u27s voice. It is an interdisciplinary study drawing theory from sociology to further understand this built environment industry problem. Sixty-nine percent of architects in Australia spend some of their work time on house projects and therefore improvements in this area can have significant impact on a considerably large portion of the profession. Habitus theory borrowed from sociology explains that the nature of architecture as a specialised activity places architects within an architectural habitus, distinguishing them from clients who are .not trained in the field. An underlying premise of thi s study is that a mismatch between the architect and client\u27s habituses occurs as they enter into a relationship on the house project. This phenomenon is termed habitus shock, referring to the client \u27s experience of disorientation as they are confronted with an unfamiliar architectural habitus on the project. Culture shock theory is examined for its contribution to explain the process to which the client adjusts to the unfamiliar environment during habitus shock. The habitus shock model proposed in this paper suggests that the client may achieve learning during habitus shock and it is this client learning that can lead to successful relationships.<br /

A Bitter Taste Receptor as a Novel Molecular Target on Cancer-Associated Fibroblasts in Pancreatic Ductal Adenocarcinoma

Cancer-associated fibroblasts (CAFs) execute diverse and complex functions in cancer progression. While reprogramming the crosstalk between CAFs and cancer epithelial cells is a promising avenue to evade the adverse effects of stromal depletion, drugs are limited by their suboptimal pharmacokinetics and off-target effects. Thus, there is a need to elucidate CAF-selective cell surface markers that can improve drug delivery and efficacy. Here, functional proteomic pulldown with mass spectrometry was used to identify taste receptor type 2 member 9 (TAS2R9) as a CAF target. TAS2R9 target characterization included binding assays, immunofluorescence, flow cytometry, and database mining. Liposomes conjugated to a TAS2R9-specific peptide were generated, characterized, and compared to naked liposomes in a murine pancreatic xenograft model. Proof-of-concept drug delivery experiments demonstrate that TAS2R9-targeted liposomes bind with high specificity to TAS2R9 recombinant protein and exhibit stromal colocalization in a pancreatic cancer xenograft model. Furthermore, the delivery of a CXCR2 inhibitor by TAS2R9-targeted liposomes significantly reduced cancer cell proliferation and constrained tumor growth through the inhibition of the CXCL-CXCR2 axis. Taken together, TAS2R9 is a novel cell-surface CAF-selective target that can be leveraged to facilitate small-molecule drug delivery to CAFs, paving the way for new stromal therapies

The Aryl Hydrocarbon Receptor Mediates Leflunomide- Induced Growth Inhibition of Melanoma Cells

A novel role of the dihydroorotatedehydrogenase (DHODH) inhibitor leflunomide as a potential anti-melanoma therapy was recently reported (Nature 471: 518-22, 2011). We previously reported that leflunomide strongly activates the transcriptional activity of the Aryl Hydrocarbon Receptor (AhR). We therefore tested whether the AhR regulates the anti-proliferative effects of leflunomide in melanoma. We first evaluated the expression of AhR in melanoma cells and found that AhR is highly expressed in A375 melanoma as well as in several other cancer cell types. To evaluate whether AhR plays a role in regulating the growth inhibitory effects of leflunomide in A375 cells, we generated a stable cell line from parental A375 cells expressing a doxycycline (DOX) inducible AhR shRNA. Using these cells in the absence or presence of DOX (normal AhR levels or AhR-knockdown, respectively) we found that the anti-proliferative effects of leflunomide, but not its metabolite A771726, were strongly dependent upon AhR expression. It has been well established that supplementation of cells with exogenous uridine completely rescues the anti-proliferative effects due to DHODH inhibition. Thus, we performed uridine rescue experiments in A375 cells to determine whether the anti-proliferative effects of leflunomide are solely due to DHODH inhibition as previously reported. Interestingly, saturating levels of uridine only modestly rescued A375 cells from the anti-proliferative effects of both leflunomide and A771726, indicating additional mechanism(s), apart from DHODH inhibition are responsible for the anti-proliferative effects of leflunomide in melanoma cells. Uridine also did not rescue MDA-MB-435S melanoma cell proliferation after leflunomide treatment. Our results reveal that the AhR is a molecular target of leflunomide and support the feasibility of the clinical application of leflunomide for treating melanoma. Furthermore, analysis of expression data from 967 cancer cell lines revealed that AhR is expressed in multiple different cancer types supporting the intriguing possibility of targeting the AhR for therapy in a number of cancers

Benzimidazoisoquinolines: a new class of rapidly metabolized aryl hydrocarbon receptor (AhR) ligands that induce AhR-dependent Tregs and prevent murine graft-versus-host disease

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that plays multiple roles in regulation of immune and inflammatory responses. The ability of certain AhR ligands to induce regulatory T cells (Tregs) has generated interest in developing AhR ligands for therapeutic treatment of immune-mediated diseases. To this end, we designed a screen for novel Treg-inducing compounds based on our understanding of the mechanisms of Treg induction by the well-characterized immunosuppressive AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). We screened a ChemBridge small molecule library and identified 10-chloro-7H-benzimidazo[2,1-a]benzo[de]​Iso-quinolin-7-one(10-Cl-BBQ) as a potent AhR ligand that was rapidly metabolized and not cytotoxic to proliferating T cells. Like TCDD,10-Cl-BBQ altered donor CD4+ T cell differentiation during the early stages of a graft versus host (GVH) response resulting in expression of high levels of CD25, CTLA-4 and ICOS, as well as several genes associated with Treg function. The Treg phenotype required AhR expression in the donor CD4+ T cells. Foxp3 was not expressed in the AhR-induced Tregs implicating AhR as an independent transcription factor for Treg induction. Structure-activity studies showed that unsubstituted BBQ as well as 4, 11-dichloro-BBQ were capable of inducing AhR-Tregs. Other substitutions reduced activation of AhR. Daily treatment with 10-Cl-BBQ during the GVH response prevented development of GVH disease in an AhR-dependent manner with no overt toxicity. Together, our data provide strong support for development of select BBQs that activate the AhR to induce Tregs for treatment of immune-mediated diseases

A Randomized Controlled Evaluation of the Efficacy of an Ankle-Foot Cast on Walking Recovery Early After Stroke: SWIFT Cast Trial

Background. Timely provision of an ankle-foot orthosis (AFO) orthotist customized for individuals early after stroke can be problematic. Objective. To evaluate the efficacy of a therapist-made AFO (SWIFT Cast) for walking recovery. Methods.This was a randomized controlled, observer-blind trial. Participants (n = 105) were recruited 3 to 42 days poststroke.All received conventional physical therapy (CPT) that included use of “off-the-shelf” and orthotist-made AFOs. People allocated to the experimental group also received a SWIFT Cast for up to 6 weeks. Measures were undertaken before randomization, 6 weeks thereafter (outcome), and at 6 months after stroke (follow-up). The primary measure was walking speed. Clinical efficacy evaluation used analysis of covariance. Results. Use of a SWIFT Cast during CPT sessions wassignificantly higher (P < .001) for the SWIFT Cast (55%) than the CPT group (3%). The CPT group used an AFO in 26% of CPT sessions, compared with 11% for the SWIFT Cast group (P = .005). At outcome, walking speed was 0.42 (standard deviation [SD] = 0.37) m/s for the CPT group and 0.32 (SD = 0.34) m/s for the SWIFT Cast group. Follow-up walking speed was 0.53 (SD = 0.38) m/s for the CPT group and 0.43 (0.34) m/s for the SWIFT Cast group. Differences, after accounting for minimization factors, were insignificant at outcome (P = .345) and follow-up (P = .360). Conclusion and implications.SWIFT Cast did not enhance the benefit of CPT, but the control group had greater use of another AFO. However, SWIFT Cast remains a clinical option because it is low cost and custom-made by therapists who can readily adapt it during the rehabilitation period

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p&lt;0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (&lt;1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (&lt;1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Relatório de estágio em farmácia comunitária

Relatório de estágio realizado no âmbito do Mestrado Integrado em Ciências Farmacêuticas, apresentado à Faculdade de Farmácia da Universidade de Coimbr