IL-18 inhibits growth of murine orthotopic prostate carcinomas via both adaptive and innate immune mechanisms

Interleukin(IL)-18 is a pleiotrophic cytokine with functions in immune modulation, angiogenesis and bone metabolism. In this study, the potential of IL-18 as an immunotherapy for prostate cancer (PCa) was examined using the murine model of prostate carcinoma, RM1 and a bone metastatic variant RM1(BM)/B4H7-luc. RM1 and RM1(BM)/B4H7-luc cells were stably transfected to express bioactive IL-18. These cells were implanted into syngeneic immunocompetent mice, with or without an IL-18-neutralising antibody (αIL-18, SK113AE4). IL-18 significantly inhibited the growth of both subcutaneous and orthotopic RM1 tumors and the IL-18 neutralizing antibody abrogated the tumor growth-inhibition. In vivo neutralization of interferon-gamma (IFN-γ) completely eliminated the anti-tumor effects of IL-18 confirming an essential role of IFN-γ as a down-stream mediator of the anti-tumor activity of IL-18. Tumors from mice in which IL-18 and/or IFN-γ was neutralized contained significantly fewer CD4+ and CD8+ T cells than those with functional IL-18. The essential role of adaptive immunity was demonstrated as tumors grew more rapidly in RAG1−/− mice or in mice depleted of CD4+ and/or CD8+ cells than in normal mice. The tumors in RAG1−/− mice were also significantly smaller when IL-18 was present, indicating that innate immune mechanisms are involved. IL-18 also induced an increase in tumor infiltration of macrophages and neutrophils but not NK cells. In other experiments, direct injection of recombinant IL-18 into established tumors also inhibited tumor growth, which was associated with an increase in intratumoral macrophages, but not T cells. These results suggest that local IL-18 in the tumor environment can significantly potentiate anti-tumor immunity in the prostate and clearly demonstrate that this effect is mediated by innate and adaptive immune mechanisms.

Four years on – are the Gazelles still running? A longitudinal study of firm performance after a period of rapid growth

Gazelles, or very rapidly growing firms, are important because they contribute disproportionately to economic growth. There is a concern that some of these firms pursue growth too aggressively resulting in lower subsequent performance. We investigate the relationship between growth and subsequent profitability for gazelle firms, and how this is moderated by firm strategy. Previous empirical research regarding the growth-profitability relationship for firms in general is rather inconclusive, with only one study specifically investigating gazelle firms. Likewise, there are theoretical arguments both for and against growth leading to profitability that equally apply to gazelle firms. Further, while contingency theory might suggest the relationship depends on the firm’s strategy, earlier studies have not investigated this relationship. We address these questions using longitudinal data (seven years) for a sample of 964 Danish Gazelle firms. Our study finds a clear positive relationship between growth and subsequent profitability among gazelle firms. Moreover, this relationship is stronger for firms pursuing a broad market strategy rather than a focus or niche strategy. An important managerial implication is that the growth strategy should be clearly integrated with the general strategic orientation of the firm.

Behavioural changes add validity to the construct of posttraumatic growth

The research aimed to identify positive behavioural changes that people may make as a result of negotiating the aftermath of a traumatic experience, thereby extending the current cognitive model of posttraumatic growth (PTG). It was hypothesised that significant others would corroborate survivor’s cognitive and behavioural reports of PTG. The sample comprised 176 participants; 88 trauma survivors and 88 significant others. University students accounted for 64% of the sample and 36% were from the broader community. Approximately one third were male. All participants completed the Posttraumatic Growth Inventory [PTGI] and open ended questions regarding behavioural changes. PTGI scores in the survivor sample were corroborated by the significant others with only the Appreciation of Life factor of the PTGI differing between the two groups (e.g., total PTGI scores between groups explained 33.64% of variance). Nearly all of the survivors also reported positive changes in their behaviour and these changes were also corroborated by the significant others. Results provide validation of the posttraumatic growth construct and the PTGI as an instrument of measurement. Findings may also influence therapeutic practice for example, the potential usefulness of corroborating others.

Identification of vitronectin as a novel insulin-like growth factor-II binding protein

We have previously reported the presence of a 70 kDa insulin-like growth factor (IGF)-II-specific binding protein in chicken serum using Western ligand blotting approaches. In order to ascertain the identity of this 70 kDa IGF-II binding species, the protein has been purified from chicken serum using a combination of ion-exchange and gel-permeation chromatography. Interestingly, amino acid sequencing of the purified protein revealed that it has the same N-terminal sequence as chicken vitronectin (VN). The protein has the ability to specifically bind IGF-II and not IGF-I as determined by ligand blotting, cross-linking and competitive binding assay approaches. In addition, the protein binds 125I-des(l-6)-IGF-II, suggesting that the interaction with IGF-II is different to those with other characterized IGF-binding proteins. Importantly, we have ascertained that both human and bovine VN also specifically bind IGF-II. These results are particularly relevant in the light of the recent report that the urokinase-type plasminogen activator receptor, a protein that also binds VN, has been shown to associate with the cation-independent mannose-6-phosphate/GF-II receptor and suggest a possible role for IGF-II in cell adhesion and invasion.

Growth-hormone-stimulated dentinogenesis in Lewis dwarf rat molars

In dentinogenesis, certain growth factors, matrix proteoglycans, and proteins are directly or indirectly dependent on growth hormone. The hypothesis that growth hormone up-regulates the expression of enzymes, sialoproteins, and other extracellular matrix proteins implicated in the formation and mineralization of tooth and bone matrices was tested by the treatment of Lewis dwarf rats with growth hormone over 5 days. The molar teeth were processed for immunohistochemical demonstration of bone-alkaline phosphatase, bone morphogenetic proteins-2 and -4, osteocalcin, osteopontin, bone sialoprotein, and E11 protein. Odontoblasts responded to growth hormone by more cells expressing bone morphogenetic protein, alkaline phosphatase, osteocalcin, and osteopontin. No changes were found in bone sialoprotein or E11 protein expression. Thus, growth hormone may stimulate odontoblasts to express several growth factors and matrix proteins associated with dentin matrix biosynthesis in mature rat molars.

Fibroblast growth factor receptor inhibition synergizes with paclitaxel and doxorubicin in endometrial cancer cells

OBJECTIVE: The fibroblast growth factor (FGF) family of signaling molecules has been associated with chemoresistance and poor prognosis in a number of cancer types, including lung, breast, ovarian, prostate, and head and neck carcinomas. Given the identification of activating mutations in the FGF receptor 2 (FGFR2) receptor tyrosine kinase in a subset of endometrial tumors, agents with activity against FGFRs are currently being tested in clinical trials for recurrent and progressive endometrial cancer. Here, we evaluated the effect of FGFR inhibition on the in vitro efficacy of chemotherapy in endometrial cancer cell lines. METHODS: Human endometrial cancer cell lines with wild-type or activating FGFR2 mutations were used to determine any synergism with concurrent use of the pan-FGFR inhibitor, PD173074, and the chemotherapeutics, doxorubicin and paclitaxel, on cell proliferation and apoptosis. RESULTS: FGFR2 mutation status did not alter sensitivity to either chemotherapeutic agent alone. The combination of PD173074 with paclitaxel or doxorubicin showed synergistic activity in the 3 FGFR2 mutant cell lines evaluated. In addition, although nonmutant cell lines were resistant to FGFR inhibition alone, the addition of PD173074 potentiated the cytostatic effect of paclitaxel and doxorubicin in a subset of FGFR2 wild-type endometrial cancer cell lines. CONCLUSIONS: Together these data suggest a potential therapeutic benefit to combining an FGFR inhibitor with standard chemotherapeutic agents in endometrial cancer therapy particularly in patients with FGFR2 mutation positive tumors.

Integrated sustainable urban infrastructure management : the Brisbane urban growth model

Sustainable urban development and the liveability of a city are increasingly important issues in the context of land use planning and infrastructure management. In recent years, the promotion of sustainable urban development in Australia and overseas is facing various physical, socioeconomic and environmental challenges. These challenges and problems arise from the lack of capability of local governments to accommodate the needs of the population and economy in a relatively short timeframe. The planning of economic growth and development is often dealt with separately and not included in the conventional land use planning process. There is also a sharp rise in the responsibilities and roles of local government for infrastructure planning and management. This increase in responsibilities means that local elected officials and urban planners have less time to prepare background information and make decisions. The Brisbane Urban Growth Model has proven initially successful in providing a dynamic platform to ensure timely and coordinated delivery of urban infrastructure. Most importantly, this model is the first step for local governments in moving toward a systematic approach to pursuing sustainable and effective urban infrastructure management.