Mycobacteria activate γδ T-cell anti-tumour responses via cytokines from type 1 myeloid dendritic cells: a mechanism of action for cancer immunotherapy

Attenuated and heat-killed mycobacteria display demonstrable activity against cancer in the clinic; however, the induced immune response is poorly characterised and potential biomarkers of response ill-defined. We investigated whether three mycobacterial preparations currently used in the clinic (BCG and heat-killed Mycobacterium vaccae and Mycobacterium obuense) can stimulate anti-tumour effector responses in human γδ T-cells. γδ T-cell responses were characterised by measuring cytokine production, expression of granzyme B and cytotoxicity against tumour target cells. Results show that γδ T-cells are activated by these mycobacterial preparations, as indicated by upregulation of activation marker expression and proliferation. Activated γδ T-cells display enhanced effector responses, as shown by upregulated granzyme B expression, production of the TH1 cytokines IFN-γ and TNF-α, and enhanced degranulation in response to susceptible and zoledronic acid-treated resistant tumour cells. Moreover, γδ T-cell activation is induced by IL-12, IL-1β and TNF-α from circulating type 1 myeloid dendritic cells (DCs), but not from type 2 myeloid DCs or plasmacytoid DCs. Taken together, we show that BCG, M. vaccae and M. obuense induce γδ T-cell anti-tumour effector responses indirectly via a specific subset of circulating DCs and suggest a mechanism for the potential immunotherapeutic effects of BCG, M. vaccae and M. obuense in cancer

Beyond equilibrium climate sensitivity

ISSN:1752-0908ISSN:1752-089

Asymmetry and duration dependence in Australian GDP and unemployment

The per iodic structure of business cycles suggests that significant asymmetries are present over different phases of the cycle. This paper uses markov regime-switching models with fixed and duration dependent transition probabilities to directly model expansions, contractions and durations in Australian GDP growth and unemployment growth. Evidence is found of significant asymmetry in growth rates across expansions and contractions for both series. GDP contractions exhibit duration dependence implying that as output recessions age the likelihood of switching into an expansion phase increases. Unemployment growth does not exhibit duration dependence in either phase. Evidence is also presented that non-linearities in unemployment growth are well explained by the asymmetries in the GDP growth cycle. The analysis suggests that recessions are periods of rapid and intense job destruction, that Australian unemployment tends to ratchet up in recessionary periods and, in contrast to US and UK studies, that shocks to Australian unemployment growth are more persistent in recessions than expansions. [E37 C5 C41]

Steepness and deepness in the Australian macroeconomy

This study uses nonparametric tests - the triples test and the BDS test, to examine whether key Australian macroeconomic aggregates exhibit nonlinearities and important 'steepness' and 'deepness' asymmetries at the business cycle frequency. Evidence is found of nonlinearities but there is little evidence of deepness in the Australian macroeconomy. However, there is evidence of steepness, especially concerning labour market variables, as well as both the CPI and M3. The evidence suggests that unemployment (employment) rises (falls) rapidly in recessions and only recovers slowly over time. Also, positive asymmetries in M3 are reflected in similar asymmetries in the CPI but not in output, consumption or investment

Phases of the Canadian business cycle

In this paper we contrast a number of univariate models of Canadian GDP. Our preferred models are used to provide a business cycle chronology for Canada, which is compared with some existing, more judgmentally determined chronologies. We find that a simple, 'two quarters of negative growth' rule for determining recession dates is the mast similar to our chronology. We also find that the mast recent recession in Canada was unique in both its length and the slow speed of recovery. JEL Classification: C22, C51, C52, E32

Are health expenditures and GDP characterized by asymmetric behaviour? Evidence from 11 OECD countries

In this article, we examine whether per-capita health expenditures and per-capita GDP for 11 OECD countries can be characterized by asymmetric behaviour. We achieve this goal by using the nonparametric Triples test suggested by Randles et al. (1980). We examine two forms of asymmetries, namely deepness and steepness. Our main finding is that for 6 out of 11 countries, namely for the USA, the UK, Japan, Spain, Finland and Iceland, either per-capita health expenditures or per-capita GDP are characterized by asymmetric behaviour. This finding to some extent casts doubt on those studies that model the relationship between health and GDP using unit-root and cointegration tests that assume symmetric disturbances.

Refining global warming projections

Accurately determining the warming associated with scenarios of greenhouse gas emissions remains an overarching aim of climate modelling. Research now shows that contemporary measurements significantly reduce uncertainty bounds and indicate that some more extreme warming predictions may be less likel

Chemokine expression by subchondral bone marrow stromal cells isolated from osteoarthritis (OA) and rheumatoid arthritis (RA) patients

We analysed the spontaneous and cytokine-stimulated production and expression in vitro of IL-8, GROα, MCP-1, RANTES, MIP-1α, MIP-1β, by subchondral bone marrow stromal cells (BMSC) isolated from RA, OA, post-traumatic (PT) patients and normal donors (ND). BMSC were cultured in vitro in the presence or absence of IL-1β and tumour necrosis factor-alpha (TNF-α), and assessed for chemokine production, expression and immunolocalization. BMSC from different sources constitutively released MCP-1, GROα and IL-8, but not MIP-1α or MIP-1β, while BMSC from ND constitutively released only IL-8 and MCP-1. IL-8, GROα and RANTES production in basal conditions was significantly higher in RA patients than in ND. RANTES production was also higher in OA and RA than in PT patients. The combination of TNF-α and IL-1β synergistically increased the production of all chemokines tested except for RANTES. Reverse transcriptase-polymerase chain reaction (RT-PCR) demonstrated that all chemokines not detectable in the supernatants were expressed at the mRNA level. Chemokine immunostaining was localized around the nuclei. This work demonstrates that BMSC from subchondral bone produce chemokines and indicates that these cells could actively participate in the mechanisms directly or indirectly causing cartilage destruction and bone remodelling