Adenosine mediates functional and metabolic suppression of peripheral and tumor-infiltrating CD8⁺ T cells.

Several mechanisms are present in the tumor microenvironment (TME) to impair cytotoxic T cell responses potentially able to control tumor growth. Among these, the accumulation of adenosine (Ado) contributes to tumor progression and represents a promising immunotherapeutic target. Ado has been shown to impair T cell effector function, but the role and mechanisms employed by Ado/Ado receptors (AdoRs) in modulating human peripheral and tumor-infiltrating lymphocyte (TIL) function are still puzzling. CD8 <sup>+</sup> T cell cytokine production following stimulation was quantified by intracellular staining and flow cytometry. The cytotoxic capacity of tumor infiltrating lymphocytes (TILs) was quantified by the chromium release assay following co-culture with autologous or anti-CD3-loaded tumor cell lines. The CD8 <sup>+</sup> T cell metabolic fitness was evaluated by the seahorse assay and by the quantification of 2-NBDG uptake and CD71/CD98 upregulation upon stimulation. The expression of AdoRs was assessed by RNA flow cytometry, a recently developed technology that we validated by semiquantitative RT-PCR (qRT-PCR), while the impact on T cell function was evaluated by the use of selective antagonists and agonists. The influence of Ado/AdoR on the PKA and mTOR pathways was evaluated by phosphoflow staining of p-CREB and p-S6, respectively, and validated by western blot. Here, we demonstrate that Ado signaling through the A2A receptor (A2AR) in human peripheral CD8 <sup>+</sup> T cells and TILs is responsible for the higher sensitivity to Ado-mediated suppression of T central memory cells. We confirmed that Ado is able to impair peripheral and tumor-expanded T cell effector functions, and we show for the first time its impact on metabolic fitness. The Ado-mediated immunosuppressive effects are mediated by increased PKA activation that results in impairment of the mTORC1 pathway. Our findings unveil A2AR/PKA/mTORC1 as the main Ado signaling pathway impairing the immune competence of peripheral T cells and TILs. Thus, p-CREB and p-S6 may represent useful pharmacodynamic and efficacy biomarkers of immunotherapies targeting Ado. The effect of Ado on T cell metabolic fitness reinforces the importance of the adenosinergic pathway as a target for next-generation immunotherapy

50-Gy Stereotactic Body Radiation Therapy to the Dominant Intraprostatic Nodule: Results From a Phase 1a/b Trial.

Although localized prostate cancer (PCa) is multifocal, the dominant intraprostatic nodule (DIN) is responsible for disease progression after radiation therapy. PCa expresses antigens that could be recognized by the immune system. We therefore hypothesized that stereotactic dose escalation to the DIN is safe, may increase local control, and may initiate tumor-specific immune responses. Patients with localized PCa were treated with stereotactic extreme hypofractionated doses of 36.25 Gy in 5 fractions to the whole prostate while simultaneously escalating doses to the magnetic resonance image-visible DIN (45 Gy, 47.5 Gy, and 50 Gy in 5 fractions). The phase 1a part was designed to determine the recommended phase 1b dose in a "3 + 3" cohort-based, dose-escalation design. The primary endpoint was dose-limiting toxicities defined as ≥grade 3 gastrointestinal (GI) or genitourinary (GU) toxicity (or both) by National Cancer Institute Common Terminology Criteria for Adverse Events (version 4) up to 90 days after the first radiation fraction. The secondary endpoints were prostate-specific antigen kinetics, quality of life (QoL), and blood immunologic responses. Nine patients were treated in phase 1a. No dose-limiting toxicities were observed at either level, and therefore the maximum tolerated dose was not reached. Further characterization of tolerability, efficacy, and immunologic outcomes was conducted in the subsequent 11 patients irradiated at the highest dose level (50 Gy) in the phase 1b expansion cohort. Toxicity was 45% and 25% for grades 1 and 2 GU, and 20% and 5% for grades 1 and 2 GI, respectively. No grade 3 or worse toxicity was reported. The average (±standard error of the mean) of the QoL assessments at baseline and at 3-month posttreatment were 0.8 (±0.8) and 3.5 (±1.5) for the bowel (mean difference, 2.7; 95% confidence interval, 0.1-5), and 6.4 (±0.8) and 7.27 (±0.9) for the International Prostate Symptom Score (mean difference, 0.87; 95% confidence interval, 0.3-1.9), respectively. A subset of patients developed antigen-specific immune responses against prostate-specific membrane antigen (n = 2), prostatic acid phosphatase (n = 1), prostate stem cell antigen (n = 4), and prostate-specific antigen (n = 2). Irradiation of the whole prostate with 36.25 Gy in 5 fractions and dose escalation to 50 Gy to the DIN was tolerable and determined as the recommended phase 1b dose. This treatment has promising antitumor activity, which will be confirmed by the ongoing phase 2 part. Preliminary QoL analysis showed minimal impact in GU, GI, and sexual domains. Stereotactic irradiation induced antigen-specific immune responses in a subset of patients

Testing the hypothesis of long-run money neutrality in the Middle East

PURPOSE - The purpose of this paper is to test the hypothesis of long-run money neutrality for Egypt, Jordan and Morocco using seasonal cointegration techniques. DESIGN/METHODOLOGY/APPROACH - The paper uses seasonal integration and cointegration techniques to test the neutrality of money hypothesis for three Middle Eastern economies, using quarterly data on money, prices and real income. The benefit of using this technique lies in its ability to distinguish between cointegration at different frequencies. FINDINGS - The empirical results show that money is cointegrated with prices, but not with output at the zero frequency for Egypt, Jordan and Morocco. This suggests that money affects nominal but not real variables in the long run, implying that money is neutral in these three Middle Eastern economies. PRACTICAL IMPLICATIONS - The implication of this finding for policy analysis suggests that the anti-inflationary policy prescription espoused by the monetarist school should be followed in these three Middle Eastern countries, in order to curb inflation. ORIGINALITY/VALUE - The paper provides further evidence in support of money neutrality using an unconventional approach for three developing Middle Eastern economies

Asymmetric monetary policy rules in Australia

In this study, the hypothesis that the Reserve Bank of Australia (RBA) implements an asymmetric monetary policy rule is tested. We estimate both linear and asymmetric monetary policy reaction functions for the period before inflation targeting was adopted, for the period when inflation targeting was explicitly adopted and for the full sample period. The results of the linear monetary policy rules are consistent with the estimates reported from other studies that estimate linear monetary policy rules for Australia. On the other hand, the results of estimating the asymmetric monetary policy rules for the pre-inflation targeting period shows that the RBA had reacted symmetrically, suggesting that it had acted with the same aggressiveness towards both inflation and output gaps of the same magnitude, over both phases of the business cycle. However, for the inflation targeting period, the results show that the RBA had reacted asymmetrically in its policy response to the inflation gap, output gap or both. A similar result is found for the full sample period. This asymmetric response supports the view that a non-linear monetary policy rule emanated from asymmetric preferences, rather than from the existence of a non-linear Phillips curve

A structural time series test of the monetary model of exchange rates under four big inflations

In this paper, the monetary model of exchange rate determination is tested using structural time series analysis under the Austrian, German, Hungarian and Polish hyperinflation episodes of the 1920s. The results obtained are highly supportive of this version of the monetary model, which explicitly allows for the phenomenon of currency substitution. They also show that the property of proportionality between the domestic money supply and the exchange rate cannot be rejected for Germany, Hungary and Poland. Furthermore, highly supportive evidence is found for the validity of the PPP relationship and the quantity theory of money, both of which are constituent components of the monetary model

The Information Content of the Reserve Bank of Australia's Inflation Forecasts

In this article, the inflation forecasts produced by the Reserve Bank of Australia (RBA) and that generated by private forecasters, are used to assess whether the Reserve Bank possesses information about inflation that the private sector does not have. The results show that the Reserve Bank inflation forecasts embody useful predictive information about inflation, beyond that contained in private forecasts, over the recent inflation targeting period

Testing the impact of inflation targeting on inflation

The purpose of this paper is to examine the impact of inflation targeting on inflation for 27 countries that have adopted an inflation-targeting regime. The paper uses intervention analysis in Harvey's structural time series model to analyse the impact of inflation targeting on inflation, using quarterly observations. This approach provides the most useful framework for separating changes that occur to a series ordinarily over time from those happening due to exogenous events identified a priori, such as inflation targeting. The empirical evidence suggests that almost all of the central banks that have pursued this strategy have been unsuccessful at controlling inflation, with the results indicating that the adoption of an inflation-targeting regime has had the perverse effect on inflation for almost every country. The implication of the finding is that central banks which have adopted an inflation-targeting regime do not appear to have been particularly successful in reducing inflation in any significant way, as is regularly claimed in the extant literature. The paper provides further evidence against the adoption of an inflation-targeting regime using an unconventional approach for 27 countries that are regarded as 'fully-fledged' inflation-targeting countries

The cyclicality of the demand for crude oil: evidence from the OECD

Purpose – The purpose of this paper is to analyse the cyclical relationship between the demand for crude oil and real output for the OECD. Design/methodology/approach – The paper employs Harvey’s structural time series model to analyse the contemporaneous and non-contemporaneous cyclical co-movement of the demand for crude oil with real output, using quarterly observations for the period 1984:1-2010:4. Findings – The empirical evidence suggests that a strong and positive cyclical relationship between the two variables exists, with the demand for crude oil being procyclically contemporaneous. Practical implications – The implication of this finding suggests that consuming countries cannot stockpile oil reserves to guard against the cyclical nature of demand, while producing countries face weak and bearish oil markets during economic recessions, because oil consuming countries cannot smooth out their demand for oil on an intertemporal basis. Originality/value – The paper provides further evidence supporting the procyclically contemporaneous relationship between the demand for crude oil and real output for the OECD

Does the Reserve Bank of Australia follow a forward-looking nonlinear monetary policy rule?

The conventional monetary policy rule describes a simple linear relationship between the domestic interest rate, inflation rate and output gap. An important extension to this rule is to incorporate the forward-looking behaviour of central banks, where it is assumed that they target an expected level of inflation instead of its current realised value. Using quarterly observations for the period 1993:1-2018:2, this paper investigates whether the conduct of monetary policy in Australia can be described by a forward-looking linear monetary policy rule, or by a nonlinear forward-looking monetary policy rule. In particular, the nonlinear forward-looking monetary policy rule is analysed in a regime-switching framework using a smooth logistic transition regression model. While the results show that the conventional forward-looking linear monetary policy rule describes the application of monetary policy in Australia reasonably well, the interest rate setting behaviour of the RBA is best described by a nonlinear forward-looking monetary policy rule