Forecast combination for discrete choice models: predicting FOMC monetary policy decisions

This paper provides a methodology for combining forecasts based on several discrete choice models. This is achieved primarily by combining one-step-ahead probability forecast associated with each model. The paper applies well-established scoring rules for qualitative response models in the context of forecast combination. Log-scores and quadratic-scores are both used to evaluate the forecasting accuracy of each model and to combine the probability forecasts. In addition to producing point forecasts, the effect of sampling variation is also assessed. This methodology is applied to forecast the US Federal Open Market Committee (FOMC) decisions in changing the federal funds target rate. Several of the economic fundamentals influencing the FOMC decisions are nonstationary over time and are modelled in a similar fashion to Hu and Phillips (2004a, JoE). The empirical results show that combining forecasted probabilities using scores mostly outperforms both equal weight combination and forecasts based on multivariate models

Characteristics of TCR repertoire associated with successful immune checkpoint therapy responses

Immunotherapies have revolutionized cancer treatment. In particular, immune checkpoint therapy (ICT) leads to durable responses in some patients with some cancers. However, the majority of treated patients do not respond. Understanding immune mechanisms that underlie responsiveness to ICT will help identify predictive biomarkers of response and develop treatments to convert non-responding patients to responding ones. ICT primarily acts at the level of adaptive immunity. The specificity of adaptive immune cells, such as T and B cells, is determined by antigen-specific receptors. T cell repertoires can be comprehensively profiled by high-throughput sequencing at the bulk and single-cell level. T cell receptor (TCR) sequencing allows for sensitive tracking of dynamic changes in antigen-specific T cells at the clonal level, giving unprecedented insight into the mechanisms by which ICT alters T cell responses. Here, we review how the repertoire influences response to ICT and conversely how ICT affects repertoire diversity. We will also explore how changes to the repertoire in different anatomical locations can better correlate and perhaps predict treatment outcome. We discuss the advantages and limitations of current metrics used to characterize and represent TCR repertoire diversity. Discovery of predictive biomarkers could lie in novel analysis approaches, such as network analysis of amino acids similarities between TCR sequences. Single-cell sequencing is a breakthrough technology that can link phenotype with specificity, identifying T cell clones that are crucial for successful ICT. The field of immuno-sequencing is rapidly developing and cross-disciplinary efforts are required to maximize the analysis, application, and validation of sequencing data. Unravelling the dynamic behavior of the TCR repertoire during ICT will be highly valuable for tracking and understanding anti-tumor immunity, biomarker discovery, and ultimately for the development of novel strategies to improve patient outcomes

Tumor infiltrating effector memory Antigen-Specific CD8+ T Cells predict response to immune checkpoint therapy

Immune checkpoint therapy (ICT) results in durable responses in individuals with some cancers, but not all patients respond to treatment. ICT improves CD8+ cytotoxic T lymphocyte (CTL) function, but changes in tumor antigen-specific CTLs post-ICT that correlate with successful responses have not been well characterized. Here, we studied murine tumor models with dichotomous responses to ICT. We tracked tumor antigen-specific CTL frequencies and phenotype before and after ICT in responding and non-responding animals. Tumor antigen-specific CTLs increased within tumor and draining lymph nodes after ICT, and exhibited an effector memory-like phenotype, expressing IL-7R (CD127), KLRG1, T-bet, and granzyme B. Responding tumors exhibited higher infiltration of effector memory tumor antigen-specific CTLs, but lower frequencies of regulatory T cells compared to non-responders. Tumor antigen-specific CTLs persisted in responding animals and formed memory responses against tumor antigens. Our results suggest that increased effector memory tumor antigen-specific CTLs, in the presence of reduced immunosuppression within tumors is part of a successful ICT response. Temporal and nuanced analysis of T cell subsets provides a potential new source of immune based biomarkers for response to ICT

Dendritic cells in cancer immunotherapy.

Contains fulltext : 83250.pdf (publisher's version ) (Open Access)Radboud Universiteit Nijmegen, 6 december 2010Promotor : Punt, C.J.A. Co-promotores : Adema, G.J., Vries, I.J.M. de192 p

STATing the importance of immune modulation by platinum chemotherapeutics.

Item does not contain fulltextPlatinum-based anticancer drugs enhance the immunostimulatory potential of DCs and decrease the immunosuppressive capacity of tumor cells. This immunomodulatory ability is based on the inhibition of STAT6-mediated expression of co-inhibitory molecule PD-L2 and opens up the possibility of using these drugs in combination with other immunostimulatory compounds

[Diagnostic image (146). A man with food passage problems. Intrathoracic pancreatic pseudocyst]

In a 76-year-old man food passage problems were due to an intrathoracic pancreatic pseudocyst

Tumor-infiltrating dendritic cells exhibit defective cross-presentation of tumor antigens, but is reversed by chemotherapy

Cross-presentation defines the unique capacity of an APC to present exogenous Ag via MHC class I molecules to CD8+ T cells. DCs are specialized cross-presenting cells and as such have a critical role in antitumor immunity. DCs are routinely found within the tumor microenvironment, but their capacity for endogenous or therapeutically enhanced cross-presentation is not well characterized. In this study, we examined the tumor and lymph node DC cross-presentation of a nominal marker tumor Ag, HA, expressed by the murine mesothelioma tumor AB1-HA. We found that tumors were infiltrated by predominantly CD11b+ DCs with a semimature phenotype that could not cross-present tumor Ag, and therefore, were unable to induce tumor-specific T-cell activation or proliferation. Although tumor-infiltrating DCs were able to take, process, and cross-present exogenous cell-bound and soluble Ags, this was significantly impaired relative to lymph node DCs. Importantly, however, systemic chemotherapy using gemcitabine reversed the defect in Ag cross-presentation of tumor DCs. These data demonstrate that DC cross-presentation within the tumor microenvironment is defective, but can be reversed by chemotherapy. These results have important implications for anticancer therapy, particularly regarding the use of immunotherapy in conjunction with cytotoxic chemotherapy

Acute generalised exanthematous pustulosis mimicking septic shock.

Contains fulltext : 57796tjioe.pdf (publisher's version ) (Closed access

Molecular pathways: the immunogenic effects of platinum-based chemotherapeutics

Item does not contain fulltextThe platinum-based drugs cisplatin, carboplatin, and oxaliplatin belong to the most widely used chemotherapeutics in oncology, showing clinical efficacy against many solid tumors. Their main mechanism of action is believed to be the induction of cancer cell apoptosis as a response to their covalent binding to DNA. In recent years, this picture has increased in complexity, based on studies indicating that cellular molecules other than DNA may potentially act as targets, and that part of the antitumor effects of platinum drugs occurs through modulation of the immune system. These immunogenic effects include modulation of STAT signaling; induction of an immunogenic type of cancer cell death through exposure of calreticulin and release of ATP and high-mobility group protein box-1 (HMGB-1); and enhancement of the effector immune response through modulation of programmed death receptor 1-ligand and mannose-6-phosphate receptor expression. Both basic and clinical studies indicate that at least part of the antitumor efficacy of platinum chemotherapeutics may be due to immune potentiating mechanisms. Clinical studies exploiting this novel mechanism of action of these old cancer drugs have been initiated. Here, we review the literature on the immunogenic effects of platinum, summarize the clinical advances using platinum as a cytotoxic compound with immune adjuvant properties, and discuss the limitations to these studies and the gaps in our understanding of the immunologic effects of these drugs. Clin Cancer Res; 20(11); 2831-7. (c)2014 AACR

Dendritic cell-based vaccines in cancer immunotherapy: an update on clinical and immunological results.

Contains fulltext : 58030.pdf (publisher's version ) (Closed access