Intrapersonal positive future thinking predicts repeat suicide attempts in hospital-treated suicide attempters

Objective: Although there is clear evidence that low levels of positive future thinking (anticipation of positive experiences in the future) and hopelessness are associated with suicide risk, the relationship between the content of positive future thinking and suicidal behavior has yet to be investigated. This is the first study to determine whether the positive future thinking–suicide attempt relationship varies as a function of the content of the thoughts and whether positive future thinking predicts suicide attempts over time. Method: A total of 388 patients hospitalized following a suicide attempt completed a range of clinical and psychological measures (depression, hopelessness, suicidal ideation, suicidal intent and positive future thinking). Fifteen months later, a nationally linked database was used to determine who had been hospitalized again after a suicide attempt. Results: During follow-up, 25.6% of linked participants were readmitted to hospital following a suicide attempt. In univariate logistic regression analyses, previous suicide attempts, suicidal ideation, hopelessness, and depression—as well as low levels of achievement, low levels of financial positive future thoughts, and high levels of intrapersonal (thoughts about the individual and no one else) positive future thoughts predicted repeat suicide attempts. However, only previous suicide attempts, suicidal ideation, and high levels of intrapersonal positive future thinking were significant predictors in multivariate analyses. Discussion: Positive future thinking has predictive utility over time; however, the content of the thinking affects the direction and strength of the positive future thinking–suicidal behavior relationship. Future research is required to understand the mechanisms that link high levels of intrapersonal positive future thinking to suicide risk and how intrapersonal thinking should be targeted in treatment interventions

A Critical Role for Natural Killer T Cells in Immunosurveillance of Methylcholanthrene-induced Sarcomas

Natural killer (NK) T cells initiate potent antitumor responses when stimulated by exogenous factors such as interleukin (IL)-12 or α-galactosylceramide (α-GalCer), however, it is not clear whether this reflects a physiological role for these cells in tumor immunity. Through adoptive transfer of NK T cells from wild-type to NK T cell–deficient (T cell receptor [TCR] Jα281−/−) mice, we demonstrate a critical role for NK T cells in immunosurveillance of methylcholanthrene (MCA)-induced fibrosarcomas, in the absence of exogenous stimulatory factors. Using the same approach with gene-targeted and/or antibody-depleted donor or recipient mice, we have shown that this effect depends on CD1d recognition and requires the additional involvement of both NK and CD8+ T cells. Interferon-γ production by both NK T cells and downstream, non-NK T cells, is essential for protection, and perforin production by effector cells, but not NK T cells, is also critical. The protective mechanisms in this more physiologically relevant system are distinct from those associated with α-GalCer–induced, NK T cell–mediated, tumor rejection. This study demonstrates that, in addition to their importance in tumor immunotherapy induced by IL-12 or α-GalCer, NK T cells can play a critical role in tumor immunosurveillance, at least against MCA-induced sarcomas, in the absence of exogenous stimulation

Co-Creating and Evaluating an App-Based Well-Being Intervention: The HOW (Healthier Outcomes at Work) Social Work Project

Stress and mental health at work are the leading causes of long-term sickness absence in the UK, with chronically poor working conditions impacting employee physiological and psychological health. Social workers play a significant part in the fabric of UK society, but have one of the most stressful occupations in the country. The aim of this project was to work with UK social workers to co-develop, implement, and evaluate a series of smartphone-based mental health initiatives. A Participatory Action Research (PAR) approach, consisting of semi-structured interviews and focus group and steering group discussions, was utilized to design the mental health and well-being interventions. Study efficacy was evaluated via a pre- and post-intervention survey and post-intervention semi-structured interviews. Interventions developed were psycho-educational, improved top-down and bottom-up communication, and provided access to a Vocational Rehabilitation Assistant for those struggling and at risk of sickness absence. Six months following dissemination, surveys demonstrated significant improvements in communication, and mean score improvements in four other working conditions. This project, therefore, demonstrates that co-developed initiatives can be positively impactful, despite post-intervention data collection being impacted by COVID-19. Future studies should build upon these findings and broaden the PAR approach nationally while taking a robust approach to evaluation

Acquired resistance to anti-PD1 therapy: checkmate to checkpoint blockade?

Editorial summary Anti-programmed cell death 1 (PD1) immunotherapies are among the most effective anti-cancer immunotherapies available; however, a large number of patients present with or develop resistance to them. Unfortunately, very little is known regarding the mechanisms of resistance to such therapies. A recent study sought to identify mutations associated with resistance to anti-PD1 therapy. Results from this study demonstrated that mutations which affected the sensitivity of tumor cells to T-cell-derived interferons, and mutations limiting tumor-cell antigen presentation, could cause acquired resistance. These findings have significant implications for understanding the mechanisms by which anti-PD1 therapies exert their efficacy, comprehending why and how some patients acquire resistance over time, and ultimately guiding the development of combination therapies designed to overcome, or potentially prevent, the development of acquired immunotherapeutic resistance

The combination of histone deacetylase inhibitors with immune-stimulating antibodies has potent anti-cancer effects

The use of immunotherapy to treat cancer is rapidly gaining momentum. Using pre-clinical mouse models, we have recently demonstrated potent and long lasting tumor regression can be elicited by immune-stimulating monoclonal antibodies (mAbs) when combined with histone deacetylase inhibitors (HDACi) and believe this therapy will have broad application in humans

Suppression of Lymphoma and Epithelial Malignancies Effected by Interferon γ

The immunosurveillance of transformed cells by the immune system remains one of the most controversial and poorly understood areas of immunity. Gene-targeted mice have greatly aided our understanding of the key effector molecules in tumor immunity. Herein, we describe spontaneous tumor development in gene-targeted mice lacking interferon (IFN)-γ and/or perforin (pfp), or the immunoregulatory cytokines, interleukin (IL)-12, IL-18, and tumor necrosis factor (TNF). Both IFN-γ and pfp were critical for suppression of lymphomagenesis, however the level of protection afforded by IFN-γ was strain specific. Lymphomas arising in IFN-γ-deficient mice were very nonimmunogenic compared with those derived from pfp-deficient mice, suggesting a comparatively weaker immunoselection pressure by IFN-γ. Single loss of IL-12, IL-18, or TNF was not sufficient for spontaneous tumor development. A significant incidence of late onset adenocarcinoma observed in both IFN-γ– and pfp-deficient mice indicated that some epithelial tissues were also subject to immunosurveillance

From mice to humans: Developments in cancer immunoediting

Cancer immunoediting explains the dual role by which the immune system can both suppress and/or promote tumor growth. Although cancer immunoediting was first demonstrated using mouse models of cancer, strong evidence that it occurs in human cancers is now accumulating. In particular, the importance of CD8+ T cells in cancer immunoediting has been shown, and more broadly in those tumors with an adaptive immune resistance phenotype. This Review describes the characteristics of the adaptive immune resistance tumor microenvironment and discusses data obtained in mouse and human settings. The role of other immune cells and factors influencing the effector function of tumor-specific CD8+ T cells is covered. We also discuss the temporal occurrence of cancer immunoediting in metastases and whether it differs from immunoediting in the primary tumor of origin

An Essential Role for Tumor Necrosis Factor in Natural Killer Cell–mediated Tumor Rejection in the Peritoneum

Natural killer (NK) cells are thought to provide the first line of defence against tumors, particularly major histocompatibility complex (MHC) class I− variants. We have confirmed in C57BL/6 (B6) mice lacking perforin that peritoneal growth of MHC class I− RMA-S tumor cells in unprimed mice is controlled by perforin-dependent cytotoxicity mediated by CD3− NK1.1+ cells. Furthermore, we demonstrate that B6 mice lacking tumor necrosis factor (TNF) are also significantly defective in their rejection of RMA-S, despite the fact that RMA-S is insensitive to TNF in vitro and that spleen NK cells from B6 and TNF-deficient mice are equally lytic towards RMA-S. NK cell recruitment into the peritoneum was abrogated in TNF-deficient mice challenged with RMA-S or RM-1, a B6 MHC class I− prostate carcinoma, compared with B6 or perforin-deficient mice. The reduced NK cell migration to the peritoneum of TNF-deficient mice correlated with the defective NK cell response to tumor in these mice. By contrast, a lack of TNF did not affect peptide-specific cytotoxic T lymphocyte–mediated rejection of tumor from the peritoneum of preimmunized mice. Overall, these data show that NK cells delivering perforin are the major effectors of class I− tumor rejection in the peritoneum, and that TNF is specifically critical for their recruitment to the peritoneum