Oncolytic and immunostimulatory efficacy of a targeted oncolytic poxvirus expressing human GM-CSF following intravenous administration in a rabbit tumor model

Targeted oncolytic poxviruses hold promise for the treatment of cancer. Arming these agents with immunostimulatory cytokines (for example, granulocyte-monocyte colony-stimulating factor; GM-CSF) can potentially increase their efficacy and/or alter their safety. However, due to species-specific differences in both human GM-CSF (hGM-CSF) activity and poxviruses immune avoidance proteins, the impact of hGM-CSF expression from an oncolytic poxvirus cannot be adequately assessed in murine or rat tumor models. We developed a rabbit tumor model to assess toxicology, pharmacodynamics, oncolytic efficacy and tumor-specific immunity of hGM-CSF expressed from a targeted oncolytic poxvirus JX-963. Recombinant purified hGM-CSF protein stimulated a leukocyte response in this model that paralleled effects of the protein in humans. JX-963 replication and targeting was highly tumor-selective after i.v. administration, and intratumoral replication led to recurrent, delayed systemic viremia. Likewise, hGM-CSF was expressed and released into the blood during JX-963 replication in tumors, but not in tumor-free animals. hGM-CSF expression from JX-963 was associated with significant increases in neutrophil, monocyte and basophil concentrations in the peripheral blood. Finally, tumor-specific cytotoxic T lymphocytes (CTL) were induced by the oncolytic poxvirus, and expression of hGM-CSF from the virus enhanced both tumor-specific CTL and antitumoral efficacy. JX-963 had significant efficacy against both the primary liver tumor as well as metastases; no significant organ toxicity was noted. This model holds promise for the evaluation of immunostimulatory transgene-armed oncolytic poxviruses, and potentially other viral species

A study to explore if dentists’ anxiety affects their clinical decision-making

Aims To develop a measure of dentists’ anxiety in clinical situations; to establish if dentists’ anxiety in clinical situations affected their self-reported clinical decision-making; to establish if occupational stress, as demonstrated by burnout, is associated with anxiety in clinical situations and clinical decision-making; and to explore the relationship between decision-making style and the clinical decisions which are influenced by anxiety. Design Cross-sectional study. Setting Primary Dental Care. Subjects and methods A questionnaire battery [Maslach Burnout Inventory, measuring burnout; Melbourne Decision Making Questionnaire, measuring decision-making style; Dealing with Uncertainty Questionnaire (DUQ), measuring coping with diagnostic uncertainty; and a newly designed Dentists’ Anxieties in Clinical Situations Scale, measuring dentists’ anxiety (DACSS-R) and change of treatment (DACSS-C)] was distributed to dentists practicing in Nottinghamshire and Lincolnshire. Demographic data were collected and dentists gave examples of anxiety-provoking situations and their responses to them. Main outcome measure Respondents’ self-reported anxiety in various clinical situations on a 11-point Likert Scale (DACSS-R) and self-reported changes in clinical procedures (Yes/No; DACSS-C). The DACSS was validated using multiple t-tests and a principal component analysis. Differences in DACSS-R ratings and burnout, decision-making and dealing with uncertainty were explored using Pearson correlations and multiple regression analysis. Qualitative data was subject to a thematic analysis. Results The DACSS-R revealed a four-factor structure and had high internal reliability (Cronbach’s α = 0.94). Those with higher DACSS-R scores of anxiety were more likely to report changes in clinical procedures (DACSS-C scores). DACSS-R scores were associated with decision-making self-esteem and style as measured by the MDMQ and all burnout subscales, though not with scores on the DUQ scale. Conclusion Dentists’ anxiety in clinical situations does affect the way that dentists work clinically, as assessed using the newly designed and validated DACSS. This anxiety is associated with measures of burnout and decision-making style with implications for training packages for dentists

Self-Compassion, emotion regulation and stress among australian psychologists: Testing an emotion regulation model of self-compassion using structural equation modeling

Psychologists tend to report high levels of occupational stress, with serious implications for themselves, their clients, and the discipline as a whole. Recent research suggests that selfcompassion is a promising construct for psychologists in terms of its ability to promote psychological wellbeing and resilience to stress; however, the potential benefits of self-compassion are yet to be thoroughly explored amongst this occupational group. Additionally, while a growing body of research supports self-compassion as a key predictor of psychopathology, understanding of the processes by which self-compassion exerts effects on mental health outcomes is limited. Structural equation modelling (SEM) was used to test an emotion regulation model of self-compassion and stress among psychologists, including postgraduate trainees undertaking clinical work (n = 198). Self-compassion significantly negatively predicted emotion regulation difficulties and stress symptoms. Support was also found for our preliminary explanatory model of self-compassion, which demonstrates the mediating role of emotion regulation difficulties in the self-compassion-stress relationship. The final self-compassion model accounted for 26.2% of variance in stress symptoms. Implications of the findings and limitations of the study are discussed

Epigenetic regulation of caloric restriction in aging

The molecular mechanisms of aging are the subject of much research and have facilitated potential interventions to delay aging and aging-related degenerative diseases in humans. The aging process is frequently affected by environmental factors, and caloric restriction is by far the most effective and established environmental manipulation for extending lifespan in various animal models. However, the precise mechanisms by which caloric restriction affects lifespan are still not clear. Epigenetic mechanisms have recently been recognized as major contributors to nutrition-related longevity and aging control. Two primary epigenetic codes, DNA methylation and histone modification, are believed to dynamically influence chromatin structure, resulting in expression changes of relevant genes. In this review, we assess the current advances in epigenetic regulation in response to caloric restriction and how this affects cellular senescence, aging and potential extension of a healthy lifespan in humans. Enhanced understanding of the important role of epigenetics in the control of the aging process through caloric restriction may lead to clinical advances in the prevention and therapy of human aging-associated diseases