Ovarian cancer is the most lethal of all gynecological cancers, and there is an urgent unmet need to develop new therapies. Epithelial ovarian cancer (EOC) is characterized by an immune suppressive microenvironment, and response of ovarian cancers to immune therapies has thus far been disappointing. We now find, in a mouse model of EOC, that clinically relevant doses of DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi, respectively) reduce the immune suppressive microenvironment through type I IFN signaling and improve response to immune checkpoint therapy. These data indicate that the type I IFN response is required for effective in vivo antitumorigenic actions of the DNMTi 5-azacytidine (AZA). Through type I IFN signaling, AZA increases the numbers of CD45 immune cells and the percentage of active CD8 T and natural killer (NK) cells in the tumor microenvironment, while reducing tumor burden and extending survival. AZA also increases viral defense gene expression in both tumor and immune cells, and reduces the percentage of macrophages and myeloid-derived suppressor cells in the tumor microenvironment. The addition of an HDACi to AZA enhances the modulation of the immune microenvironment, specifically increasing T and NK cell activation and reducing macrophages over AZA treatment alone, while further increasing the survival of the mice. Finally, a triple combination of DNMTi/HDACi plus the immune checkpoint inhibitor α-PD-1 provides the best antitumor effect and longest overall survival, and may be an attractive candidate for future clinical trials in ovarian cancer.

SUMMARY We define how chronic cigarette smoke-induced time-dependent epigenetic alterations can sensitize human bronchial epithelial cells for transformation by a single oncogene. The smoke-induced chromatin changes include initial repressive polycomb marking of genes, later manifesting abnormal DNA methylation by 10 months. At this time, cells exhibit epithelial to mesenchymal changes, anchorage-independent growth and upregulated RAS/MAPK signaling with silencing of hyper-methylated genes, which normally inhibit these pathways and are associated with smoking related NSCLC. These cells, in the absence of any driver gene mutations, now transform by introducing a single KRAS mutation and form adeno-squamous lung carcinomas in mice. Thus, epigenetic abnormalities may prime for changing oncogene senescence to addiction for a single key oncogene involved in lung cancer initiation.

Once individual users' safety and functionality needs are satisfied, pleasure should be considered in the design of products, systems, tools, and environments. 8 ERGONOMICS IN DESIGN. WINTER 2005 n this article, we introduce a new term into the human factors/ergonomics lexicon: hedonomics.We define hedonomics as that branch of science and design devoted to the promotion of pleasurable human-technology interaction. In advocating for hedonomics, we seek to augment and expand ergonomists' arsenal for improving the design of all human-machine technology.Our intention here is to (a) provide a philosophical framework for hedonomics; (b) contribute a model of a design priority hierarchy, in which we explain in detail the concept of individuation as the ultimate human approach to technology; and (c) offer potential design guidelines for and areas of hedonomic research that we believe should be pursued as an agenda for progress in the near future. GENESIS AND MEANING OF HEDONOMICSLike the term ergonomics, hedonomics is derived from two Greek roots: hedon(e), meaning joy or pleasure, and nomos, meaning law-like or collective. In ergonomics, our traditional moral ethos is founded on the praiseworthy efforts to prevent people's pain and suffering, predominantly in the workplace. These concerns have grown over recent decades into a formal branch of science now devoted to a wider set of improvements in all physical and cognitive environments, thus serving to enhance the overall quality of life.In contrast to the prevention of pain, but much in the same realm of human-technology interaction, hedonomics is primarily concerned with the promotion of pleasure. Hedonomics and human factors/ergonomics (HF/E) are consequently two sides of the same coin. However, whereas HF/E is often handicapped by trying to show the value of preventing events that eventually do not happen, hedonomics, being a positive enterprise, rejoices in the advantage of showing the value of events that do.Fundamentally, ergonomics and hedonomics are synergistic perspectives directed toward the same goal of optimized human-technology interaction, which is central to the goal of all future design. Perhaps our first responsibility is to clarify an important issue. Although one of us (Hancock) coined the term hedonomics, the pioneering work in this area is primarily that of others (for example,

Abnormalities in glutamate neurotransmission may have a role in the pathophysiology of adolescent depression. The present pilot study examined changes in cortical glutamine/glutamate ratios in depressed adolescents receiving high-frequency repetitive transcranial magnetic stimulation. Ten adolescents with treatment-refractory major depressive disorder received up to 30 sessions of 10-Hz repetitive transcranial magnetic stimulation at 120% motor threshold with 3,000 pulses per session applied to the left dorsolateral prefrontal cortex. Baseline, posttreatment, and 6-month follow-up proton magnetic resonance spectroscopy scans of the anterior cingulate cortex and left dorsolateral prefrontal cortex were collected at 3T with 8-cm3 voxels. Glutamate metabolites were quantified with 2 distinct proton magnetic resonance spectroscopy sequences in each brain region. After repetitive transcranial magnetic stimulation and at 6 months of follow-up, glutamine/glutamate ratios increased in the anterior cingulate cortex and left dorsolateral prefrontal cortex with both measurements. The increase in the glutamine/glutamate ratio reached statistical significance with the TE-optimized PRESS sequence in the anterior cingulate cortex. Glutamine/glutamate ratios increased in conjunction with depressive symptom improvement. This reached statistical significance with the TE-optimized PRESS sequence in the left dorsolateral prefrontal cortex. High-frequency repetitive transcranial magnetic stimulation applied to the left dorsolateral prefrontal cortex may modulate glutamate neurochemistry in depressed adolescents.