From Shattered Assumptions to Weakened Worldviews: Trauma Symptoms Signal Anxiety Buffer Disruption

The fundamental assertion of worldview-based models of posttraumatic stress disorder (PTSD) is that trauma symptoms result when traumatic experiences cannot be readily assimilated into previously held worldviews. In two studies, we test the anxiety buffer disruption hypothesis, which states that trauma symptoms result from the disruption of normal death anxiety–buffering functions of worldviews. In Study 1, participants with trauma symptoms greater than the cutoff for PTSD evinced greater death thought accessibility than those with subclinical or negligible symptoms after a reminder of death. In Study 2, participants with clinically significant trauma symptoms showed no evidence of worldview defense though death thoughts were accessible. These results support the anxiety buffer disruption hypothesis and suggest an entirely new approach to experimental PTSD research

Detecting Subtle Changes in Visuospatial Executive Function and Learning in the Amnestic Variant of Mild Cognitive Impairment

BACKGROUND AND PURPOSE: Amnestic mild cognitive impairment (aMCI) is a putative prodromal stage of Alzheimer's disease (AD) characterized by deficits in episodic verbal memory. Our goal in the present study was to determine whether executive dysfunction may also be detectable in individuals diagnosed with aMCI. METHODS: This study used a hidden maze learning test to characterize component processes of visuospatial executive function and learning in a sample of 62 individuals with aMCI compared with 94 healthy controls. RESULTS: Relative to controls, individuals with aMCI made more exploratory/learning errors (Cohen's d = .41). Comparison of learning curves revealed that the slope between the first two of five learning trials was four times as steep for controls than for individuals with aMCI (Cohen's d = .64). Individuals with aMCI also made a significantly greater number of rule-break/error monitoring errors across learning trials (Cohen's d = .21). CONCLUSIONS: These results suggest that performance on a task of complex visuospatial executive function is compromised in individuals with aMCI, and likely explained by reductions in initial strategy formulation during early visual learning and "on-line" maintenance of task rules

Targeting transcription regulation in cancer with a covalent CDK7 inhibitor

Tumour oncogenes include transcription factors that co-opt the general transcriptional machinery to sustain the oncogenic state, but direct pharmacological inhibition of transcription factors has so far proven difficult. However, the transcriptional machinery contains various enzymatic cofactors that can be targeted for the development of new therapeutic candidates, including cyclin-dependent kinases (CDKs). Here we present the discovery and characterization of a covalent CDK7 inhibitor, THZ1, which has the unprecedented ability to target a remote cysteine residue located outside of the canonical kinase domain, providing an unanticipated means of achieving selectivity for CDK7. Cancer cell-line profiling indicates that a subset of cancer cell lines, including human T-cell acute lymphoblastic leukaemia (T-ALL), have exceptional sensitivity to THZ1. Genome-wide analysis in Jurkat T-ALL cells shows that THZ1 disproportionally affects transcription of RUNX1 and suggests that sensitivity to THZ1 may be due to vulnerability conferred by the RUNX1 super-enhancer and the key role of RUNX1 in the core transcriptional regulatory circuitry of these tumour cells. Pharmacological modulation of CDK7 kinase activity may thus provide an approach to identify and treat tumour types that are dependent on transcription for maintenance of the oncogenic state.National Institutes of Health (U.S.) (Grant HG002668)National Institutes of Health (U.S.) (Grant CA109901

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Diagnosing the Prodromal State of Alzheimer\u27s Disease

Mild Cognitive Impairment- Amnestic Subtype (MCIa) is a putative prodromal stage of Alzheimer’s Disease (AD) characterized by focal deficits in episodic verbal memory. Less is known about relative deficits in visuospatial learning, although there is ample evidence indicating involvement of the hippocampus in visuospatial learning, as well as hippocampal degeneration in early AD. The aim of this study was to better characterize the components of working memory dysfunction in people with MCIa to increase the ability to reliably diagnose this disease. Fifty-six elderly adults diagnosed with MCIa and 94 healthy elderly completed a hidden maze learning task. Results indicated similar functioning between groups on measures of reasoning, problem solving, and accuracy. However, MCIa subjects were less efficient at learning the hidden path, making more errors per second on average (Cohen’s d= -.78) and requiring a longer time to complete the maze (Cohen’s d=.77). The learning curve between the first two trials was four times as steep for healthy elderly compared to MCIa (slopes = 4.9 vs. 1.24, respectively), indicating that MCIa subjects exhibited relative difficulty in holding and making effective use of an internal spatial map in order to improve performance. Our results suggest that MCIa patients have focal deficits in visuospatial working memory, with relative preservation of functioning on other more global measures of cognitive functioning. This particular pattern of results may be specific to the amnestic variant of MCI

The Groton Maze Learning Test: Stimulus and Examples of Error Types.

<p>Tiles shaded in gray represent one of the hidden maze pathways on the GMLT; numbers indicate order of moves for a sample participant; Move 2 to 3 (shown in black): exploratory error; Move 3 to 4 (shown in red): rule-break error (tapping on same tile twice); Move 8 to 9 (shown in green): perseverative error; Move 12 to 13 (shown in grey): rule break error (not moving back to the last correct tile); Move 16 to 17 (shown in blue): rule break error (no moving diagonally); Move 20 to 21 (shown in purple): rule break error (moving backwards along the maze).</p

Demographic characteristics of healthy elderly and aMCI groups.

<p><i>Note</i>: aMCI = Mild cognitive impairment-amnestic subtype; SD = standard deviation.</p><p>*Groups differ, p<.05.</p

Mean Exploratory Errors and Rule Break Errors (with Standard Errors) over five learning trials of the Groton Maze Learning Test in Healthy Controls versus aMCI groups.

<p>Mean Exploratory Errors and Rule Break Errors (with Standard Errors) over five learning trials of the Groton Maze Learning Test in Healthy Controls versus aMCI groups.</p

Neuropsychological tests used to classify Healthy Elderly and aMCI groups.

<p>*Groups differ, p<.05, +aMCI group impaired (mean performance more than 1 SD below healthy elderly mean performance), SD = standard deviation, aMCI = Amnestic mild cognitive impairment.</p