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Background: We conducted a phase I study with a granulocyte macrophage colony stimulating factor (GMCSF)-expressing oncolytic adenovirus, ONCOS-102, in patients with solid tumors refractory to available treatments. The objectives of the study were to determine the optimal dose for further use and to assess the safety, tolerability and adverse event (AE) profile of ONCOS-102. Further, the response rate and overall survival were evaluated as well as preliminary evidence of disease control. As an exploratory endpoint, the effect of ONCOS 102 on biological correlates was examined.
Methods: The study was conducted using a classic 3 + 3 dose escalation study design involving 12 patients. Patients were repeatedly treated intratumorally with ONCOS-102 plus daily low-dose oral cyclophosphamide (CPO). Tumor response was evaluated with diagnostic positron emission tomography (PET) and computed tomography (CT). Tumor biopsies were collected at baseline and after treatment initiation for analysis of immunological correlates. Peripheral blood mononuclear cells (PBMCs) were collected at baseline and during the study to assess antigen specificity of CD8+ T cells by interferon gamma (IFNγ) enzyme linked immunospot assay (ELISPOT).
Results: No dose limiting toxicity (DLT) or maximum tolerated dose (MTD) was identified for ONCOS-102. Four out of ten (40 %) evaluable patients had disease control based on PET/CT scan at 3 months and median overall survival was 9.3 months. A short-term increase in systemic pro-inflammatory cytokines and a prominent infiltration of TILs to tumors was seen post-treatment in 11 out of 12 patients. Two patients showed marked infiltration of CD8+ T cells to tumors and concomitant systemic induction of tumor-specific CD8+ T cells. Interestingly, high expression levels of genes associated with activated TH1 cells and TH1 type immune profile were observed in the post-treatment biopsies of these two patients.
Conclusions: ONCOS-102 is safe and well tolerated at the tested doses. All three examined doses may be used in further development. There was evidence of antitumor immunity and signals of clinical efficacy. Importantly, treatment resulted in infiltration of CD8+ T cells to tumors and up-regulation of PD-L1, highlighting the potential of ONCOS-102 as an immunosensitizing agent for combinatory therapies with checkpoint inhibitors.
Trial registration: NCT01598129. Registered 19/04/2012
The key cognitive impairments of children with attention deficit/-hyperactivity disorder (ADHD) include executive control functions such as inhibitory control, task-switching, and working memory (WM). In this training study we examined whether task-switching training leads to improvements in these functions. Twenty children with combined type ADHD and stable methylphenidate medication performed a single-task and a task-switching training in a crossover training design. The children were randomly assigned to one of two groups. One group started with the single-task training and then performed the task-switching training and the other group vice versa. The effectiveness of the task-switching training was measured as performance improvements (relative to the single-task training) on a structurally similar but new switching task and on other executive control tasks measuring inhibitory control and verbal WM as well as on fluid intelligence (reasoning). The children in both groups showed improvements in task-switching, that is, a reduction of switching costs, but not in performing the single-tasks across four training sessions. Moreover, the task-switching training lead to selective enhancements in task-switching performance, that is, the reduction of task-switching costs was found to be larger after task-switching than after single-task training. Similar selective improvements were observed for inhibitory control and verbal WM, but not for reasoning. Results of this study suggest that task-switching training is an effective cognitive intervention that helps to enhance executive control functioning in children with ADHD.
Recent research has revealed that learning behavior is associated with academic achievement at the college level, but the impact of specific learning strategies on academic success as well as gender differences therein are still not clear. Therefore, the aim of this study was to investigate gender differences in the incremental contribution of learning strategies over general cognitive ability in the prediction of academic achievement. The relationship between these variables was examined by correlation analyses. A set of t-tests was used to test for gender differences in learning strategies, whereas structural equation modeling as well as multi-group analyses were applied to investigate the incremental contribution of learning strategies for male and female students’ academic performance. The sample consisted of 461 students (mean age = 21.2 years, SD = 3.2). Correlation analyses revealed that general cognitive ability as well as the learning strategies effort, attention, and learning environment were positively correlated with academic achievement. Gender differences were found in the reported application of many learning strategies. Importantly, the prediction of achievement in structural equation modeling revealed that only effort explained incremental variance (10%) over general cognitive ability. Results of multi-group analyses showed no gender differences in this prediction model. This finding provides further knowledge regarding gender differences in learning research and the specific role of learning strategies for academic achievement. The incremental assessment of learning strategy use as well as gender-differences in their predictive value contributes to the understanding and improvement of successful academic development.
Cognitive flexibility, the ability to flexibly switch between tasks, is a core dimension of executive functions (EFs) allowing to control actions and to adapt flexibly to changing environments. It supports the management of multiple tasks, the development of novel, adaptive behavior and is associated with various life outcomes. Cognitive flexibility develops rapidly in preschool and continuously increases well into adolescence, mirroring the growth of neural networks involving the prefrontal cortex. Over the past decade, there has been increasing interest in interventions designed to improve cognitive flexibility in children in order to support the many developmental outcomes associated with cognitive flexibility. This article provides a brief review of the development and plasticity of cognitive flexibility across early and middle childhood (i.e., from preschool to elementary school age). Focusing on interventions designed to improve cognitive flexibility in typically developing children, we report evidence for significant training and transfer effects while acknowledging that current findings on transfer are heterogeneous. Finally, we introduce metacognitive training as a promising new approach to promote cognitive flexibility and to support transfer of training.
Over the last decade, the prospect of improving or maintaining cognitive functioning has provoked a steadily increasing number of cognitive training studies. Central target populations are individuals at risk for a disadvantageous development, such as older adults exhibiting cognitive decline or children with learning impairments. They rely on cognitive resources to meet the challenges of an independent life in old age or requirements at school.
To support daily cognitive functioning, training outcomes need to generalize to other cognitive abilities. Such transfer effects are, however, highly discussed. For example, recent meta-analyses on working memory training differed in the conclusion on the presence (Au et al., 2015; Karbach and Verhaeghen, 2014) or absence of transfer effects (Melby-Lervåg and Hulme, 2013). Usually training-specific design factors such as type, intensity, duration, and feedback routines are discussed as reasons for such inconsistent findings. However, even individuals participating in exactly the same training regime highly differ in their training outcomes. We argue that it is time to study the individual development during trainings to understand these differential outcomes. It is time to have a closer look at the intraindividual training data.
Late stage cancer is often associated with reduced immune recognition and a highly immunosuppressive tumor microenvironment. The presence of tumor infiltrating lymphocytes (TILs) and specific gene-signatures prior to treatment are linked to good prognosis, while the opposite is true for extensive immunosuppression. The use of adenoviruses as cancer vaccines is a form of active immunotherapy to initialise a tumor-specific immune response that targets the patient’s unique tumor antigen repertoire. We report a case of a 68-year-old male with asbestos-related malignant pleural mesothelioma who was treated in a Phase I study with a granulocyte-macrophage colony‑stimulating factor (GM-CSF)-expressing oncolytic adenovirus, Ad5/3-D24-GMCSF (ONCOS-102). The treatment resulted in prominent infiltration of CD8C lymphocytes to tumor, marked induction of systemic antitumor CD8C T-cells and induction of Th1- type polarization in the tumor. These results indicate that ONCOS-102 treatment sensitizes tumors to other immunotherapies by inducing a T-cell positive phenotype to an initially T-cell negative tumor.
According to a popular stereotype, women are better at multitasking than men, but empirical evidence for gender differences in multitasking performance is mixed. Previous work has focused on specific aspects of multitasking or has not considered gender differences in abilities contributing to multitasking performance. We therefore tested gender differences (N = 96, 50% female) in sequential (i.e., task switching) and concurrent (i.e., dual tasking) multitasking, while controlling for possible gender differences in working memory, processing speed, spatial abilities, and fluid intelligence. Applying two standard experimental paradigms allowed us to test multitasking abilities across five different empirical indices (i.e., performance costs) for both reaction time (RT) and accuracy measures, respectively. Multitasking resulted in substantial performance costs across all experimental conditions without a single significant gender difference in any of these ten measures, even when controlling for gender differences in underlying cognitive abilities. Thus, our results do not confirm the widespread stereotype that women are better at multitasking than men at least in the popular sequential and concurrent multitasking settings used in the present study.
