Antagonism of regulatory ISGs enhances the anti-melanoma efficacy of STING agonists

BackgroundStimulator of Interferon Genes (STING) is a dsDNA sensor that triggers type I inflammatory responses. Recent data from our group and others support the therapeutic efficacy of STING agonists applied intratumorally or systemically in a range of murine tumor models, with treatment benefits associated with tumor vascular normalization and improved immune cell recruitment and function within the tumor microenvironment (TME). However, such interventions are rarely curative and STING agonism coordinately upregulates expression of immunoregulatory interferon-stimulated genes (ISGs) including Arg2, Cox2, Isg15, Nos2, and Pdl1 that may limit treatment benefits. We hypothesized that combined treatment of melanoma-bearing mice with STING agonist ADU-S100 together with antagonists of regulatory ISGs would result in improved control of tumor growth vs. treatment with ADU-S100 alone.MethodsMice bearing either B16 (BRAFWTPTENWT) or BPR20 (BRAFV600EPTEN-/-) melanomas were treated with STING agonist ADU-S100 plus various inhibitors of ARG2, COX2, NOS2, PD-L1, or ISG15. Tumor growth control and changes in the TME were evaluated for combination treatment vs ADU-S100 monotherapy by tumor area measurements and flow cytometry/transcriptional profiling, respectively.ResultsIn the B16 melanoma model, we noted improved antitumor efficacy only when ADU-S100 was combined with neutralizing/blocking antibodies against PD-L1 or ISG15, but not inhibitors of ARG2, COX2, or NOS2. Conversely, in the BPR20 melanoma model, improved tumor growth control vs. ADU-S100 monotherapy was only observed when combining ADU-S100 with ARG2i, COX2i, and NOS2i, but not anti-PD-L1 or anti-ISG15. Immune changes in the TME associated with improved treatment outcomes were subtle but included increases in proinflammatory innate immune cells and activated CD8+CD69+ T cells and varied between the two tumor models.ConclusionsThese data suggest contextual differences in the relative contributions of individual regulatory ISGs that serve to operationally limit the anti-tumor efficacy of STING agonists which should be considered in future design of novel combination protocols for optimal treatment benefit

Aneuploidy and prognosis of non-small-cell lung cancer: a meta-analysis of published data

In lung cancer, DNA content abnormalities have been described as a heterogeneous spectrum of impaired tumour cell DNA histogram patterns. They are merged into the common term of aneuploidy and probably reflect a high genotypic instability. In non-small-cell lung cancer, the negative effect of aneuploidy has been a subject of controversy inasmuch as studies aimed at determining the survival–DNA content relationship have reported conflicting results. We made a meta-analysis of published studies aimed at determining the prognostic effect of aneuploidy in surgically resected non-small-cell lung cancer. 35 trials have been identified in the literature. A comprehensive collection of data has been constructed taking into account the following parameters: quality of specimen, DNA content assessment method, aneuploidy definition, histology and stage grouping, quality of surgical resection and demographic characteristics of the analysed population. Among the 4033 assessable patients, 2626 suffered from non-small-cell lung cancer with aneuploid DNA content (overall frequency of aneuploidy: 0.65; 95% CI: (0.64–0.67)). The DerSimonian and Laird method was used to estimate the size effects and the Peto and Yusuf method was used in order to generate the odds ratios (OR) of reduction in risk of death for patients affected by a nearly diploid (non-aneuploid) non-small-cell lung cancer. Survivals following surgical resection, from 1 to 5 years, were chosen as the end-points of our meta-analysis. Patients suffering from a nearly diploid tumour benefited from a significant reduction in risk of death at 1, 2, 3 and 4 years with respective OR: 0.51, 0.51, 0.45 and 0.67 (P< 10−4for each end-point). 5 years after resection, the reduction of death was of lesser magnitude: OR: 0.87 (P = 0.08). The test for overall statistical heterogeneity was conventionally significant (P< 0.01) for all 5 end-points, however. None of the recorded characteristics of the studies could explain this phenomenon precluding a subset analysis. Therefore, the DerSimonian and Laird method was applied inasmuch as this method allows a correction for heterogeneity. This method demonstrated an increase in survival at 1, 2, 3, 4 and 5 years for patients with diploid tumours with respective size effects of 0.11, 0.15, 0.20, 0.20 and 0.21 (value taking into account the correction for heterogeneity;P< 10−4for each end-point). Patients who benefit from a surgical resection for non-small-cell lung cancer with aneuploid DNA content prove to have a higher risk of death. This negative prognostic factor decreases the probability of survival by 11% at one year, a negative effect deteriorating up to 21% at 5 years following surgery. © 2001 Cancer Research Campaign http://www.bjcancer.co

Stress and breast cancer: from epidemiology to molecular biology

Stress exposure has been proposed to contribute to the etiology of breast cancer. However, the validity of this assertion and the possible mechanisms involved are not well established. Epidemiologic studies differ in their assessment of the relative contribution of stress to breast cancer risk, while physiological studies propose a clear connection but lack the knowledge of intracellular pathways involved. The present review aims to consolidate the findings from different fields of research (including epidemiology, physiology, and molecular biology) in order to present a comprehensive picture of what we know to date about the role of stress in breast cancer development

Using student data to improve response to a multisyllabic word reading intervention : the effects of varying levels of data use

One recommended way to intensify intervention, particularly for struggling readers with the most severe difficulties, is intervention intensification using student data—a process referred to as data-based individualization (DBI; Deno & Mirkin, 1977; National Center on Intensive Intervention [NCII], 2013). To date, there is a dearth of research on word reading interventions that target 4ᵗʰ and 5ᵗʰ grade students (Wanzek, Wexler, Vaughn, & Ciullo, 2010), as well as reading interventions that utilize DBI to intensify such interventions (Filderman, Toste, Didion, Peng, & Clemens, 2018). As such, this randomized controlled trial explored the use of DBI for 4ᵗʰ and 5ᵗʰ grade struggling readers within the context of a research-based multisyllabic word reading intervention (Toste, Capin, Vaughn, Roberts, & Kearns, 2017; Toste, Capin, Williams, Cho, & Vaughn, 2019). In addition to adding to the literature on this understudied population, I also evaluated whether the use of data to customize instruction at the beginning of intervention is enough to improve results of struggling readers, or whether additional adjustment using progress monitoring with explicit decision-making rules improves results above and beyond initial customization of intervention protocol. Accordingly, I compared two treatment conditions to a business-as-usual condition. One treatment condition received initial customization of intervention, with adjustments made to the amount of time students spent in each of the instructional components based on their initial decoding abilities. The second treatment condition received the same customization, but at the mid-point of the study, ongoing curriculum-based measurement and specific subskill mastery measurement was used to evaluate student response, with instruction individualized for students who demonstrated inadequate response. Results indicated that students in both treatment conditions outperformed the comparison condition on multisyllabic word reading, and that students in the DBI condition also outperformed comparison students on decoding. Both treatment conditions performed worse than the comparison on a test of sentence-level comprehension efficiency. I conclude with a discussion of the potential reasons for these findings, as well as implications and future directions for research and practice.Special Educatio

De la rétroactivité de la condition dans les conventions.

Diss. doct. Pari

Some Characteristics of Successful Alumni

published or submitted for publicatio

The anti-inflammatory action of some steroid glycoside alkaloids isolated from crown gall tumors

The work described in this thesis presents data which shows that the steroid glycoside alkaloids (Tomatine and Gomatine) recently isolated from crown gall infected tomato stalks exert anti-inflammatory activity in experimental animals. The oral or parenteral administration of Tomatine one hour prior to injecting carrageenan into rat hind paws significantly inhibited paw swelling in both intact and adrenalectomized animals

Data Teams in Teacher Preparation: Improving Data-Based Instruction in Reading

Education and Child Studie