Search results for "Heck"
showing 10 items of 682 documents
R-Roscovitine (Seliciclib) prevents DNA damage-induced cyclin A1 upregulation and hinders non-homologous end-joining (NHEJ) DNA repair.
2010
Abstract Background CDK-inhibitors can diminish transcriptional levels of cell cycle-related cyclins through the inhibition of E2F family members and CDK7 and 9. Cyclin A1, an E2F-independent cyclin, is strongly upregulated under genotoxic conditions and functionally was shown to increase NHEJ activity. Cyclin A1 outcompetes with cyclin A2 for CDK2 binding, possibly redirecting its activity towards DNA repair. To see if we could therapeutically block this switch, we analyzed the effects of the CDK-inhibitor R-Roscovitine on the expression levels of cyclin A1 under genotoxic stress and observed subsequent DNA damage and repair mechanisms. Results We found that R-Roscovitine alone was unable …
Efficacy and safety of first-line checkpoint inhibitors-based treatments for non-oncogene-addicted non-small-cell lung cancer: a systematic review an…
2021
Background: Frontline immune checkpoint inhibitors (ICI)-based regimens in non-oncogene-addicted non-small-cell lung cancer (NSCLC) have been deeply investigated. To rank the available therapeutic options, we carried out a systematic review and Bayesian meta-analysis. Methods: A comprehensive search for randomized controlled trials (RCTs) of ICI regimens, and a pairwise and a network meta-analysis (NMA) with an all-comers and a stratified strategy were conducted. Endpoints were overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and treatment-related adverse events (TRAEs). Results: Nineteen RCTs involving 17 treatment regimens were included. For the all-co…
Investigation of the immune infiltrate of melanoma metastases under immune checkpoint inhibition.
2017
9570 Background: Tumor infiltrating lymphocytes (TIL) play a crucial role in the therapeutic impact of immune checkpoint blockers. Methods: We investigated metastases from 56 melanoma patients before and during treatment with immune checkpoint blockers (i) immunohistochemically, (ii) with TCR repertoire profiling and (iii) analysis of the transcriptome. The patients were treated with ipilimumab (n = 25) or pembrolizumab (n = 23) or ipilimumab/nivolumab (n = 7); half of them had a disease control, the other half progressed as best response to treatment. Results: In contrast to previous reports immunohistochemical analysis of the immune infiltrate revealed no significant difference in the nu…
Baseline circulating myeloid-derived suppressor cells subpopulations, neutrophils/lymphocytes ratio, and response to PD-1/PD-L1 inhibitor in non-smal…
2020
e15042 Background: Inhibitors of immune checkpoint PD-1/PD-L1 (ICI) have become a care standard in non-small cell lung cancer (NSCLC). Despite promising results, some patients cannot take advantage of immunotherapy effects. Nowadays, neither predictive nor prognostic circulating biomarkers have been found in order to select patients or to predict response to ICI. Myeloid-derived suppressor cells (MDSC) are potent immunity suppressors and may represent both a potential prognostic and a predictive biomarker. We aimed to assess the role of pretreatment circulating MDSC subpopulations on ICI outcomes in NSCLC patients. Methods: 86 NSCLC patients treated with ICI and 10 healthy donors in 3 cent…
Role of PD-L1 expression in triple-negative breast cancer stem cells.
2018
12081Background: Triple negative breast cancer (TNBC) is characterized by poor prognosis, lack of specific-targeted agents and is in need of new therapeutics. Immune checkpoint blockers have shown ...
Topotecan-triggered degradation of topoisomerase I is p53-dependent and impacts cell survival.
2005
Abstract The anticancer drug topotecan belongs to the group of topoisomerase I (topo I) inhibitors. In the presence of topotecan, topo I cleaves the DNA but is unable to religate the single-strand break. This leads to stabilization of topo I-DNA–bound complexes and the accumulation of DNA strand breaks that may interfere with DNA replication. The molecular mechanism of controlling the repair of topo I-DNA covalent complexes and its impact on sensitivity of cells to topotecan is largely unknown. Here, we used mouse embryonic fibroblasts expressing wild-type p53 and deficient in p53, in order to elucidate the role of p53 in topotecan-induced cell death. We show that p53-deficient mouse embryo…
The EUROCARE-5 study on cancer survival in Europe 1999-2007: Database, quality checks and statistical analysis methods
2015
Abstract Background Since 25 years the EUROCARE study monitors the survival of cancer patients in Europe through centralised collection, quality check and statistical analysis of population-based cancer registries (CRs) data. The European population covered by the study increased remarkably in the latest round. The study design and statistical methods were also changed to improve timeliness and comparability of survival estimates. To interpret the EUROCARE-5 results on adult cancer patients better here we assess the impact of these changes on data quality and on survival comparisons. Methods In EUROCARE-5 the survival differences by area were studied applying the complete cohort approach to…
RB acute loss induces centrosome amplification and aneuploidy in murine primary fibroblasts
2006
AbstractBackgroundIncorrect segregation of whole chromosomes or parts of chromosome leads to aneuploidy commonly observed in cancer. The correct centrosome duplication, assuring assembly of a bipolar mitotic spindle, is essential for chromosome segregation fidelity and preventing aneuploidy. Alteration of p53 and pRb functions by expression of HPV16-E6 and E7 oncoproteins has been associated with centrosome amplification. However, these last findings could be the result of targeting cellular proteins in addition to pRb by HPV16-E7 oncoprotein. To get a more detailed picture on the role of pRb in chromosomal instability and centrosome amplification, we analyzed the effects of the acute loss …
Abstract 1847: Anti-GARP antibody DS-1055a augments antitumor immunity by depleting highly suppressive GARP+ regulatory T cells
2021
Abstract Immune checkpoint blockers (ICBs) have drastically changed the clinical care of cancer; however, the population of patients who can benefit is relatively small because of intrinsic or acquired resistance to immune therapy. To evade immune destruction, tumors exploit several distinct strategies including immunosuppressive cells such as regulatory T (Treg) cells. Treg cells, an essential component for maintaining self-tolerance, inhibit antitumor immunity, consequently hindering protective cancer immunosurveillance and hampering effective antitumor immune responses in tumor-bearing hosts. It is often reported that a high ratio of Treg cells to effector CD8+ T cells is associated with…
Abstract B290: Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors.
2013
Abstract The recent clinical success of therapeutic blockade of the immune checkpoint Programmed Death (PD)-1 in advanced lung cancer patients suggests that mechanisms of immune escape may contribute to lung tumor pathogenesis. We identified a correlation between Epidermal Growth Factor Receptor (EGFR) pathway activation and a gene signature indicative of immunosuppression manifested by upregulation of PD-1, PD-L1, cytotoxic T lymphocyte antigen-4 (CTLA-4) and multiple tumor-promoting inflammatory cytokines. Accordingly, we identified a decrease in the number of cytotoxic T cells and an increase in markers of T cell exhaustion in genetically engineered mouse models (GEMMs) of EGFR-driven lu…