tbuckley/cabot-search huggingface dataset:
Abstract 5914: URI participates in cisplatin-induced DNA damage repair of gastric cancer cells via the ATM/CHK2 pathway
Authors: Huiqin Bian, Yaojuan Lu, Yu Gu, Xiaojing Zhang, Lichun Sun, Junxia Gu, Qiping Zheng
Journal: Cancer Research (2020)

Abstract Gastric cancer is the most common gastrointestinal malignant tumor and also the second leading cause of cancer-related mortality worldwide. Given its high rate of non- symptoms at early stage, gastric cancer is usually diagnosed at middle or advanced stage with metastasis. Therefore, chemotherapy, including Cisplatin, becomes a main treatment option, in addition to surgery. However, it is not uncommon for patients to develop cisplatin resistance which limits its clinical applications. URI, a prefoldin family member and also an oncoprotein, has been shown to promote multiple cancer development, including gastric cancer. The aim of this study was to investigate how URI may participate in the DNA damage repair of gastric cancer cells induced by Cisplatin and its possible mechanism via the ATM/CHK2 pathway. URI knockdown cell lines from gastric cancer cells MGC-803 and SGC-7901 were established and treated with different concentrations of Cisplatin. Cell viability, proliferation and apoptosis were analyzed by CCK-8, EDU assay, and flow cytometry respectively. DNA injury marker H2AX were examined by qRT-PCR and Western blot analysis. Comet assay was used to detect the DNA damage. The results showed that URI knockdown reduces cell viability and proliferation, as well as the Cisplatin-induced apoptosis of gastric cancer cells. Cisplatin dose responsively induced DNA damage in gastric cancer cells and URI knockdown enhanced this damage as indicated by comet assay and increased γH2AX expression. We have also detected increased levels of P-ATM and P-CHK2 in gastric cancer cells treated with Cisplatin, while URI knockdown decreased the P-ATM and P-CHK2 expression after the cells were treated with cisplatin for 12 hours. Taken together, our results support that URI reduces DNA damage and promotes DNA repair of gastric cancer cells induced by cisplatin and therefore, enhances its resistance possibly via the ATM/CHK2 pathway Citation Format: Huiqin Bian, Yaojuan Lu, Yu Gu, Xiaojing Zhang, Lichun Sun, Junxia Gu, Qiping Zheng. URI participates in cisplatin-induced DNA damage repair of gastric cancer cells via the ATM/CHK2 pathway [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5914.
Abstract 2906: SGN-B6A: A new MMAE ADC targeting integrin beta-6 in multiple carcinoma indications
Authors: Robert P. Lyon, Michael W. Schmitt, Mechthild Jonas, Christopher E. Franz, Esther S. Trueblood, Roma Yumul, Lori Westendorf, Maureen C. Ryan
Journal: Cancer Research (2020)

Abstract The integrins are a large family of cell surface receptors with diverse roles in cellular adhesion, motility, and cytokinesis. Functional integrins exist as heterodimers consisting of single alpha and beta chains. Within this family, integrin beta-6 (which dimerizes exclusively with isoform alpha-v) is of particular note for its role in cancer. Integrin beta-6 is overexpressed in numerous solid tumors and multiple investigators have noted its expression as a negative prognostic indicator in diverse cancers including colorectal, non-small cell lung, gastric, and cervical. SGN-B6A is an antibody-drug conjugate (ADC) targeting integrin beta-6 to deliver the clinically validated payload monomethyl auristatin E (MMAE). The antibody component of SGN-B6A is specific for integrin beta-6 and does not bind other alpha-v family members. In preclinical studies, this ADC has demonstrated activity in vivo in models derived from pancreatic, pharyngeal, and bladder carcinomas spanning a range of antigen expression levels at doses of 1 or 3 mg/kg given weekly for three doses. In exploratory toxicology studies in cynomolgus monkeys, doses of up to 5 mg/kg weekly for three doses or 6 mg/kg every 3 weeks for two doses were tolerated. Hematologic toxicities typical of MMAE ADCs were dose limiting and no evidence of target-mediated toxicity was observed. A Phase I first-in-human study is planned to evaluate the safety and antitumor activity of SGN-B6A in a variety of solid tumors known to express integrin beta-6. Citation Format: Robert P. Lyon, Michael W. Schmitt, Mechthild Jonas, Christopher E. Franz, Esther S. Trueblood, Roma Yumul, Lori Westendorf, Maureen C. Ryan. SGN-B6A: A new MMAE ADC targeting integrin beta-6 in multiple carcinoma indications [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2906.
Abstract 3323: <i>In situ</i> multiplex analysis of resident microglia and infiltrating macrophages in glioblastoma
Authors: Nicolas Goulange, Amanda Finan-Marchi, Maroua Tliba, Manon Motte, Fanny Estermann, Alexandre Vernay, Jean-Philippe Coton, Renaud Burrer
Journal: Cancer Research (2020)

Abstract Glioblastoma mutliforme (GBM) is the most malignant primary brain tumor. Resident microglia and peripheral infiltrating macrophages account for up to half of the non-neoplastic cells in a GBM. These tumor-associated macrophages have been implicated in proliferation, angiogenesis, and immunosuppression in GBM and can influence the efficacy of chemo-, radio-, and immunotherapies. However, certain cancer specific interactions have been associated with either microglia or macrophages, necessitating an approach that can delineate the two populations. Multiplex immunofluorescence offers a technical advantage that allows for the profound phenotyping of cells in the tumor microenvironment as well as their spatial organization. We have designed a multiplex immunofluorescence protocol to differentiate microglia and infiltrating M1/M2 macrophages in GBM in situ. Human GBM tissues were investigated with a multiplex panel consisting of GFAP, TMEM119, CD68, c-maf, and CD163. After multi-spectral acquisition, the microglia and macrophage populations could be easily phenotyped and localized in all of the tissues examined. Microglia and peripherally recruited M1 and M2 macrophages were quantified. The spatial distribution of the populations within the tumor core, edge, or margin was evaluated. The approach presented here demonstrates the power of multiplex immunohistochemistry in the phenotyping and spatial analysis of resident and recruited immune cell populations on a single tissue section and the potential application of this method in clinical studies. Citation Format: Nicolas Goulange, Amanda Finan-Marchi, Maroua Tliba, Manon Motte, Fanny Estermann, Alexandre Vernay, Jean-Philippe Coton, Renaud Burrer. In situ multiplex analysis of resident microglia and infiltrating macrophages in glioblastoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3323.
Abstract 1752: Inhibition of histone demethylase KDM6B as a promising target for non-small cell lung cancer
Authors: Jessika C. Lesbon, Pedro L. Xavier, Taismara K. Garnica, Arina L. Rochetti, Rui M. Reis, Susanne Müller, Heidge Fukumasu
Journal: Cancer Research (2020)

Abstract Despite advances in diagnostic and therapeutic approaches, the majority of lung cancer patients still progress to advanced stages with metastatic lesions. Abnormalities in epigenetic mechanisms are related to the most malignant cancer phenotypes. Thus, there is an increasing interest in the development and validation of drugs that targets epigenetic proteins. Trimethylation of H3K27 is an important post-translational modification and some studies have shown that KDM6B (lysine (K)-specific demethylase 6B), an H3K27 demethylase, is a crucial regulator involved in tumorigenesis and play important roles in various types of cancers. In this study, our goal was to determine potential epigenetic targets to control invasion and migration of NSCLC cancer cells. Initially, KDM6B was found a promise target through in silico analysis for the inverse correlation between gene expression and overall survival on 2438 NSCLC cases from GEO, EGA and TCGA using KMplotter tool and selecting the genes according to HR and p-values (HR &amp;gt; 1 and p &amp;lt; 0.05). Next, NSCLC cell lines (A549, H23, H2126 and H1568) were evaluated for the expression of the KDM6B using CellExpress tool and next by real-time PCR and one cell was chosen for cytotoxicity of the KDM6B inhibitor (GSK-J4) for 72h by MTT assay. The IC50 value and the regression curve were calculated with 6.0 Prism (GraphPad Software, USA). KDM6B gene expression was inversely correlated with patient survival rate for pulmonary adenocarcinoma (HR= 2.81; p= 6,3E-09). All pulmonary adenocarcinoma cell lines expressed KDM6B gene and low expression in healthy lung tissue (Z-score= 2.8). The KDM6B IC50 for A549 cells was 2.78±0.09μM. These early findings report that KDM6B as a promising target for epigenetic therapy for pulmonary adenocarcinoma. Therefore, our next step will be to evaluate the potential of KDM6B inhibition on the phenotype of cancer cell migration and invasion and global analysis of gene expression to understand genes and mechanisms associated with possible inhibitory effects of KDM6B. Citation Format: Jessika C. Lesbon, Pedro L. Xavier, Taismara K. Garnica, Arina L. Rochetti, Rui M. Reis, Susanne Müller, Heidge Fukumasu. Inhibition of histone demethylase KDM6B as a promising target for non-small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1752.
Abstract SY20-01: USP18 modulates the ISGylome immune signaling, and sensitizes tumor cells to irradiation and CTL recognition
Authors: Benedikt Kessler
Journal: Cancer Research (2021)

Abstract Interferon (IFN) signalling pathways, a key element of the innate immune response, contribute to resistance to conventional chemotherapy, radiotherapy, and immunotherapy, and are often deregulated in cancer. The deubiquitylating enzyme USP18 is a major negative regulator of the IFN signalling cascade and is the predominant human protease that cleaves ISG15, a ubiquitin-like protein tightly regulated in the context of innate immunity, from its modified substrate proteins in vivo. In this study, using advanced proteomic techniques, we have significantly expanded the USP18-dependent ISGylome and proteome in a chronic myeloid leukaemia (CML)-derived cell line. USP18-dependent effects were explored further in CML and colorectal carcinoma cellular models. Novel ISGylation targets were characterised that modulate the sensing of innate ligands, antigen presentation and secretion of cytokines. Consequently, CML USP18-deficient cells are more antigenic, driving increased activation of cytotoxic T lymphocytes (CTLs) and are more susceptible to irradiation. Our results provide strong evidence for USP18 in regulating antigenicity and radiosensitivity, highlighting its potential as a cancer target. Citation Format: Benedikt Kessler. USP18 modulates the ISGylome immune signaling, and sensitizes tumor cells to irradiation and CTL recognition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr SY20-01.
Patients With Type 2 Diabetes Have an Increased Demand for Pacemaker Treatment: A Comparison With Age- and Sex-Matched Control Subjects From the General Population
Authors: Elina Rautio, Fredrik Gadler, Soffia Gudbjörnsdottir, Stefan Franzén, Lars Rydén, Ann-Marie Svensson, Linda G. Mellbin
Journal: Diabetes Care (2020)

OBJECTIVE Patients with type 2 diabetes have an increased risk for cardiovascular disease, including arrhythmias. The prevalence of bradyarrhythmia and the subsequent need for treatment with pacemakers (PMs) is less well explored in a contemporary patient population. The current study explores 1) whether patients with type 2 diabetes have an increased demand for PM implantation compared with an age- and sex-matched control population without diabetes and 2) patient characteristics associated with an increased demand for receiving a PM. RESEARCH DESIGN AND METHODS In this population-matched registry study, a total of 416,247 patients with type 2 diabetes from the Swedish National Diabetes Registry and 2,081,235 age- and sex-matched control subjects selected from the general population were included between 1 January 1998 and 31 December 2012 and followed until 31 December 2013. Mean follow-up time was 7 years. Cox proportional hazards regression analyses were performed to estimate the demand of PM treatment and the factors identifying patients with such demand. RESULTS Type 2 diabetes was associated with an increased need of PM treatment (hazard ratio 1.65 [95% CI 1.60–1.69]; P &amp;lt; 0.0001), which remained (1.56 [1.51–1.60]; P &amp;lt; 0.0001) after adjustments for age, sex, educational level, marital status, country of birth, and coronary heart disease. Risk factors for receiving a PM included increasing age, HbA1c, BMI, diabetes duration, and lipid- and blood pressure–lowering medication. CONCLUSIONS The need for PM treatment is higher in patients with type 2 diabetes than in matched population-based control subjects. Age, diabetes duration, and HbA1c seem to be risk factors for PM treatment.
Human keratinocytes release the endogenous ß-galactoside-binding soluble lectin BP (IgE-binding protein) which binds to Langerhans cells where it selectively modulates their binding capacity for hypo sialylated IgE species.
Authors: A. Wollenberg, H. Delasalle, D. Hanau, F. T. Liu, T. Bieber
Journal: The Journal of Experimental Medicine (1993)
Abstract 4956: PrPc depletion in glioblastoma patient derived xenograft cells by CRISPR/Cas9
Authors: Maria Isabel Melo Escobar, Barbara Paranhos Coelho, Mariana Brandão Prado, Rebeca Iglesia, Marilene Hohmuth Lopes
Journal: Cancer Research (2020)

Abstract Glioblastoma (GBM), the most common primary malignant brain tumor, exhibits a highly proliferative cell subpopulation called Glioblastoma stem-like cells (GSCs), presumed to contribute to the aggressive behavior of GBM. Our group has shown that the Prion Protein (PrPC), a cell surface glycoprotein and regulator of several stem cell functions, is enriched in GSCs and co-expresses with conventional GSCs markers. PrPC has been proposed as a scaffold protein, able to govern the assembly of multi-component complexes in the cell membrane. Integrin α6 (ITGA6), a cell surface laminin receptor, is enriched in GSCs as well, and exhibits relevant effects on GSCs biology, related to self-renewal and migration. To investigate a potential association between PrPC and ITGA6, we will perform loss-of-function experiments in GSCs via siRNA and CRISPR/Cas9 to characterize these cell surface molecules expression and their effect on GSCs proliferation, migration and invasion. Preliminary results show that depletion of PrPC perturbates ITGA6 labeling on plasma membrane of GSC. Thus far, cells from patient-derived xenografts (GBM33-PDX2) were transfected a construct for PrPC knockout by CRISPR/Cas9 via Nucleofector Technology. We found around 60% GFP-positive cells via flow cytometry for the CRISPR pool and we are currently isolating clones to confirm PrPC expression. Remarkably, the colonies exhibited distinct morphologies such as neural-like, epithelial-like and stem cell-like, indicating the heterogenous nature of this tumor. Western blotting assays will be performed to assess PrPC and ITGA6 expression in both commercial cell line U87 and GBM33-PDX2. The characterization of PrPC-ITGA6 association might provide insight into GSCs behavior and new anti-GBM therapeutic strategies. Citation Format: Maria Isabel Melo Escobar, Barbara Paranhos Coelho, Mariana Brandão Prado, Rebeca Iglesia, Marilene Hohmuth Lopes. PrPc depletion in glioblastoma patient derived xenograft cells by CRISPR/Cas9 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4956.
Abstract 2568: Characterization of metabolic changes induced by anti-cancer drugs in MCF7 and MDA-MB-231 cell lines
Authors: David L. Hoffman, Michael Pisano
Journal: Cancer Research (2020)

Abstract Chemotherapeutics can have profound effects on cancer cell metabolism due to either direct or indirect effects. In many instances these effects can vary based on cell type, and level of cancer type aggressiveness. Here we focus on two breast cancer cell lines MCF7, and the triple negative MDA-MB-231 cells in a panel of assays designed to study specific aspects of cellular metabolism. The cells will be screened against three chemotherapeutics which have previously been shown to have effects on cellular metabolism, paclitaxel, AG-879 and oxaliplatin, and the mitochondrial targeted antioxidant mitoquinol (MitoQ), which has been shown to exhibit anticancer properties. Assays in this panel include cell growth, mitochondrial function, oxidative stress, lysosomal function and lipid storage. Through the utilization of this panel of assays panel, we compare the different metabolic phenotypes of two breast cancer cell lines with varied severity. Additionally, we demonstrate the effects that a small subset of anti-cancer agents has across a wide range of metabolic processes Citation Format: David L. Hoffman, Michael Pisano. Characterization of metabolic changes induced by anti-cancer drugs in MCF7 and MDA-MB-231 cell lines [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2568.
Abstract 564: Futibatinib (TAS-120) plus chemotherapy demonstrates a synergistic effect across various <i>FGFR</i>-deregulated cancer cell lines and xenograft models
Authors: Hiroshi Sootome, Akihiro Miura, Toshiharu Komori, Hiroshi Hirai
Journal: Cancer Research (2020)

Abstract Introduction: Futibatinib, a selective, irreversible fibroblast growth factor receptor (FGFR) 1-4 inhibitor, has antitumor activity in FGFR-deregulated cancer models. The potential synergistic antitumor effects of targeted therapy plus chemotherapy (chemo) was evaluated by combining futibatinib with cytotoxic agents in in vitro and in vivo models. Methods: Gastric, breast, lung, endometrial, and bladder cancer cell lines with various FGFR aberrations were treated with futibatinib and cytotoxic agents (5-FU, paclitaxel, cisplatin, or gemcitabine) individually or in combination. In vitro cytotoxicity of futibatinib was assessed by PARP cleavage activity. Any combination effect on cell growth was determined by the Bliss independence method, combination index (CI; CalcuSyn software), or isobologram analysis. The antitumor effects of futibatinib plus S-1 or paclitaxel and futibatinib plus gemcitabine or cisplatin were evaluated in gastric FGFR2-amplified SNU-16 and endometrial FGFR2-N549K-mutated AN3CA mouse xenograft models, respectively, by measuring relative tumor volume (RTV). Results: A synergistic effect on cell growth inhibition was observed with futibatinib plus chemo in SNU-16 cells (CIs at ED90 were 0.50 [5-FU], 0.71 [paclitaxel], 0.76 [cisplatin], and 0.29 [gemcitabine]). Increased PARP cleavage and decreased cell growth were observed in SNU-16 cells treated with futibatinib plus 5-FU vs monotherapy. Synergized cell growth inhibition occurred in various FGFR-deregulated cancer cell lines. In xenograft models, vs monotherapy, a significant reduction (P&amp;lt;0.01) in RTV occurred with futibatinib plus S-1, paclitaxel (Table), or cisplatin and a numerically greater reduction with futibatinib plus gemcitabine. Table.Relative tumor volume in SNU-16 mouse xenografts treated with futibatinib or paclitaxel or combination therapyTreatment (mg/kg/d)Relative tumor volumeDay 0Day 4Day 8Day 11Day 15Control11.562.373.344.58Futibatinib (5)a11.321.952.773.83Futibatinib (15)a11.211.822.453.16Paclitaxel (60)b10.480.410.410.59Futibatinib + paclitaxel (5 + 60)c10.470.270.170.14Futibatinib + paclitaxel (15 + 60)c10.440.220.120.07aDays 1-14 (oral).bDay 1 (intravenous).cDays 1-14 + Day 1. Conclusions: Futibatinib showed a synergistic antitumor effect in vitro and in vivo when combined with various cytotoxic agents. These data are promising and warrant further investigation. Citation Format: Hiroshi Sootome, Akihiro Miura, Toshiharu Komori, Hiroshi Hirai. Futibatinib (TAS-120) plus chemotherapy demonstrates a synergistic effect across various FGFR-deregulated cancer cell lines and xenograft models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 564.
Abstract 4576: Oncolytic vaccinia virus TG6010 expressing cytidine deaminase induces DNA damage and shows potent anti-tumor effects
Authors: Johann Foloppe, Juliette Kempf, Christelle Pichon, Annie Findeli, Isabelle Farine, Julie Hortelano, Baptiste Moreau, Michèle Klein, Sandrine Cochin, Renée Brandely, Véronique Koerper, Nathalie Silvestre, Christelle Machon, Jérôme Guitton, Eric Quéméneur, Philippe Erbs
Journal: Cancer Research (2020)

Abstract The recombinant Vaccinia virus Copenhagen strain deleted in Thymidine Kinase and Ribonucleotide Reductase (VVCOPTK−RR−) is a potent and versatile oncolytic platform that has demonstrated strong activity in various preclinical models. The deletion of such VV genes inhibits viral replication in normal cells, while retaining therapeutic replication in tumor cells. TG6002, a VVCOPTK−RR− expressing the suicide gene FCU1, is under investigation in Phase I trials in patients with advanced gastrointestinal tumors. We have developed a new product based on the VVCOPTK−RR− vector, named TG6010, expressing the human cytidine deaminase (CDA) that efficiently catalyzes the deamination of cytidine and deoxycytidine to uridine and deoxyuridine, respectively. The tumor specific expression of CDA by the VV leads to a depletion of cytidine and deoxycytidine. This cytidine/deoxycytidine depletion resulting from CDA overexpression, activated a DNA damage response highlighted by an induction of H2AX phosphorylation. Next, to validate the potential therapeutic use of TG6010, we analyzed the effects of the virus on human xenograft tumors implanted in mice. We observed, after systemic injection of TG6010, high expression of CDA in the tumors with a significant increase in DNA damage in vivo as revealed by the γH2AX foci assay. In addition, intraperitoneal administration of TG6010 in a xenograft model of human ovarian carcinomatosis resulted in significantly prolonged animal survival. In conclusion, the oncolytic vaccinia virus expressing the cytidine deaminase (TG6010) has shown potent anti-tumor effects. Mechanistically, due to the cytidine deaminase overexpression, we observed induction of a DNA damage response. These are data encouraging of clinical development for this highly potent oncolytic Vaccinia virus TG6010 against ovarian cancer. Citation Format: Johann Foloppe, Juliette Kempf, Christelle Pichon, Annie Findeli, Isabelle Farine, Julie Hortelano, Baptiste Moreau, Michèle Klein, Sandrine Cochin, Renée Brandely, Véronique Koerper, Nathalie Silvestre, Christelle Machon, Jérôme Guitton, Eric Quéméneur, Philippe Erbs. Oncolytic vaccinia virus TG6010 expressing cytidine deaminase induces DNA damage and shows potent anti-tumor effects [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4576.