tbuckley/cabot-search huggingface dataset:
Abstract 4915: Nerve growth factor (NGF) facilitates LOX expression and promotes tumor metastasis by inhibiting miR-149-5p in human chondrosarcoma cells
Authors: Anoop Thadevoos Louis, Chih-Yang Lin, Chih-Hsin Tang
Journal: Cancer Research (2020)

Abstract Chondrosarcomas are malignant bone tumors that commonly produce cartilaginous chondroid matrix and are associated with metastases in the lung, especially in patients with high-grade chondrosarcoma. Neurotrophins such as nerve growth factor (NGF) are recognized as being drivers of neurogenesis during development and regeneration, and their expression in human tumors can stimulate cancer cell growth. Importantly, the infiltration of nerves in the tumor microenvironment actively stimulates cancer cell mitogenesis, invasiveness and metastasis. Until now, it has been unclear as to the potential involvement of NGF in human chondrosarcoma metastasis. This study reports that NGF induces migration and invasion of chondrosarcoma cell lines JJ012 and SW1353 and significantly increasing LOX expression. Significant dose-dependent increases were observed in levels of LOX mRNA and protein expression in both cell lines. In immunohistochemistry analyses, levels of NGF and LOX expression in human chondrosarcoma cartilage correlated with tumor stage and were substantially higher than NGF and LOX expression in normal cartilage. NGF-induced stimulation of metastasis and increases in LOX expression were prevented by pretreatment of the cell lines with PI3K, Akt and mTOR inhibitors, or transfection with small interfering RNAs (siRNAs). Further analysis revealed that NGF induced PI3K/Akt/mTOR signaling and dose-dependently downregulated mature microRNA-149-5p (miR-149-5p), which targets the 3' untranslated region (3'-UTR) of LOX. Furthermore, JJ012 cells overexpressing NGF induced LOX expression and increased cell migration and invasion. In summary, NGF stimulates LOX expression and promotes chondrosarcoma cell migration and invasion by inhibiting miR-149-5p via the PI3K/Akt/mTOR signaling pathway. Citation Format: Anoop Thadevoos Louis, Chih-Yang Lin, Chih-Hsin Tang. Nerve growth factor (NGF) facilitates LOX expression and promotes tumor metastasis by inhibiting miR-149-5p in human chondrosarcoma cells [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 4915.
Abstract 2391: Centromeric chromatin alteration is associated with increase in alphoid array replication fork speed in ovarian cancer cell lines
Authors: Indri Erliandri, Christophe Redon, Jung-Hyun Kim, Haiqing Fu, Mirit Aladjem, William Reinhold, Vladimir Larionov
Journal: Cancer Research (2020)

Abstract The centromere is well known as the center point of cell division, with aberrant centromeric function leading to mitotic dysfunction and chromosomal abnormalities. These abnormalities may in turn lead to diseases, including cancer and premature aging. Binding of CENPB to the CENPB box is orchestrated epigenetically, and has emerged as an important factor in the regulation of the centromeric-chromatin structural landscape. CENP-B depletion that resulted in euchromatization of the alphoid centromere array, also is associated with elevated centromeric DNA replication activity. Observation in two ovarian cancer cells from NCI-60 collection; OVCAR3 and SKOV3, identified as having low and high expression of CENPB RNA respectively, indicates the different level of centromeric DNA instability. Centromeric DNA damage fraction is more abundant and replication fork velocity is elevated in less CENPB expresser cells, indicates alphoid array alteration. We conclude that CENP-B is required for maintenance of centromeric chromatin structure and centromeric DNA integrity. Citation Format: Indri Erliandri, Christophe Redon, Jung-Hyun Kim, Haiqing Fu, Mirit Aladjem, William Reinhold, Vladimir Larionov. Centromeric chromatin alteration is associated with increase in alphoid array replication fork speed in ovarian cancer 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 2391.
Abstract 14419: GSNOR Deficiency Causes Aberrant Placental S-nitrosylation and Preeclampsia
Authors: Shathiyah Kulandavelu, Raul A Dulce, Christopher I Murray, Wayne Balkan, Jennifer E Van Eyk, Joshua M Hare
Journal: Circulation (2019)

Introduction: Preeclampsia (PE), a leading cause of maternal and fetal mortality and morbidity, is characterized by an increase in S-nitrosylated (SNO) proteins and reactive oxygen species (ROS), s...
Abstract 3549: Low frequency of germline mutations in <i>POLE</i> and <i>POLD1</i> proofreading domains in Middle Eastern colorectal cancers
Authors: Rong Bu, Abdul K. Siraj, Kaleem Iqbal, Sandeep K. Parvathareddy, Tariq Masoodi, Nabil Siraj, Nabil Siraj, Maha Al-Rasheed, Sarah Siraj, Yan Kong, Saeeda O. Ahmed, Khadija A.S. Al-Obaisi, Ingrid G. Victoria, Khawla S. Al-Kuraya
Journal: Cancer Research (2020)

Abstract Colorectal cancer (CRC) is one of the main causes of cancer related morbidity and mortality. Only ~ 5% of all CRCs occur as a result of mutations in well-defined CRC predisposing genes. The underlying causes in genetically unexplained CRC cases from Middle Eastern region are still unknown. We performed Capture sequencing and Sanger sequencing to screen the proofreading domains of DNA Polymerase Epsilon (POLE) and DNA Polymerase Delta 1 (POLD1) genes to find out the genetic causes in over 1100 CRC cases from Middle Eastern region. In our cohort, five mutations (0.44%) were identified in 1135 CRC cases, four in POLE gene (0.35%, 4/1135) and one (0.1%, 1/1135) in POLD1 gene. These mutations have been infrequently reported in Western populations. Furthermore, low expression of POLE was noted in 38.9% (417/1071) of cases and showed significant association with lymph node involvement (p=0.0184) and grade 3 tumors (p=0.0139). Whereas, low expression of POLD1 was observed in 51.9% (555/1069) of cases and was significantly associated with adenocarcinoma histology (p=0.0164), larger tumor size (T3 and T4 tumors; p=0.0012) and stage III tumors (p=0.0341). Our findings revealed that there was a low frequency of mutations in POLE and POLD1 proofreading region in CRC cases and established that the mutations in the proofreading domain of these two genes were a rare cause of CRC in Middle Eastern region. It is feasible to screen multiple cancer related genes in CRC patients from Middle Eastern region using multigene panels including POLE and POLD1. Citation Format: Rong Bu, Abdul K. Siraj, Kaleem Iqbal, Sandeep K. Parvathareddy, Tariq Masoodi, Nabil Siraj, Nabil Siraj, Maha Al-Rasheed, Sarah Siraj, Yan Kong, Saeeda O. Ahmed, Khadija A.S. Al-Obaisi, Ingrid G. Victoria, Khawla S. Al-Kuraya. Low frequency of germline mutations in POLE and POLD1 proofreading domains in Middle Eastern colorectal cancers [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 3549.
Abstract 901: Ferritin nanocages to deliver CD47 antagonist, SIRPγ, for cancer immunotherapy
Authors: Yoonjeong Choi, Insan Kim
Journal: Cancer Research (2020)

Abstract Eliciting effective tumor antigen-specific immunity requires targeting the initial stages of the anticancer immunity cycle, including activation of antigen presenting cells (APCs) for tumor antigen uptake and presentation, and T cell priming. Here, the research aimed to explore the novel immunotherapeutic strategy using protein nanocage platform that enhances the phagocytic activity of phagocytes in combination with treatment of immunogenic cell death inducing agents, which could boost processing of antigens by APCs, thereby trigger efficient antitumor immunity. The recombinant ferritin protein nanocages expressing SIRPγ peptides, named FHSirpγ, was designed to interact with CD47 of cancer cells, which could effectively blocking ‘don't eat me signal', CD47. The binding affinity of FHSirpγ to cancer cells was reinforced by adapting several mutations on protein sequence, which showed up to 10 folds of improvement. Therefore, FHSirpγ was able to successfully stimulate phagocytosis of phagocytes toward various cancer cells, e.g. HT29, B16F10, CT26.CL25 and J558, up to approximately 2 folds in vitro. In the aspect of improvement in antigen release, Carfilzomib(CFZ), the FDA approved 2nd generation proteasome inhibitor on multiple myeloma, was treated to cancer cells, which showed tolerable level of cell cytotoxicities and enhanced release of danger associated molecular patterns(DAMPs), such as HSP70 and HMGB1, which were detected from cell culture medium after 24hrs of incubation on above mentioned cell lines. The antitumorigenic efficacy was preliminary verified in the case of B16F10 and J558 implanted murine tumor model, which showed approximately 75% of tumor growth regression when FHSirpγ and CFZ were treated intravenously. Overall, treatment of FHSirpγ showed antitumor efficacy via enhancement of phagocytosis in vivo and in vitro, especially when combined with immunogenic cell death inducer. Citation Format: Yoonjeong Choi, Insan Kim. Ferritin nanocages to deliver CD47 antagonist, SIRPγ, for cancer immunotherapy [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 901.
Abstract 5991: Glucose metabolic reprogramming in HBV-related hepatocellular carcinoma through C-terminal truncated HBx protein suppression of TXNIP
Authors: Yu Zhang
Journal: Cancer Research (2020)

Abstract Hepatitis B virus (HBV) infection has been proven strongly associated with the initiation and progression of hepatocellular carcinoma (HCC). However, a substantial amount of virally-induced mechanisms that cause malignant transformation in the liver remains largely unexplored, especially for HBV-induced metabolic reprogramming. In the present study, we identified and confirmed the HBV integration breakpoints clustering at the C-terminal X gene is a tumor-specific event, and the C-terminal HBx is expressed more frequently in the tumors than normal liver tissues. Then, the oncogenic effect of the truncated HBx was validated in vitro and in vivo. Transcriptome sequencing revealed that TXNIP, as a downstream target of truncated HBx, negatively regulates glucose metabolism. Screening of public database and our clinical cohort exhibited that TXNIP is significantly down-regulated in HCC patients with truncated HBx expression, compared to those with full-length HBx expression and HBV-negative patients. Lower expression of TXNIP is negatively correlated with patient survival. We also reported evidence that truncated HBx down-regulates TXNIP expression by transactivation via the transcriptional repressor NFACT2. Additionally, the re-introduction of TXNIP inhibited the metabolic reprogramming from mitochondrial respiration to aerobic glycolysis induced by truncated HBx and further resulted in HCC growth arrest in vitro and in vivo. In summary, our finding proposes a promising diagnostic and therapeutic strategy for HBV-induced HCC. Citation Format: Yu Zhang. Glucose metabolic reprogramming in HBV-related hepatocellular carcinoma through C-terminal truncated HBx protein suppression of TXNIP [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 5991.
Abstract 3595: Riboprotein variant and their role in chondrogenic differentiation and osteosarcoma development
Authors: Emilien Orgebin, Benjamin Ory, Francois Lamoureux, Marie-Francoise O'Donohue, Céline Charrier, Pierre-Emmanuel Gleizes, Bertrand Isidor, Marc Baud'huin
Journal: Cancer Research (2020)

Abstract Variants in genes encoding ribosomal proteins (RPs) have thus far been associated with Diamond-Blackfan anemia, a rare inherited bone marrow failure, and isolated congenital asplenia. We reported recently one de novo missense variant and three de novo splice variants in the RPL13 gene, which encodes ribosomal protein RPL13/eL13, in four unrelated individuals with a rare bone dysplasia causing severe short stature. The three splice variants (c.477+1G&amp;gt;T, c.477+1G&amp;gt;A, and c.477+2 T&amp;gt;C) result in partial intron retention, which leads to an 18-amino acid insertion. These RPL13 variants define a human ribosomopathy leading to a rare skeletal dysplasia and highlight the role of this ribosomal protein in bone development. It has been shown that patients suffering from ribosomopathies have a highly predisposition to develop cancer compared to general population. Moreover, recent studies have also revealed that mutations in factors involved in ribosome synthesis appear to be drivers of tumorigenesis in sporadic cancers. In this study, we focused on the role of variants of the riboprotein RPL13 in the bone biology and in the development of osteosarcoma. Mesenchymal stem cells expressing variants of RPL13 or wild type RPL13 have been cultured for chondrogenic and osteoblastic differentiation. Our results show that RPL13 variants did not modified the capacity of cells to differentiate into osteoblasts. However, the chondrogenic differentiation was increased in cells expressing variants of RPL13. The expression of sox9 and collagen type X were investigated by immunochemistry on chondrocyte micromass and revealed an increase of expression of these markers in RPL13 variants cells. We next investigated the role of variants of RPL13 in osteosarcoma cell lines. Several cell lines were transduced by lentiviral vector to produce variants of RPL13. The variants induced an increase of cell proliferation and survival. The clonogenecity and the invasion have been also studied. Taken together, these data show that variants of a gene encoding for a riboprotein causing a ribosomopathy could have an effect on chondrogenic differentiation and on osteosarcoma development. Citation Format: Emilien Orgebin, Benjamin Ory, Francois Lamoureux, Marie-Francoise O'Donohue, Céline Charrier, Pierre-Emmanuel Gleizes, Bertrand Isidor, Marc Baud'huin. Riboprotein variant and their role in chondrogenic differentiation and osteosarcoma development [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 3595.
Abstract 5548: Indicators of immune activation upon p14ARF and interferon-beta gene transfer in a human melanoma cell line
Authors: Otto Luiz Cerqueira, Maria Alejandra Salomon, Elaine Cristina Cardoso, Tharcisio Citrangulo Tortelli, Bryan Eric Strauss
Journal: Cancer Research (2020)

Abstract Immunoevasion adopted by tumor cells is an important cancer hallmark and understanding of its mechanisms has generated promising therapeutic approaches. In this context, triggering immunogenic cell death (ICD) is a promising idea since it alarms the immune system by attracting a myriad of cell populations that promote innate and adaptive immune responses. Since melanomas preserve wild-type p53 in over 80% of cases, our group developed a gene therapy strategy that utilizes an adenoviral vector with a p53-responsive promoter (PG). Here we present a critical advance for our approach, examining the immune activating potential of combined p14ARF and IFN-beta gene transfer in human melanoma cells. Our results indicate that IFN-beta alone or in combination with p14ARF was able to induce massive cell death accompanied by caspase 3/7 activation in the human melanoma cell line SKMEL147. In our animal model of in situ gene therapy, s.c. SKMEL147 tumors were established in Nod-scid mice before intratumoral virus injection, revealing tumor inhibition and improved survival in response to IFN-beta alone or in combination with p14ARF. However, this model cannot reveal immune activation and so far the benefit of p14ARF has not been revealed. Strikingly, three markers of ICD (exposition of calrecticulin, secretion of ATP and IFN-beta) were induced only when cells were treated with combined p14ARF and IFN-beta gene transfer. We then used PBMCs derived from normal donors as a source of DCs and lymphocytes. Coculture of DCs with previously-transduced SKMEL147 exhibit a typical phenotype of activation. Finally, coculture of these exposed DCs with lymphocytes results in high-level secretion of proinflammatory cytokines, followed by the increase of IL-10 in the samples treated with combination of p14ARF and IFN-beta. Collectively, our results indicate that the advantage of p14ARF and INF-beta delivered by our adenoviral system is the induction of cell death in human melanoma cells by an immune-activating mechanism. Future studies will include examination of this phenomenon in tumors from melanoma patients and using their own PBMCS. In parallel, the use of PDX model for in situ treatment will also be explored. Citation Format: Otto Luiz Cerqueira, Maria Alejandra Salomon, Elaine Cristina Cardoso, Tharcisio Citrangulo Tortelli, Bryan Eric Strauss. Indicators of immune activation upon p14ARF and interferon-beta gene transfer in a human melanoma cell line [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 5548.
Abstract 590: Efficacy evaluation of bispecific antibodies in humanized mice after B cell depletion
Authors: Tian Gan, Dirui Li, Hao Yang, Gary Ng, Yanan Li, Qingcong Lin
Journal: Cancer Research (2020)

Abstract The development of bifunctional/multifunctional therapeutics have gained tremendous traction in recent years. Preclinical efficacy evaluation of bi-functional antibody drugs faces two main problems: first is the often limited cross-reaction between the anti-human antibody and murine target in animals; second is the reduced efficacy as a result of neutralization of antibodies by anti-drug antibodies (ADA) in animals due to the high immunogenicity of some bi-specific antibodies. To eliminate the ADA production against bi-specific therapeutic agents, Biocytogen developed a B cell depletion method based on humanized mouse syngeneic xenograft tumor model for preclinical efficacy evaluation of bispecific antibodies. To a syngeneic xenograft tumor model (PD-L1 humanized mice inoculated subcutaneously with MC38-hPD-L1 cells), CD20 antibody was injected to deplete B cells in the mice for the inhibition anti-antibody production. A model bi-specific agent against PD-L1 and TGF-β was sequentially injected to the mice. The tumor inhibitory effect of the bi-specific was assessed by tumor growth inhibition rate (TGI) calculated from measured tumor volume. Blood samples were drawn from mice for B cell analysis. The clearance of B cells in the blood flow and the serum concentration (including ADA) in mice were analyzed by flow cytometry and ELISA, respectively. The results showed that B cells were effectively eliminated from the murine blood after injection of CD20 antibody. Despite of the absence of B cells, the tumor growth was inhibited upon the treatment with M7824 analog, compared with the control group. Corresponding to the efficacy results, the mice in B cells-depleted group maintained a normal drug concentration in the blood while reducing the production of anti-drug antibodies. In summary, the B cell depletion mice have been validated as a promising model for the efficacy evaluation of complex structure antibody (bi or multi-functional antibody). Citation Format: Tian Gan, Dirui Li, Hao Yang, Gary Ng, Yanan Li, Qingcong Lin. Efficacy evaluation of bispecific antibodies in humanized mice after B cell depletion [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 590.
Abstract 2207: Upfront metronomic chemotherapy synergizes with immunotherapy to optimize chemoimmunotherapy in squamous cell lung carcinoma
Authors: Xi-Ran He, Yang Du, Yu-Shen Jin, Hua Bai, Jie Tian, Jie Wang
Journal: Cancer Research (2020)

Abstract Background and purpose: For squamous cell lung carcinoma (SQCLC), the survival benefits of combining chemotherapy (at the maximum tolerated dose, MTD) with concurrent immune checkpoint inhibitors (ICIs), also known as chemoimmunotherapy, have been confirmed in recent clinical trials. Nevertheless, the actual relationship between MTD chemotherapy and ICIs remains controversial, as most oncologists considered that MTD chemotherapeutic agents could cause immunosuppression. Hence, we attempted to optimize and assess different combinatorial patterns of chemoimmunotherapy in SQCLC. Methods: We utilized the in vitro SQCLC cell lines, in vivo syngeneic immunocompetent mouse models, and patient samples to fully explore how to increase the ectopic lymphoid-like structures (ELSs) and the therapeutic targets for anti-programmed death 1 (PD-1) / anti PD-1 ligand (PD-L1) monoclonal antibodies (mAbs), as well as the underlying mechanisms, in order to render SQCLC to be more sensitive to ICIs and improve the efficacy of chemoimmunotherapy. Results: Low-dose chemotherapeutic agents induced SQCLC cells to undergo immunogenic cell death (ICD) by activating the PI3K/Akt/NF-κB signaling pathway and thereby enhancing neoantigen exposure. Following, the high mobility group box-1 released by cells undergoing ICD promoted neoantigen uptake and presentation by activating dendritic cells (DCs) and consequently invoking specific T cell responses. In vivo, low-dose chemotherapeutic agents activated systemic immune responses and immunological memory, and enhanced antitumor ELSs compared with routine MTD chemotherapy. Moreover, the upfront metronomic (low-dose and frequent administration) chemotherapy extended the time window of the immunostimulatory effect and synergized better with the subsequent administration of anti-PD-1/PD-L1 mAbs. One possible mechanism of this synergy is increasing the activated type I macrophages, DCs, and cytotoxic CD8+ T cells, and maintaining the diversity and normal composition of intestinal gut microbiota. In contrast, when combined with ICIs, the effects of routine MTD chemotherapy appeared to be additive rather than synergistic. Conclusion: The upfront metronomic chemotherapy better synergizes with immunotherapy over the routine MTD chemotherapy in SQCLC. This preclinical study provides a novel strategy to optimize chemoimmunotherapy, and it is worth being translated into the clinic in the future. Citation Format: Xi-Ran He, Yang Du, Yu-Shen Jin, Hua Bai, Jie Tian, Jie Wang. Upfront metronomic chemotherapy synergizes with immunotherapy to optimize chemoimmunotherapy in squamous cell lung carcinoma [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 2207.