tbuckley/cabot-search huggingface dataset:
Abstract 689: Anti-tumor activity of <i>Bifidobacterium</i> secreting dual specific T cell redirecting antibody against EGFR/HER3-expressing cancer
Authors: Satoshi Kobayashi, Koichiro Shioya, Yuji Seki, Tomio Matsumura, Yasuyoshi Kanari, Yuko Shimatani, Hikaru Nakazawa, Mitsuo Umetsu, Shiro Kataoka, Takaaki Nakamura
Journal: Cancer Research (2020)

Abstract Anti-cancer therapies targeting EGFR family, including monoclonal antibodies and kinase inhibitors, are the state of art for solid tumors such as colorectal and non-small cell lung cancers. T cell redirecting bispecific antibodies are a promising approach for cancer immune therapy, whereas their application is limited to hematological malignancy due to adverse events caused by the systemic exposure to highly immunologically active molecule. To avoid the immunological adverse events, we have created a recombinant Bifidobacterium (APS002) that specifically colonizes in solid tumor and continuously secretes T cell redirecting antibody. The antibody was designed to form a diabody based on the sequence of dual specific antibody for EGFR/HER3 and CD3. The diabody (termed DBERB1) comprises the equal amount of two polypeptides, anti-h CD3 (VL) - anti-EGFR/hHER3 (VH) and anti-hEGFR/hHER3 (VL) - anti-hCD3 (VH), respectively. DBERB1 bound to human EGFR and HER3, and human CD3. DBERB1 demonstrated potent cytotoxic activities against EGFR- and HER3-expressing human colon cancer HCT116 cells in the presence of human peripheral blood mononuclear cells (hPBMC) with EC50 values of 3 - 9 × 10−12 M. When APS002 was i.v. dosed to HCT116 tumor-bearing SCID mice inoculated with hPBMC, APS002 colonized only in the tumor and DBERB1 was detected in the tumors but not in the plasma. The growth of HCT116 tumors was significantly suppressed by APS002 but not by Bifidobacterium transfected with control vector. In conclusion, our study in the mouse model indicates that APS002 is a novel and an extremely potent anti-cancer agent distributed only in the tumor. We are currently preparing for pre-clinical studies for the future clinical trials. Citation Format: Satoshi Kobayashi, Koichiro Shioya, Yuji Seki, Tomio Matsumura, Yasuyoshi Kanari, Yuko Shimatani, Hikaru Nakazawa, Mitsuo Umetsu, Shiro Kataoka, Takaaki Nakamura. Anti-tumor activity of Bifidobacterium secreting dual specific T cell redirecting antibody against EGFR/HER3-expressing 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 689.
Abstract 4355: Different strategies for peritoneal lavage cytology testing in the staging of gastric cancer: A cost-effectiveness analysis
Authors: Qifei He, Jinyi Zhu, Anqiang Wang, Xia Li, Zhaode Bu, Jiafu Ji
Journal: Cancer Research (2020)

Abstract Background &amp; Aims: The positive peritoneal cytology (PCY) indicates metastasis disease in patients with gastric cancer (GC); thus, the cytology testing is directly related to subsequent treatments, patients' prognoses, and medical costs. However, the cost-effectiveness of PCY testing remains unclear. We aim to evaluate the cost-effectiveness of PCY testing by comparing two active testing strategies of a guideline-recommended intraoperative laparoscopic peritoneal lavage (ILPL) and a newly proposed preoperative percutaneous peritoneal lavage (PPPL), and a third strategy of exploratory laparotomy with no cytology testing (ELNC) among GC patients. Methods: We developed a decision-analytic Markov model to compare the cost-effectiveness of the above three strategies for a hypothetical cohort of GC patients with curative intent after initial imaging, from the perspective of Chinese society. Quality-adjusted life-years (QALYs), transition probabilities and costs were modeled using data mainly from published literature. We performed base case analysis and measured incremental cost-effectiveness ratios (ICERs) for various strategies, which were compared to a willingness-to-pay (WTP) threshold that was set to a three-fold of Chinese gross domestic product (GDP) per capita, $29,313/QALY gained. Furthermore, we conducted both one-way and probabilistic sensitivity analyses to investigate the model's robustness. Results: In the base case analysis, we found that ELNC was dominated (i.e., more expensive and less effective) by PPPL and ILPL. ILPL was the most cost-effective method, with an ICER of US $16,673/QALY compared to PPPL. One-way sensitivity analyses demonstrated that the exploratory laparotomy mortality following ILPL and the peritoneal cytology prevalence were the only two influential parameters within their plausible range when assessing the cost-effectiveness of PPPL and ILPL. In the probabilistic sensitivity analyses, the probability of ILPL being cost-effective was 71.3% at the WTP threshold of $29,313/QALY; however, PPPL was more likely to be cost-effective when the willing-to-pay (WTP) threshold was below $17,020/QALY gained. Conclusion: Cytology testing for GC staging through either ILPL or PPPL dominated ELNC in patients with curative intent. Moreover, ILPL was the most cost-effective modality at the current WTP threshold, while PPPL could potentially be cost-effective in lower-income areas. Citation Format: Qifei He, Jinyi Zhu, Anqiang Wang, Xia Li, Zhaode Bu, Jiafu Ji. Different strategies for peritoneal lavage cytology testing in the staging of gastric cancer: A cost-effectiveness analysis [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 4355.
Nanoformulation of BRD4-Degrading PROTAC: Improving Druggability To Target the ‘Undruggable’ MYC in Pancreatic Cancer
Authors: Tamara Minko
Journal: Trends in Pharmacological Sciences (2020)

In a recent study, Saraswat and colleagues identified a novel proteolysis targeting chimera (PROTAC), ARV-825 (ARV), that efficiently degrades bromodomain-containing protein 4 (BRD4) to drug the 'undruggable' MYC in pancreatic cancer. ARV-loaded polyethylene glycol-poly lactic acid-co-glycolic acid (PLGA-PEG) polymeric nanoparticles (ARV-NPs) showed promising anticancer activity in both 2D cell culture and 3D multicellular tumor spheroid models of pancreatic cancer. This study demonstrates a unique therapeutic strategy in which targeting BRD4 for degradation via the E3 ubiquitin ligase cereblon (CRBN) pathway leads to sustained inhibition of oncogenic MYC expression for effective treatment of pancreatic cancer.
Abstract 3265: Anti-GITR agonist antibody for cancer immunotherapy
Authors: Teddy Yang, Ken Dai, Dongxu Wang, Qianqian Qi, Hu Liu
Journal: Cancer Research (2020)

Abstract Glucocorticoid-induced TNFR-related (GITR) is a gene coding for a member of the TNF receptor superfamily. GITR is expressed at low levels on resting responder T lymphocytes and is up-regulated in T regulatory cells (Treg cells) and in activated T cells. GITR agonist which upregulated co-stimulatory signal to T cells or inhibition of Treg induced suppression which reverts Treg proliferation, is likely to enhance immunity in response to infection and tumor immunity. Therefore, GITR is currently of interest to immunologists as a co-stimulatory immune checkpoint molecule. In this study, various types of GITR immunogens, including gene, protein and cell line, are used for H2L2 mice immunization. Then we generate and characterize panels of anti-GITR monoclonal antibodies which not only could specifically bind to human GITR, but also show cross-reactivity to cyno GITR. Such anti-GITR antibody can increase the expression of NF-κB gene by cross-linking by anti-Fab, and induce the release of INF-γ from T cell. In harsh pH or temperature condition, the anti-GITR antibody can keep the stability. And at high concentration, the viscosity of the anti-GITR antibody is good. Moreover, in vivo study showed that the anti-GITR antibody can effectively inhibit tumor growth. Above results demonstrated that the anti-GITR antibody is expected to develop further for clinical study single or combine with other immune checkpoint antibody. Citation Format: Teddy Yang, Ken Dai, Dongxu Wang, Qianqian Qi, Hu Liu. Anti-GITR agonist antibody 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 3265.
Association of Mobile Phone Location Data Indications of Travel and Stay-at-Home Mandates With COVID-19 Infection Rates in the US
Authors: Song Gao, Jinmeng Rao, Yuhao Kang, Yunlei Liang, Jake Kruse, Dorte Dopfer, Ajay K. Sethi, Juan Francisco Mandujano Reyes, Brian S. Yandell, Jonathan A. Patz
Journal: JAMA Network Open (2020)

A stay-at-home social distancing mandate is a key nonpharmacological measure to reduce the transmission rate of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), but a high rate of adherence is needed.To examine the association between the rate of human mobility changes and the rate of confirmed cases of SARS-CoV-2 infection.This cross-sectional study used daily travel distance and home dwell time derived from millions of anonymous mobile phone location data from March 11 to April 10, 2020, provided by the Descartes Labs and SafeGraph to quantify the degree to which social distancing mandates were followed in the 50 US states and District of Columbia and the association of mobility changes with rates of coronavirus disease 2019 (COVID-19) cases.State-level stay-at-home orders during the COVID-19 pandemic.The main outcome was the association of state-specific rates of COVID-19 confirmed cases with the change rates of median travel distance and median home dwell time of anonymous mobile phone users. The increase rates are measured by the exponent in curve fitting of the COVID-19 cumulative confirmed cases, while the mobility change (increase or decrease) rates were measured by the slope coefficient in curve fitting of median travel distance and median home dwell time for each state.Data from more than 45 million anonymous mobile phone devices were analyzed. The correlation between the COVID-19 increase rate and travel distance decrease rate was -0.586 (95% CI, -0.742 to -0.370) and the correlation between COVID-19 increase rate and home dwell time increase rate was 0.526 (95% CI, 0.293 to 0.700). Increases in state-specific doubling time of total cases ranged from 1.0 to 6.9 days (median [interquartile range], 2.7 [2.3-3.3] days) before stay-at-home orders were enacted to 3.7 to 30.3 days (median [interquartile range], 6.0 [4.8-7.1] days) after stay-at-home social distancing orders were put in place, consistent with pandemic modeling results.These findings suggest that stay-at-home social distancing mandates, when they were followed by measurable mobility changes, were associated with reduction in COVID-19 spread. These results come at a particularly critical period when US states are beginning to relax social distancing policies and reopen their economies. These findings support the efficacy of social distancing and could help inform future implementation of social distancing policies should they need to be reinstated during later periods of COVID-19 reemergence.
PB1697 ANALYSIS OF MICRO-RNAS EXPRESSION PROFILE IN EXOSOMES DERIVED FROM ACUTE MYELOID LEUKEMIA BY KNOCKDOWN P62 AND THE EFFECT ON ANGIOGENESIS
Authors: L. C, L. ZG, L. PQ, H. R
Journal: HemaSphere (2019)

Background: Leukemic cells could stimulate neovascularization in bone marrow and this angiogenesis has been linked to adverse prognosis in AML. Exosomes could accelerate angiogenesis and promote tumor progression by harboring microRNAs (miRNAs). So the exosomal miRNAs may become new targets for AML treatment. High p62 expression is related to poor prognosis of AML, however, the regulation of angiogenensis by p62 is remain largely unknown. Aims: The aim of this study was to investigate the effect of p62 on miRNAs expression profile in exosomes derived from AML and the effect of exosomes derived from AML cells on angiogenesis. Methods: Electron microscopy and Western blot(WB) were used to confirm the exosomes derived from U937 cells, the controls and the cells knockdown p62. The Exiqon v19.0 microRNA MicroArray was used for profiling of miRNAs in exosomes derived from our specimens. The miRCURY™ Hy3™/Hy5™ Power labeling kit was used for miRNA labelling. Then the Hy3™-labeled samples were hybridized on the miRCURYTM LNA Array (v.19.0). The gene ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) databases were used to predict the biological functions and potential mechanisms of the differentially expressed miRNAs in AML exosomes. Quantitative real-time polymerase chain reaction(qRT-PCR) was used to confirm the results of two downregulated microRNAs of exosomes. Then endothelial cell tube formation assays were used to investigate the effect of the angiogenesis of HUVECs which added exosomes derived from cells. Results: We demonstrated that 2080 miRNAs were expressed in exosomes derived from U937 cells with knockdown p62 and the controls, of which 215 miRNAs were upregulated and 208 miRNAs were downregulated in U937 cells with knockdown p62(Fold Change≥2.0, P < 0.05). The results revealed miR-3064-3p and miR-339-5p were downregulated in U937 cells with knockdown p62 by qRT-PCR and consistent with microarray profile. GO pathway analysis indicated that the highest enrichment was intercellular part by miRNA. There were 1460 biological processes in downregulated transcripts and there were 19 pathways related with vesicle and 1515 pathways in upregulated transcripts and 8 pathways about vesicle by BP analysis. MF analysis inducted protein binding, transcription regulator activity and DNA binding transcription factor activity were enriched (P < 0.05). Pathway analysis indicated that 84 pathways corresponded to upregulated transcripts and 55 pathways corresponded to downregulated transcripts (P < 0.05). Then we found that exosomes deviated from U937 cells can promote the angiogenesis of HUVECs Summary/Conclusion: Our data suggested that miRNA in exosomes may play an important role in the pathogenesis of AML, and knockdown p62 may treat AML by the miRNAs in exosomes as reducing angiogenesis.
Abstract 1644: Detection and quantification of lymphedema using optical coherence tomography lymphangiography
Authors: Jennifer Y. Kwan, Valentin Demidov, Blake Jones, Wei Shi, Justin Williams, Costel Flueraru, Kenneth W. Yip, Fei-Fei Liu, Alex Vitkin
Journal: Cancer Research (2020)

Abstract Purpose: Imaging of the lymphatic system is important for monitoring and quantification of the vasculature of tumours and in lymphatic disorders (e.g. lymphedema, an obstruction of the lymphatic system that occurs as a side-effect of cancer treatments such as radiation and/or surgery). Traditional methods of lymphangiography require injection of a contrast agent to visualize the lymphatic system, which may be suboptimal when there is lymphatic obstruction. Thus, there is a need to develop intrinsic-contrast, high-resolution volumetric (3D) non-invasive quantitative in vivo imaging systems for both pre-clinical and potentially clinical use. Methods: An emerging non-invasive 3D imaging technology called optical coherence tomography (OCT) lymphangiography was optimized to visualize lymphatic vasculature and edema within tissues of C57BL/6 mice under normal and surgically-induced lymphedematous conditions. A murine tail lymphedema model was created by micro-surgical obstruction of the superficial and deep lymphatic networks under a dissecting microscope. OCT imaging was validated against fluorescent microscopy, an established but contrast-agent-dependent lymphangiography technique, as well as histology. Fluorescent microscopy was performed with intradermal injection of FITC-dextran followed by imaging with the AxioZoom.V16 Stereo Zoom Microscope. Immunofluorescence staining was performed with an anti-LYVE1 (Lymphatic Vessel Endothelial Receptor 1) antibody. Results: Comparing 3D OCT images and their 2D projections under normal and lymphedematous conditions showed significantly different networks. Quantification analysis revealed increased lymphatic vasculature dilation (~4X in vessel diameters, p&amp;lt;0.01) and increased fluid accumulation (~3X in edematous regions, p&amp;lt;0.05) under lymphedema conditions. Lymphatic vascular dilation and edema were confirmed by fluorescent microscopy and histology. Conclusions: OCT is an emerging non-invasive volumetric imaging modality that can be adapted to visualize lymphatic vasculature within normal and lymphedematous tissues without the use of vascular contrast agents. Furthermore, OCT has the ability to quantify the degree of vessel dilation and edema accumulation. Citation Format: Jennifer Y. Kwan, Valentin Demidov, Blake Jones, Wei Shi, Justin Williams, Costel Flueraru, Kenneth W. Yip, Fei-Fei Liu, Alex Vitkin. Detection and quantification of lymphedema using optical coherence tomography lymphangiography [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 1644.
Abstract 6119: RNAi rat models for drug discovery
Authors: Chia-Lin Wang, Yu-ting Yang, Ana Vasileva, Allison Maurice, Lukas Dow, Johannes Zuber, Scott Lowe, Prem K. Premsrirut
Journal: Cancer Research (2020)

Abstract The cost of drug development has skyrocketed to an estimated $2.6B for every FDA approved drug primarily due to failures from lack of efficacy or safety. This suggests that our current preclinical validation process has been insufficient in predicting therapeutic potential and toxicity in humans. While genetically engineered mice have become the gold standard for dissecting cancer mechanisms and evaluating novel drug targets in vivo, the rat has historically been the major model species in many biomedical fields, notably toxicology and carcinogenicity testing; and for many scientists, the rat still remains the preferred rodent due to their larger size for surgical manipulation, repeat blood sampling, and their cognitive and physiological characteristics that more closely resemble humans than their mouse counterparts. Moreover, many hormone-dependent tumors cannot be engineered in mouse models and are better modeled in rats. Here, we take advantage of our two-step engineering approach and exploit the efficiency of CRISPR-based targeting to develop RNAi rat models that enable inducible and reversible gene silencing to simulate therapeutic regimes. We demonstrate that our approach allows us to rapidly generate RNAi rat models and mimic the function of the targeted small molecule inhibitors, such as BET inhibitors targeting Brd4. These results demonstrate that our high-throughput system currently used to generate RNAi mice is also applicable to the rat system and, by extension, other mammalian models. Inducible RNAi rat models will undoubtedly be powerful tools that can be used to model human cancers, to mimic the action of putative drugs, and to assess the potential of therapeutic targeting strategies in vivo prior to the costly drug development, ultimately guiding the development of safer and more effective drugs. Citation Format: Chia-Lin Wang, Yu-ting Yang, Ana Vasileva, Allison Maurice, Lukas Dow, Johannes Zuber, Scott Lowe, Prem K. Premsrirut. RNAi rat models for drug discovery [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 6119.
Abstract 1545: IGF2BP2 over-expression induces epithelial mesenchymal transition &amp; promotes tumor progression in ESCC cells
Authors: Pei Li, Xuan-Yu HU, Xing-Ge Liu, Bei-Bei Sha, Ying DU, Ping CHEN
Journal: Cancer Research (2020)

Abstract Esophageal cancer (EC) is a common form of malignant tumor with high morbidity &amp; mortality worldwide. IGF2BP2/ IMP2 (insulin-like growth factor 2 mRNA binding protein 2) belongs to a large family of RBPs (RNA binding proteins) that coordinates the export, trafficking, precise localization and translation of RNA in cells. Analysis of TCGA data (results from GEPIA, http://gepia.cancer-pku.cn/) showed that IGF2BP2 over-expressed in ESCA and many other types of human cancers. However, whether and how IGF2BP2 affects EC progression is still unclear. In this study, the expression of IGF2BP2 in esophageal squamous cancer cell lines and normal esophageal epithelial cells(Het) were investigated to explore the relationship between IGF2BP2 and epithelial-mesenchymal transition(EMT)in the ESCC. Methods: IGF2BP2 was knocked down in the Kyse150 cells by siRNA while upregulated by infection lentivirus with IGF2BP2 cDNA in the Eca109 cells. Then Western blotting was used to detect the protein expression of IGF2BP2, p38, P-p38, ERK and EMT markers in these cells. Results: In this study, the results showed that the expression of the epithelial marker, E-cadherin protein increased and the mesenchymal markers, N-cadherin, Snail, and Slug protein decreased after IGF2BP2 knockdown in Kyse150 cells. Meanwhile, the EMT features were promoted in the Eca109 cell after IGF2BP2 upregulation, shown as a reduction in epithelial marker E-cadherin with an increase in mesenchymal markers: N-cadherin, Snail, and Slug. Results from Western blotting showed that IGF2BP2 protein expression was independent of p38 and ERK protein levels. Conclusion: These data indicated that IGF2BP2 could promote the process of EMT in ESCC cells and might serve as a new therapeutic target for the treatment of esophageal cancer. Keywords: IGF2BP2; esophageal cancer; EMT Citation Format: Pei Li, Xuan-Yu HU, Xing-Ge Liu, Bei-Bei Sha, Ying DU, Ping CHEN. IGF2BP2 over-expression induces epithelial mesenchymal transition &amp; promotes tumor progression in ESCC 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 1545.
Abstract 4571: Development of glycoconjugate based anticancer immunotherapy
Authors: Xuefei Huang
Journal: Cancer Research (2020)

Abstract Tumor associated carbohydrate antigens (TACAs) are attractive targets for the development of anticancer immunotherapy. Mucin-1 (MUC1) is a representative member of the TACA family. Naturally existing MUC1 can contain multiple types of O-linked glycans, including the Thomsen-Friedenreich (Tf) antigen and the Sialyl Thomsen-nouveau (STn) antigen. In order to target these antigens as potential anti-cancer vaccines, MUC1 glycopeptides SAPDT*RPAP (T* is the glycosylation site) bearing the Tf and the STn antigen respectively have been synthesized. Bacteriophage Qβ carrier is a powerful carrier for antigen delivery. The conjugates of MUC1-Tf and -STn glycopeptides with Qβ were utilized to immunize the immune-tolerant human MUC1 transgenic (MUC1.Tg) mice, which elicited superior levels of anti-MUC1 IgG antibodies with titers reaching over 2 million units. The IgG antibodies recognized a wide range of MUC1 glycopeptides bearing diverse glycans. Antibodies induced by Qβ-MUC1-Tf showed strongest binding with MUC1 expressing melanoma B16-MUC1 cells and effectively killed these cells in vitro. Vaccination with Qβ-MUC1-Tf first followed by tumor challenge in a lung metastasis model showed significant reductions of the number of tumor foci in the lungs of immunized mice as compared to those in control mice. This was the first time that MUC1-Tf based vaccine has shown in vivo efficacy in a tumor model. As such, Qβ-MUC1 glycopeptide conjugates have great potentials as anti-cancer vaccines. Citation Format: Xuefei Huang. Development of glycoconjugate based anticancer 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 4571.