tbuckley/cabot-search huggingface dataset:
Abstract 1038: Metformin inhibits epithelial-mesenchymal transition in human pancreatic cancer cell lines
Authors: Juichiro Yoshida, Takeshi Ishikawa, Yuki Endo, Shinya Matsumura, Takayuki Ohta, Katsura Mizushima, Yasuko Hirai, Tetsuya Okayama, Naoyuki Sakamoto, Ken Inoue, Kazuhiro Katada, Kazuhiro Kamada, Kazuhiko Uchiyama, Tomohisa Takagi, Yuji Naito, Yoshito Itoh
Journal: Cancer Research (2019)

Abstract Background: Epithelial-mesenchymal transition (EMT) is considered to be a crucial event in the development of cancer metastasis. Metformin is an antidiabetic drug used in treatment of type 2 diabetes. Recently, increasing evidence has indicated that metformin can inhibit tumor growth, however, effect of metformin on EMT remains still well unknown. Methods: We investigated whether metformin inhibits EMT in the human pancreatic cancer cell lines (PANC-1, BXPC-3, and MIAPaCa-2). Pancreatic cancer cells were stimulated TGF-β1 (10ng/ml) with or without metformin(10mM). After 48h, we evaluated for EMT-related factors using western blot analyses, immunocytochemistry and RT-PCR. Wound healing assay was performed to determine cell migration. Results: The cells stimulated TGF-β1 acquired elongated and fusiform morphology, and metformin inhibited the TGF-β1-induced morphological changes in PANC-1 and BXPC-3 cells. Wound healing assay of PANC-1 and MIAPaCa-2 cells showed that significant wound healing was seen after 24h in cells treated with TGF-β1 compared with the control, and metformin inhibited wound closure. E-cadherin expression weakened after exposure to TGF-β1, but it was reversed by metformin in these cell lines. Metformin treatment reduced the expression of mesenchymal markers (Vimentin, N-cadherin and αSMA) induced by TGF-β1 in these cell lines. Exposure of cells to TGF-β1 resulted in the phosphorylation of mTOR, and exposure of cells to metformin resulted in the phosphorylation of AMPK and blocked the phosphorylation of mTOR in BXPC-3 cells. Furthermore, cell viability was no significantly change between exposing metformin or not. Discussion: Our results indicate that metformin inhibits TGF-β1 induced EMT in human pancreatic cancer cells. Moreover, our results suggest that metformin induces the phosphorylation of AMPK and inhibits TGF-β1 induced mTOR activation in BXPC-3 cells. Citation Format: Juichiro Yoshida, Takeshi Ishikawa, Yuki Endo, Shinya Matsumura, Takayuki Ohta, Katsura Mizushima, Yasuko Hirai, Tetsuya Okayama, Naoyuki Sakamoto, Ken Inoue, Kazuhiro Katada, Kazuhiro Kamada, Kazuhiko Uchiyama, Tomohisa Takagi, Yuji Naito, Yoshito Itoh. Metformin inhibits epithelial-mesenchymal transition in human pancreatic cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1038.
Abstract 2264: Synergistic combination of oncolytic virotherapy and immunotherapy for glioma
Authors: Bingtao Tang, Zong Sheng Guo, David L. Bartlett, David Yan, Claire P. Schane, Jia Liu, Grant McFadden, Joanna L. Shisler, Edward J. Roy
Journal: Cancer Research (2019)

Abstract Oncolytic viral immunotherapy is a novel approach to cancer treatment. Viruses can directly kill cancer cells, provide antigens to dendritic cells to stimulate a T cell response, and make cancer cells express genes of immune-enhancing cytokines locally within the tumor microenvironment. We hypothesized that the combination of oncolytic virus with a local stimulus for activating tumor-specific T cells and an anti-immunosuppressant would improve treatment of gliomas. An oncolytic virus encoding IL15-IL15Rα (the T cell activating stimulus) and the prostaglandin synthesis inhibitor celecoxib (the anti-immunosuppressant) were combined with adoptive transfer of tumor-specific T cells. Two oncolytic poxviruses, vvDD vaccinia virus and myxoma virus, were each engineered to express the fusion protein IL15-IL15Rα and a fluorescent protein (YFP or tdTomato Red). Viral gene expression was tested in the murine glioma line GL261 in vitro and in vivo. Orthotopic GL261 tumors in immunocompetent C57BL/6 mice were treated with vvDD-IL15-Rα vaccinia virus or vMyx-IL15Rα-tdTr combined with other treatments, including vaccination with GARC-1 peptide (a neoantigen for GL261), rapamycin, celecoxib, and adoptive T cell therapy. We found that vvDD-IL15-Rα and vMyx-IL15Rα-tdTr each infected and killed GL261 cells in vitro. In vivo, NK cells and CD8+ T cells were increased in the tumor due to the expression of IL15-IL15Rα. Each component of a combination treatment contributed to prolonging survival: an oncolytic virus, the IL15-IL15Rα expressed by the virus, a source of T cells (whether by pre-vaccination or adoptive transfer), and prostaglandin inhibition all synergized to produce total elimination of gliomas in a majority of mice. vvDD-IL15-Rα occasionally caused encephalitis, but vMyx-IL15Rα-tdTr was safe and effective, causing a strong infiltration of tumor-specific T cells and eliminating gliomas in 83% of treated mice. All these facts suggest that IL15-IL15Rα-armed oncolytic poxviruses provide potent antitumor effects against brain tumors when combined with adoptive T cell therapy, rapamycin and celecoxib. Citation Format: Bingtao Tang, Zong Sheng Guo, David L. Bartlett, David Yan, Claire P. Schane, Jia Liu, Grant McFadden, Joanna L. Shisler, Edward J. Roy. Synergistic combination of oncolytic virotherapy and immunotherapy for glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2264.
RAS mutations in circulating tumor DNA (ctDNA) and clinical outcomes of rechallenge treatments with anti-EGFR antibodies in patients with metastatic colorectal cancer (mCRC)
Authors: Y. Sunakawa, M. Nakamura, M. Ishizaki, M. Kataoka, H. Satake, M. Kitazono, H. Yanagisawa, Y. Kawamoto, H. Kuramochi, H. Ohori, M. Nakamura, K. Takahashi, F. Maeda, C. Komeno, M. Takeuchi, M. Fujii, T. Yoshino, W. Ichikawa, A. Tsuji
Journal: Annals of Oncology (2019)
Tumor-associated myeloid derived suppressor cells of granulocytic nature as a potential biomarker for prognostication of response in treatment of diffuse large cell lymphoma.
Authors: Kalyan Kusum Mukherjee, Sukanya Dhar, Mohona Chakraborty, Rajib Bhattacharjee, Shayani Bhanja, Subhadip Das, Sarbari Ghosh, Madhurima Sarkar, Shayani Dasgupta, Diptendu Ghosh, Anamika Bose, Rathindranath Baral
Journal: Journal of Clinical Oncology (2019)

e19040 Background: NHL is a type of lymphoma either B or T cell origin. However, 85% is of B cell type, especially diffuse large B cell lymphoma (DLBCL) with CD20+ in nature. Standard of care of CD20+DLBCL is R-CHOP 6 to 8 cycles and 66% patients generally respond to this treatment. Remaining 34% is still unresponsive to R-CHOP. Thus, establishment of a biomarker is required to intensify the treatment.Out of different scope of biomarker development, alterations in immune cellular components within tumor microenvironment may be tried as a potential biomarker to assess the possibility of occurrence of residual disease and relapse within 2 years for the DLBCL patients with 6-8 cycles of R-CHOP. Methods: 51 of selected pt.CD20 + DLBCL were treated with 6-8 cycles of R-CHOP and included in the present study. A panel of immune cells CD4 + , CD8 + T cells, CD4 + CD25 + FoxP3 regulatory T cells, CD33 + CD11b + CD14 -/+ MDSCs and CD8 + CD45RO + Memory T cells were studied by flow-cytometry at different phases of treatment. Results: Within 51selected patients, 9 were disease free and 11patients exhibited stable disease for 2years (stable, non-relapsed, n = 20) following the completion of treatment. Rest of the patients (n = 31) showed relapse in different time periods within 2 years. Among several immune cells, CD33 + CD11b + MDSCs were remarkably elevated in high grade residual and relapsed DLBCL patients compared to non-relapsed patients and normal healthy individuals. CD33 + CD14 - granulocytic, but not CD33 + CD14 + monocytic MDSCs are mostly increased in relapsed patients than those having stable disease. CD4 + CD25 + FoxP3 regulatory T cells are also elevated in relapsed DLBCL patients, but increment is not comparable as MDSCs. No significant alteration was noticed in CD4 + and CD8 + T cells. Among relapsed patients CD8 + CD45RO + Memory T cells are increased, those are mostly corrupted in nature. Conclusions: Observed correlation between increased granulocytic MDSCs with the occurrence of residual disease and/or relapse suggests granulocytic MDSCs might be a potential biomarker for prediction of residual and relapse for DLBCL patients.
Abstract 530: Phosphatidylserine-targeting antibody combined with chemoradiation enhances systemtic anti-tumor immunity
Authors: Yifan Wang, Zhigang Liu, Weiye Deng, Betty Y. Kim, Steven H. Lin, Wen Jiang
Journal: Cancer Research (2019)

Abstract The discovery of immune checkpoint blockades have resulted in significant clinical benefits for patients with metastatic cancers including non-small cell lung cancer (NSCLC). Nevertheless, a large proportion of patients do not respond to such therapy. Strategies to enhance the therapeutic efficacy of cancer immunotherapy among a larger group of patients are urgently needed. Increasing the recognition of cancer cells by immune system may enhance response to immunotherapies. Tumor-associated macrophage (TAM) is the most abundant immune cell in most solid tumors, and is critical in bridging innate and adaptive immune system functions. Cancer cells overexpress multiple immune suppressive molecules including phosphatidylserine (PS) to inhibit immunological functions of TAMs. PS expression can be enhanced by cancer therapeutics such as radiation to induce immune suppression. Our results show that radiation increased expression of PS on lung cancer cells. The combination of PS blocking antibody with radiation decreased immune-suppressive phagocytosis and enhanced antigen presentation of macrophages. In murine lung cancer models, combination treatment of PS blockade and chemoradiation more effectively controlled tumor growth and prolonged survival than each treatment used alone. In a bilateral lung cancer tumor model, addition of PS blockade to chemoradiation promoted cytotoxic T cell infiltration and induced tumor growth inhibition of the non-irradiated tumors. Together, our results demonstrate that PS-targeting antibodies may be combined with chemoradiation to enhance intrinsic tumor immunogenicity and activate systemic anti-tumor immune responses. This approach may provide new routes for improving the efficacy of modern immunotherapeutics. Citation Format: Yifan Wang, Zhigang Liu, Weiye Deng, Betty Y. Kim, Steven H. Lin, Wen Jiang. Phosphatidylserine-targeting antibody combined with chemoradiation enhances systemtic anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 530.
Searching for the origin of the enigmatic circulating T follicular helper cells
Authors: Savita Pahwa
Journal: Journal of Clinical Investigation (2019)

T follicular helper (Tfh) cells in germinal centers of secondary lymphoid organs are pivotal for B and T cell interactions required for induction of humoral immunity. It has long been debated whether Tfh cells exit from lymph nodes into the blood as circulating Tfh cells. In this issue of the JCI, Vella et al. have taken the bull by the horns and applied considerable technical muscle to answer this question. By analyzing phenotype, transcriptome, epigenetic profile, and T cell receptor clonotype, the authors provide evidence that a subset of cTfh cells do indeed originate in lymph nodes and traffic into the blood via the thoracic duct.
Abstract 18214: Aggressive Risk Factor Management Reduces Platelet Activation and Improves Endothelial Function in Patients With AF: Implications for Stroke Reduction
Authors: Rajeev K Pathak, Scott Willoughby, Dennis H Lau, Prashanthan Sanders
Journal: Circulation (2016)

Objective: Presence of cardiac risk factors increases risk of thromboembolism in atrial fibrillation (AF). We sought to assess the effect of aggressive risk factor management on atrial thrombogenes...
Abstract 794: Inhibition of mitochondrial metabolism by a novel agent targeting RUNX2-DNA binding in breast cancer
Authors: Myoung Sook Kim, Ramkishore Gernapudi, Yessenia C. Cedeno, Brian M. Polster, Geoffrey D. Girnun, Antonino Passaniti
Journal: Cancer Research (2019)

Abstract The RUNX2 transcription factor promotes breast cancer growth and metastasis through interactions with a variety of cofactors that activate or repress target genes. RUNX2 knockdown decreases expression levels of glycolytic genes such as LDHA, HK2 and GLUT-1, but upregulates PDHA1 mRNA level and enzymatic activity, which is consistent with lower glycolytic potential. Using a direct computer-assisted drug discovery (CADD) approach, we identified CADD522 as a small molecule that inhibits the RUNX2-DNA binding, transcriptional activity of RUNX2, and expression of RUNX2 target genes. We also observed that CADD522 inhibits breast cancer growth and metastasis using in vitro and in vivo tumor models. RUNX2-activated glucose utilization and GLUT-1 levels were also reduced by CADD522. New data also define CADD522 as a potential antitumor agent that downregulates the levels of metabolites in the TCA cycle and inhibits mitochondrial oxygen consumption rates. Our results support the observations that CADD522 could regulate cellular metabolism through modulation of both glycolytic metabolism and mitochondrial oxidative phosphorylation. To address the mechanisms by which CADD522 exerts its inhibitory effects on mitochondrial metabolism, we performed RNA-Sequencing analysis in breast cancer cells and identified several specific molecular signatures that determine cellular response to RUNX2 and CADD522. Further pathway changes in mitochondrial function as well as validation of differentially expressed genes that play critical roles in mitochondrial metabolism are under investigation. Citation Format: Myoung Sook Kim, Ramkishore Gernapudi, Yessenia C. Cedeno, Brian M. Polster, Geoffrey D. Girnun, Antonino Passaniti. Inhibition of mitochondrial metabolism by a novel agent targeting RUNX2-DNA binding in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 794.
Genetic Characterization of Measles and Rubella Viruses Detected Through Global Measles and Rubella Elimination Surveillance, 2016–2018
Authors: Kevin E. Brown, Paul A. Rota, James L. Goodson, David Williams, Emily Abernathy, Makoto Takeda, Mick N. Mulders
Journal: MMWR Morbidity and Mortality Weekly Report (2019)

All six World Health Organization (WHO) regions have established measles elimination goals, and three regions have a rubella elimination goal. Each region has established a regional verification commission to monitor progress toward measles elimination, rubella elimination, or both, and to provide verification of elimination* (1,2). To verify elimination, high-quality case-based surveillance is essential, including laboratory confirmation of suspected cases and genotyping of viruses from confirmed cases to track transmission pathways. In 2000, WHO established the Global Measles and Rubella Laboratory Network (GMRLN) to provide high-quality laboratory support for surveillance for measles, rubella, and congenital rubella syndrome (3). GMRLN is the largest globally coordinated laboratory network, with 704 laboratories supporting surveillance in 191 countries (4). This report updates a previous report and describes the genetic characterization of measles and rubella viruses during 2016-2018 (5). The genetic diversity of measles viruses (MeVs) and rubella viruses (RuVs) has decreased globally following implementation of measles and rubella elimination strategies. Among 10,857 MeV sequences reported to the global Measles Nucleotide Surveillance (MeaNS) database during 2016-2018, the number of MeV genotypes detected in ongoing transmission decreased from six in 2016 to four in 2018. Among the 1,296 RuV sequences submitted to the global Rubella Nucleotide Surveillance (RubeNS) database during the same period, the number of RuV genotypes detected decreased from five in 2016 to two in 2018. To strengthen laboratory surveillance for measles and rubella elimination, specimens should be collected from all confirmed cases for genotyping, and sequences from all wild-type measles and rubella viruses should be submitted to MeaNS and RubeNS in a timely manner.
Abstract 57: Alterations In Left Ventricular Function After High-voltage Electrical Injury Assessed By Two-dimensional Speckle Tracking Echocardiography
Authors: Seong Hwan Kim, Hong Euy Lim, Eung Ju Kim, Woo Hyuk Song, Yong Hyun Kim, Jeong Cheon Ahn, Wan Joo Shim, Goo-Yeung Cho, Min-Kyu Kim, Woo-Jung Park, Jong-Hyun Kim
Journal: Circulation (2007)

Myocardial damage after exposure to high-voltage electrical current has been reported to result in a serious and often life-threatening situation. However, because the diagnosis of myocardial injur...
Failure of Etanercept and Methotrexate Combination Therapy to Surpass Etanercept Monotherapy in Psoriatic Arthritis—What About the Joint Counts? Comment on the Article by Mease et al
Authors: Arghya Chattopadhyay, Shefali K. Sharma, Shankar Naidu, Varun Dhir
Journal: Arthritis & Rheumatology (2019)
Abstract 2630: Inhibition of bone morphogenetic protein receptor 2 increases mitochondrial permeability and the downregulation of XIAP in lung cancer cells
Authors: Rachel E. NeMoyer, Elaine Langenfeld, John Langenfeld
Journal: Cancer Research (2019)

Abstract Bone morphogenetic protein receptor (BMP) inhibitors have been shown to induce death of lung cancer cells, which involves the downregulation of x-linked inhibitor of apoptosis protein (XIAP). XIAP is a potent inhibitor of executioner caspases that promotes resistance to many chemotherapeutic agents. The mechanism by which inhibiting BMP signaling downregulates XIAP has not been elucidated. We find that the BMP inhibitors JL5 and DMH2 downregulate XIAP and enhances cell death of TRAIL, Taxol, and AEG a Smac mimetic. JL5, which inhibits both type I and type II BMP receptors, enhances cell death of cancer therapeutics by decreasing the expression of XIAP, which leads to an increase in caspase activity. The downregulation of XIAP is mediated by the inhibition of the BMP type II receptor and not the BMP type I receptors. Knockdown of BMPR2 but not the BMP type I receptors increases mitochondrial permeability resulting in the release of cytochrome c and Smac/Diablo into the cytosol. These studies suggest that the inhibition of BMPR2 increases cytosolic Smac/Diablo that inhibits XIAP enhancing apoptotic cell death of cancer therapeutics. Citation Format: Rachel E. NeMoyer, Elaine Langenfeld, John Langenfeld. Inhibition of bone morphogenetic protein receptor 2 increases mitochondrial permeability and the downregulation of XIAP in lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2630.
Phase 1/2 trial of acalabrutinib plus pembrolizumab (Pem) in relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL).
Authors: Thomas E. Witzig, Kami J. Maddocks, Sven De Vos, Roger M. Lyons, William Jeffery Edenfield, Jeff Porter Sharman, Julie Vose, Habte Aragaw Yimer, Helen Wei, Edward M Chan, Priti Patel, Christopher Di Simone, Mitul Gandhi, Jennifer Vaughn, Kathryn Kolibaba, Bruce D. Cheson, Felipe Samaniego
Journal: Journal of Clinical Oncology (2019)

7519 Background: Acalabrutinib, a highly selective, potent, covalent Bruton tyrosine kinase (BTK) inhibitor, has a 24% overall response rate (ORR) as a single agent in R/R DLBCL. Pem targets PD-1, an immune checkpoint that limits anticancer responses. Pem showed responses in patients (pts) with Richter transformation who failed ibrutinib and can augment acalabrutinib activity in vitro. This study assessed acalabrutinib + Pem in R/R DLBCL. Methods: Pts with DLBCL, ≥1 prior chemoimmunotherapy and no prior allogeneic transplant received acalabrutinib 100 mg PO BID until progressive disease (PD) + Pem 200 mg/kg IV Q3W up to 2 y. Germinal center B-cell (GCB) vs non-GCB subtype was assessed by immunohistochemistry. Primary endpoint was safety. Results: Sixty-one pts (30 GCB; 31 non-GCB) were accrued, with a median age (range) of 67 y (30-85) and a median of 3 (1-8) prior therapies; 1 pt had prior autologous transplant. The most common Gr 3/4 adverse events (AEs) were neutropenia (15%) and anemia (11%). Gr 5 AEs were respiratory failure (n=3), sepsis, septic shock and abdominal abscess (n=1 each). All Gr atrial fibrillation was 5% (n=3), and major hemorrhage (≥ Gr 3) was 11% (4 gastrointestinal, 1 pulmonary, 1 epistaxis, 1 hematuria). Gr 3/4 immune-mediated events were elevated alanine aminotransferase (n=4), pneumonitis (n=2) and colitis (n=1). The ORR was 26% (Table) and was similar in GCB (27%) and non-GCB (26%) tumors. The median time on study was 5.2 mo (0.4-30.4+). Acalabrutinib/Pem discontinuations were due to PD (62%/56%) and AEs (15%/26%). As of June 2018, 10 pts remain on study; 6 on active therapy and 7 without PD. Conclusions: Acalabrutinib + Pem was well tolerated, with meaningful activity and some exceptional responders (&gt;24 mo) in these R/R DLBCL pts. Randomized trials of the combination vs single agent are needed. Clinical trial information: NCT02362035. [Table: see text]
Abstract 4729: Targeting c-MYCdegradation as a novel therapeutic strategy for osteosarcoma: Studies in canine and human osteosarcoma cells
Authors: Ya-Ting Yang, Vilma Yuzbasiyan-Gurkan, Jetze J. Tepe
Journal: Cancer Research (2019)

Abstract Osteosarcoma (OS) is the most common bone tumor in both humans and dogs, and has a nearly ten-fold higher incidence in dogs than humans. For the past twenty years, despite advances in treatment of other cancers, the overall survival rates for OS have stagnated. Thus, there is a great need for novel therapeutic strategies. In osteosarcoma, MYC activation is critical for both initiation and maintenance of tumorigenesis and tissue invasion. While targeting c-MYC is a rational strategy to treat OS, c-MYC has evaded therapeutic manipulation to date. In this study, we evaluated using a novel proteasome modulator, TCH-165, which induces c-MYC degradation, and compared it with convention treatments in in vitro studies. We demonstrated dose dependent decrease of c-MYC protein expression with TCH-165 treatment. Utilizing seven canine OS cell lines and three human OS cell line, we determined that the IC50 values for TCH-165 range from 2.2 to 11.6 μM in canine OS, 3.1 to 4.5 μM in human OS cell lines, while IC50 of several primary canine ranged from 22.3 μM to &amp;gt;200μM, suggesting a wide margin of safety. In cell cycle studies, we showed that TCH-165 resulted in G1 arrest after 12 hours of incubation. In addition, we examined the potential of combing TCH-165 with convention therapeutic agents. We selected carboplatin, one of the standard anti-tumor drugs for OS. Combination index calculations using TCH-165 and carboplatin in the canine D17 cell line support synergistic effects of this combination. The data point to potential novel avenues for treatment of OS which can be further examined in proof of concept studies in dogs with OS, serving as a relevant translational model, and accelerate drug development for human OS patients. Citation Format: Ya-Ting Yang, Vilma Yuzbasiyan-Gurkan, Jetze J. Tepe. Targeting c-MYCdegradation as a novel therapeutic strategy for osteosarcoma: Studies in canine and human osteosarcoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4729.