tbuckley/cabot-search huggingface dataset:
Abstract 2394: Discovery of small anti-PD-L1 peptides for cancer immunotherapy
Authors: Hao Liu, Zhen Zhao, Yuanke Li, Kun Cheng
Journal: Cancer Research (2019)

Abstract Immunotherapy using checkpoint inhibitors, especially PD-1/PD-L1 inhibitors, has now evolved into the most promising therapy for cancer patients. However, most of these inhibitors are monoclonal antibodies, and their large size may limit their tumor penetration, leading to suboptimal efficacy. As a result, there has been a growing interest in developing low-molecular-weight checkpoint inhibitors. Using a phage display peptide library, we discover small peptide-based anti-PD-L1 inhibitors to block the PD-1/PD-L1 interaction. These peptides exhibit high affinity and specificity to human PD-L1 as well as PD-L1-positive human cancer cells. Molecular docking studies indicate that the CLP002 peptide specifically binds to PD-L1 at the residues where PD-L1 interacts with PD-1. Compared to anti-PD-L1 antibody, the anti-PD-L1 peptides exhibited better tumor penetration in a 3D tumor spheroid model. The CLP002 peptide restores proliferation and prevents apoptosis of T cells that are co-cultured with cancer cells. The CLP002 peptide also inhibits tumor growth and increases survival of CT26 tumor-bearing mice, suggesting that the CLP002 peptide represents a promising low-molecular-weight checkpoint inhibitor for cancer immunotherapy. Citation Format: Hao Liu, Zhen Zhao, Yuanke Li, Kun Cheng. Discovery of small anti-PD-L1 peptides for cancer immunotherapy [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 2394.
Abstract 1188: Reversing epigenetic gene silencing to overcome immune evasion in CNS malignancies
Authors: Nivedita M. Ratnam, Heather M. Sonnemann, Mark R. Gilbert, Amber J. Giles
Journal: Cancer Research (2019)

Abstract Glioblastoma remains a lethal brain cancer, and current treatment provides only modest survival benefit. Immunotherapy is currently being investigated as a potential treatment for this disease, but immune cell trafficking to tumor is hampered. Glioblastoma are immunologically “cold”, lacking infiltrating lymphocytes. Tumors epigenetically silence the expression of chemokines that attract lymphocytes to evade immune attack. Previous studies in ovarian cancer demonstrated that the histone methyltransferase inhibitor, GSK126, increased T cell infiltration into the tumor, promoting immune-mediated tumor suppression. Lymphocyte infiltration was driven by elevated expression of interferon gamma (IFNγ)-induced chemokines CXCL9 and CXCL10. In the current study, we evaluate the ability of GSK126 to similarly reverse the silencing of CXCL9 and CXCL10 and thereby improve immunotherapy outcome for glioblastoma. We first determined that treatment of murine and human glioblastoma cell lines with GSK126 increased IFNγ-mediated gene expression of CXCL9 and CXCL10 by qPCR and protein by ELISA. Subsequently, transwell migration assays performed using human and murine T cells demonstrated increased T cell migration when exposed to conditioned medium from tumor cells treated with GSK126 and IFNγ. In addition, T cells exposed to GSK126 and IFNγ up regulated CXCR3, the receptor for CXCL9 and CXCL10 and further increased their expression of IFNγ. The in vivo efficacy of GSK126 was tested in combination with anti-PD-1 antibody in C57Bl/6 mice subcutaneously implanted with the syngeneic glioma cell line CT2A. Mice treated with a combination of GSK126 and anti-PD-1 antibody showed a significant decrease in tumor volume with treatment, providing an overall survival benefit compared the anti-PD-1 or GSK126 alone. Taken together, our data suggests a therapeutic role for GSK126 in glioblastoma that could enhance current immunotherapy regimens by reversing the epigenetic changes that enable immune cell evasion and encourage immune cell trafficking to the tumor. Citation Format: Nivedita M. Ratnam, Heather M. Sonnemann, Mark R. Gilbert, Amber J. Giles. Reversing epigenetic gene silencing to overcome immune evasion in CNS malignancies [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 1188.
Abstract 10437: Poor Adherence to Medications and Risk-Reduction Behaviors After a Stroke or Transient Ischemic Attack in a Predominantly Inner-city Black Population: A Pilot Study
Authors: Phyllis Supino, Alison Baird, Helen Valsamis, Steven Levine, Daniel Santarsieri, Ofek Hai, Nasimullah Khan, Monica Diaz, Marvin Moser, Jeffrey Borer
Journal: Circulation (2013)

Background: Nonadherence to prescribed medications and to recommended risk-reduction behaviors (RRBs) after hospital discharge is associated with recurrent vascular events and death among patients ...
Abstract 1870: Polyphenols from Korean artemisia annua L (pKAL) showed anti-cancer effects by multiple mechanisms on HCT116 human colorectal cancer cells
Authors: Won Sup Lee, Anjugam Paramanantham, Eun Joo Jeong, Suchismita Raha, Hye Jung Kim, GonSup Kim, Sung Chul Shin
Journal: Cancer Research (2019)

Abstract Artemisia annua L., (Gaddongsook in Korean), an annual herb, has been used for a long time in Korean folk medicine for the treatment of infectious or chronic disorder In addition, it possesses anti-inflammatory, and anti-cancer activity. However, the molecular mechanism for anti-cancer properties of Korean Artemisia annua is still unclear. Here, we investigated the anti-cancer effects of we investigated the anti-cancer effects of polyphenols from Korean Artemisia annua (pKAL) on HCT116 human colon cancer cells. pKAL induced cell death associated with the alteration of cell morphology and DNA content. Annexin V and PI staining revealed that late phase apoptosis. pKAL induced ROS generation and the cell death was recovered by NAC. Western blot revealed that pKAL significantly up-regulated the gamma-H2AX, p21, p53, p62 and cleavage of caspases-3 and PARP in HCT116 cells. pKAL induced changes in the expression of p53-dependent targets (p53, p21, Bax, Bak, and Fas). It also induced alteration of the expression of autophagy-related proteins (beclin1, p62, LC3-I, and LC3-II) posttranslational modification of proteins (Lamin A/C, HSP90, GM130) involved in the maintenance of intracellular membrane integrity. Unexpectedly, the effect of pKAL on cell death pKAL was similar in both the P53 wild-type and p53-null HCT116 colon cancer cells, although there was some difference in cell cycle arrest; in P53 wild-type cells, pKAL appeared to induce G1 arrest at lower concentration (50 μg/mL), whereas in p53-null cells, pKAL induced G2/M arrest. The cell death was regulated by JNK and p38 MAPK signaling. The cancer effects of pKAL was similar in p53-null NCI-H1299 cells. We also investigated the protein changes that is related to cell death and cell integrity with anti-body array, which revealed that pKAL induced changes in NF-Kb, PI3K, Ras, TGF-beta signaling too. In conclusion, these findings suggest that pKAL induced anticancer effects by inducing late phase apoptotic cell death at least in part through p38 MAPK and JNK pathways in HCT 1116 human colon cancer cells. It also induced alteration of cell morphology mimic to necrosis in some cells with changes of proteins involved in the maintenance of intracellular membrane integrity. These effects was p53-independent. Citation Format: Won Sup Lee, Anjugam Paramanantham, Eun Joo Jeong, Suchismita Raha, Hye Jung Kim, GonSup Kim, Sung Chul Shin. Polyphenols from Korean artemisia annua L (pKAL) showed anti-cancer effects by multiple mechanisms on HCT116 human colorectal 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 1870.
Analysis of patient screening in the phase III, international, randomized, open-label APACT trial
Authors: M. Reni, J. Winter, G. Tortora, U. Pelzer, H. Riess, H. Chang, E. O’Reilly, D. Oh, I. Alés Diaz, M. Milella, J. Bendell, B. Garlipp, M. Tempero, T. Macarulla, E. Van Cutsem, J. Berlin, D. Goldstein, B. Lu, J. Jeanes, P. Philip
Journal: Annals of Oncology (2019)
Abstract 2204: Novel FAK/ALK/ROS1 inhibitor APG-2449 synergizes with osimertinib in preclinical xenograft models of EGFR-mutant NSCLC
Authors: Guangfeng Wang, Douglas D. Fang, Ping Min, Ran Tao, Chunyang Tang, Shoulai Gu, Li Rui, Jiajun Li, Jingwen Wang, Miaoyi Wu, Yingfeng Li, Dingxiong Chen, Fei Zhang, Kejie Lian, Feifei Zhang, Lvcheng Wang, Rongcheng Xu, Dajun Yang, Yifan Zhai
Journal: Cancer Research (2019)

Abstract Focal adhesion kinase (FAK) plays an important role in cell migration, growth factor signaling, cell cycle progression and cellular survival. It had been shown that FAK and SRC family kinases were able to sustain downstream AKT and MAPK signaling under continuous EGFR inhibition driven by osimertinib (AZD9291), a mutant-selective third-generation EGFR inhibitor. Incomplete inhibition of AKT and MAPK was consistently observed even under increased concentrations of osimertinib and led to acquired resistance to osimertinib, implicating the need of combination therapy with FAK/SRC inhibitors to enhance antitumor activity of osimertinib and overcome its resistance. APG-2449 is a novel oral active small-molecular inhibitor that targets FAK, ALK and ROS1. In this study, we investigated the effect of combination treatment with APG-2449 and osimertinib using NSCLC NCI-H1975 cells carrying EGFRL858R/T790M mutation and an osimertinib-resistant patient-derived xenograft (PDX) model carrying EGFRT790M/19del/C797S mutation. In vitro, the combination treatment with APG-2449 and osimertinib synergistically inhibited the proliferation of NCI-H1975 cells. In vivo, APG-2449 significantly enhanced antitumor activity of osimertinib in NCI-H1975 xenograft models, leading to complete or partial tumor regression. More profound antitumor activity of this combination was also demonstrated in the osimeritinib-resistant PDX model in comparison with single agents. In term of mechanism, the combination arm significantly suppressed the on-target phosphorylation of EGFR, FAK and SRC, as well as AKT and ERK in NCI-H1975 xenografts. Collectively, these results suggest that addition of APG-2449 to osimeritinib may enhance antitumor activity and suppress the development of resistance in NSCLC. Citation Format: Guangfeng Wang, Douglas D. Fang, Ping Min, Ran Tao, Chunyang Tang, Shoulai Gu, Li Rui, Jiajun Li, Jingwen Wang, Miaoyi Wu, Yingfeng Li, Dingxiong Chen, Fei Zhang, Kejie Lian, Feifei Zhang, Lvcheng Wang, Rongcheng Xu, Dajun Yang, Yifan Zhai. Novel FAK/ALK/ROS1 inhibitor APG-2449 synergizes with osimertinib in preclinical xenograft models of EGFR-mutant NSCLC [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 2204.
Looking Forward, Not Backward, on Watch and Wait for Rectal Cancer—In Reply
Authors: J. Joshua Smith, Julio Garcia-Aguilar, Philip B. Paty
Journal: JAMA Oncology (2019)

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Abstract 3619: Nanoparticle formulation of VERU 111 for pancreatic cancer treatment
Authors: Vivek K. Kashyap, Bilal B. Hafeez, Qinghui Wang, Neeraj Chauhan, Prashanth K. Nagesh, Murali M. Yallapu, Duane D. Miller, Wei Li, Meena Jaggi, Subhash C. Chauhan
Journal: Cancer Research (2019)

Abstract Background: Pancreatic cancer (PanCa) is one of the leading causes of cancer-related mortality in the United States due to very limited therapeutic options. Thus, developing novel therapeutic strategies will help for the management of this disease. We recently identified VERU-111, a novel synthetic molecule which showed potent anti-cancer effect against PanCa via targeting clinically important βIII and βIV tubulin isoforms. In this study, we synthesized and characterized its novel nanoformulation (MNP-VERU) and evaluated its therapeutic effects in vitro and xenograft mouse model. Methods: MNPs were prepared by chemical precipitation method and loaded with VERU-111 using diffusion method. This formulation was characterized for particle size, chemical composition, and drug loading efficiency, using various physico-chemical methods (TEM, FT-IR, DSC, TGA, and HPLC). The internalization of MNP-VERU was achieved after 6 hours incubation with MNP-VERU in PanCa cells. To determine therapeutic efficacy of MNP-VERU, we performed various in vitro (MTS, wound healing, boyden chamber real-time xCELLigence, and apoptosis assays) and in vivo (mouse tumor xenograft) studies using PanCa. Effect of MNP-VERU on various key oncogenic signaling pathways, and miRNAs was evaluated by Western blot, immunohistochemistry (IHC), confocal microscopy, qRT-PCR and in situ hybridization (ISH) analyses respectively. Result: Our novel MNP-VERU formulation provided average size of 110 nm in dynamic light scattering (DLS) and exhibited -8.23 to -11.65 mV zeta potential with an outstanding loading efficiency (94%). Cellular uptake and internalization studies demonstrate that MNP-VERU escape lysosomal degradation, providing efficient endosomal release to cytosol. MNP-VERU showed remarkable anti-cancer potential in various PanCa cells (Panc-1, AsPC-1, HPAF-II, BxPC-3, MiaPaca) and more effectively repressed βIII and βIV tubulin isoforms via restoring the expression of miR-200c. MNP-VERU more effectively suppressed AsPC-1 cells derived xenograft tumors in athymic nude mice. Conclusions: Taken together, our results suggest that MNP-VERU has more anti-cancer potential than free VERU-111 against PanCa. MNP-VERU may reduce the toxicity and improve the bioavailability of free VERU-111 and could be used for the management of PanCa. Citation Format: Vivek K. Kashyap, Bilal B. Hafeez, Qinghui Wang, Neeraj Chauhan, Prashanth K. Nagesh, Murali M. Yallapu, Duane D. Miller, Wei Li, Meena Jaggi, Subhash C. Chauhan. Nanoparticle formulation of VERU 111 for pancreatic cancer treatment [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 3619.
Endoscopic ultrasound-guided management of malignant afferent loop syndrome after gastric bypass: from diagnosis to therapy
Authors: Laurent Monino, Marc Barthet, Jean Michel Gonzalez
Journal: Endoscopy (2019)

Afferent loop syndrome (ALS) is a known complication of surgical gastrectomy [1], caused by benign or malignant obstruction of the afferent limb, which induces digestive intolerance and reflux cholangitis. With the explosion of bariatric surgery, a new patient population with altered anatomy has emerged [2], presenting new endoscopic challenges. Therapeutic possibilities using endoscopic ultrasound (EUS) are constantly increasing thanks to new devices [3] [4]. We present an original case of a patient with ALS due to pancreatic adenocarcinoma that occurred years after a gastric bypass.
Abstract 14324: Validation of the ACC/AHA PCE Performance in Hispanics: Insights From Multi-Ethnic Study of Atherosclerosis and Dallas Heart Study
Authors: Karen P Flores Rosario, Anurag Mehta, Rohan Khera, Pedro Engel Gonzalez, Ambarish Pandey, Amit Khera, Colby Ayers, Roger Blumenthal, Khurram Nasir, Robert Kaplan, Michael Blaha, Carlos J Rodriguez, Parag Joshi
Journal: Circulation (2018)

Background: Despite atherosclerotic cardiovascular disease (ASCVD) being the leading cause of death among Hispanics in the US, there is no validated ASCVD risk assessment tool in Hispanics. We eval...
Abstract 1276: Inhibition of lipid metabolism decreases proliferation and increases radiosensitvity in EGFR-TKI resistant NSCLC cells with bFGF secretion
Authors: Wei Wang, Shunli Peng, Rong Wang, yueyun Ma, Longhui Zhong
Journal: Cancer Research (2019)

Abstract Primary and acquired EGFR-TKIs resistance restricts the benefit of EGFR-TKIs to EGFR mutant NSLCLC patients. Recent studies found that metabolic reprogramming might contribute to develop metastasis and drug resistance of tumor cells. Therefore, illustrating the metabolism change is meaningful and targeting the peculiar metabolic pathways might be considered as potential therapeutic strategies for EGFR-TKIs resistant NSCLC. We separated single clones from gefitnib resistant NSCLC cells, by exposing EGFR-mutant EGFR-TKIs sensitive PC-9 cells into increasing concentrations of gefitnib. Among the numerous clones, clone 5 was resistant to gefitinib or AZD9291 and named as PC-9GR-FGF because of high level of bFGF secretion. We found that bFGF promote the transcription of SREBP-1 and its downstream genes, acetyl-CoA carboxylase alpha (ACC), ATP citrate lyase (ACLY) and fatty acid synthase (FASN) in PC-9 cells. Compared to PC-9 cells, higher ACC expression was detected in PC-9GR-FGF cells. Basing on TCGA database (lung Adenocarcinoma, provisional), patients with high ACC expression showed significant shorter PFS (progression-free survival) and OS (overall survival) compared to those with low ACC expression in the EGFR-mutant NSCLC (p&amp;lt;0.05, N=32). Down-regulation of ACC by siRNA or TOFA, a small molecular ACC inhibitor, mederately decreased the proliferation of PC-9 cells whereas strongly decreased proliferation of PC-9GR-FGF cells in vitro and in vivo. Moreover, Reactive oxygen species (ROS) and oxidative stress scavenger, NAC and ferrostatin-1, failed to reverse the effect of ACC inhibition in PC-9 and PC-9GR-FGF cells. Furthermore, after down-regulation or inhibition of ACC, stronger G2/M arrest and more accumulation of DNA damage marker, γH2AX, were found in PC-9GR-FGF cells compared with PC-9 cells. In addition, ACC expression were increased after irradiation of X-ray in PC-9GR-FGF cells, and inhibition of ACC increased accumulation of γH2AX induced by X-rays in PC-9GR-FGF cells. Our research gives a view sight into lipid metabolism changes in EGFR-mutant NSCLC cells before and after acquired EGFR-TKIs resistance, and explores the possibility of combination strategy with radiotherapy and anti-cancer lipid metabolism therapy. Citation Format: Wei Wang, Shunli Peng, Rong Wang, yueyun Ma, Longhui Zhong. Inhibition of lipid metabolism decreases proliferation and increases radiosensitvity in EGFR-TKI resistant NSCLC cells with bFGF secretion [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 1276.
Abstract 17983: Optimal Chest Compression Rate During CPR: The Importance of Filling Time
Authors: James K Russell, Dana Zive, Mohamud R Daya
Journal: Circulation (2016)

Introduction: AHA 2015 Guidelines for cardiopulmonary resuscitation (CPR) recommended an upper rate limit of 120 compressions per minute (cpm) based on observational data showing optimal survival w...
Whole exome sequencing (WES) of non-small cell lung cancer (NSCLC) for tumor mutational burden (TMB) analysis and long-term benefit to immune checkpoint inhibitors (ICIs).
Authors: Enriqueta Felip, Alejandro Navarro, Ana Callejo, Alex Martinez Marti, Susana Cedres, Nuria Pardo, Javier Ros, Juan David Assaf, Anna Pedrola, Cristina Viaplana, Irene Sansano, Jose Jimenez, Paolo Nuciforo, Miriam Sansó, Rodrigo Dienstmann, Ramon Amat, Francesco M Mancuso, Ana Vivancos
Journal: Journal of Clinical Oncology (2019)

9071 Background: ICIs have significantly changed the therapeutic landscape of advanced NSCLC. As such, characterizing predictive markers of long-term clinical benefit is a critical objective. TMB quantification using targeted gene panels associates with long-term response to ICIs in NSCLC patients (Rizvi H ASCO 18). Although TMB quantified by targeted NGS correlates with that of WES, caution may be needed when using smaller panels. Methods: Here we analyzed WES of tumors and matched normal tissue from 67 NSCLC patients including 42 treated with ICIs. We correlated TMB with clinico-pathological features and outcomes. TMB was categorized as high vs. low according to the upper quartile of cohort distribution. Results: The median TMB was 2.68 non-synonymous variants (nSNVs)/Mb, ranging from 0 to 15.6 nSNVs/Mb, with upper quartile at 5.42 nSNVs/Mb. TMB was higher for smoker/current smoker (median 3.51) compared to never smokers (median 0.94, p = 0.0048) but no differences were seen in elderly ( &gt; 70 years) vs. young patients or across histologies (squamous, adeno and other) and stages at diagnosis. In patients treated with ICIs, median TMB was 5.44 for those achieving complete response, 3.87 for patients with partial response and 2.42 for patients with progressive disease (PD) (p = 0.04). Moreover, improved clinical outcomes were associated with higher TMB (Table). In patients treated with ICIs, TMB as continuous variable had an impact on progression free survival (PFS) (p = 0.03). Median PFS was 22.3 months (mo) (14-not reached) for those with high TMB and 6.4 mo (3-16) for those with low TMB (HR 0.34, 0.13-0.9, p = 0.03). Median overall survival was not reached for those patients with high TMB and 32 mo (22-43) for those with low TMB (HR 0.29, 0.1-0.86, p = 0.02). Conclusions: High TMB correlates with long-term ICI benefit in NSCLC patients. Mutations in individual genes potentially linked to long-term benefit or resistance to ICIs will be presented. [Table: see text]