tbuckley/cabot-search huggingface dataset:
Abstract 3628: PD-1 checkpoint blockade therapy enhances adoptive immunotherapy by human Vγ2Vδ2 T cells against prostate tumors in a preclinical model
Authors: Mohanad H. Nada, Hong Wang, Craig Morita
Journal: Cancer Research (2018)

Abstract Cancer immunotherapy is an effective treatment against a variety of malignancies. Checkpoint blockade with anti-PD-1 or anti-CTLA-4 antibodies has resulted in durable clinical responses. However, targeting PD-1 or PD-L1 provides clinical benefits for only a minority of patients. Moreover, the effectiveness of checkpoint blockade correlates with the numbers of nonsynonymous mutations present in the tumor explaining the poor responsiveness of certain tumors such as prostate cancers. Therefore, additional therapies are needed for patients not currently responding. Unlike αβT cells, the anti-tumor activity of Vγ2Vδ2 T cells does not require MHC and is independent of the number of tumor mutations. Instead, Vγ2Vδ2 T cells use their TCRs to surveil tumor cells for alterations in isoprenoids metabolism induced by bisphosphonate treatment in a process requiring butyrophilin 3A1. This allows Vγ2Vδ2 T cells to recognize and kill all types of tumors. In clinical trials involving more than 200 patients, adoptive immunotherapy with Vγ2Vδ2 T cells has been proven to be safe. However, there have been few partial or complete responses with the most common beneficial response being stable disease. To find ways to increase its effectiveness, we have now assessed the benefits of combining PD-1 checkpoint blockade with the adoptive transfer of human Vγ2Vδ2 T cells. Vγ2Vδ2 T cells were found to express the major inhibitory receptors, PD-1, CTLA-4, LAG3, and TIM3 at varying times during the fourteen day ex vivo expansion period. To assess the effect of checkpoint blockade in vivo, immunodeficient NSG mice were inoculated with human PC-3 prostate cancer cells that naturally express the PD-L1 ligand. After 2 weeks, weekly treatments were started with intravenous pamidronate followed a day later by purified Vγ2Vδ2 T cells combined with either anti-PD-1 (clone J116) or control IgG1 mAbs. The addition of anti-PD-1 mAb treatment, markedly enhanced Vγ2Vδ2 T cell immunity to PC-3 tumors. Combination treatment was able to reduce tumor volume almost to zero after 5 weeks. These results demonstrate that PD-1 checkpoint blockade can greatly enhance adoptive immunotherapy with γδ T cells in a preclinical tumor model and suggests that combination therapy with anti-PD1 and Vγ2Vδ2T cells could be an effective strategy to treat patients with a variety of cancers. Citation Format: Mohanad H. Nada, Hong Wang, Craig Morita. PD-1 checkpoint blockade therapy enhances adoptive immunotherapy by human Vγ2Vδ2 T cells against prostate tumors in a preclinical model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3628.
Abstract 3501: Adipocytes sustain pancreatic cancer progression through a non-canonical WNT paracrine network inducing ROR2 nuclear shuttling
Authors: Carmine Carbone, Geny Piro, Raffaela Santoro, Francesca Simionato, Valeria Merz, Camilla Zecchetto, Aldo Scarpa, Giampaolo Tortora, Davide Melisi
Journal: Cancer Research (2018)

Abstract Background: Solid epidemiological evidences connect obesity with incidence, stage, and survival in pancreatic cancer. However, the underlying mechanistic basis linking adipocytes to pancreatic cancer progression remain largely elusive. We hypothesized that factors secreted by adipocytes could be responsible for epithelial-to-mesenchymal transition (EMT) induction and, in turn, a more aggressive phenotype in models of pancreatic preneoplastic lesions. Methods: We studied the role of factors secreted by two adipogenic model systems from primary human Bone Marrow Stromal Cells (hBMSC) in an in vitro experimental cell transformation model system of human pancreatic ductal epithelial (HPDE) cell stably expressing activated KRAS (HPDE/KRAS). Results: We measured a significant induction of EMT and aggressiveness in HPDE and HPDE/KRAS cell lines when cultured with medium conditioned by fully differentiated adipocytes (ADIPOCM) if compared with the same cells cultured with medium conditioned by hBMSC (hBMSCCM) from two different healthy donors. Several genes coding for soluble modulators of the non-canonical WNT signaling pathway, including FRZB, SFRP2, RSPO1, WNT5A and 5B were significantly overexpressed in fully differentiated adipocytes than in their respective in hBMSC. ADIPOCM induced the overexpression and the nuclear translocation of the Frizzled family member Receptor tyrosine kinase-like orphan receptor (Ror) 2 in HPDE and HPDE/KRAS cells. Vantictumab, an anti-Frizzled monoclonal antibody, reduced ROR2 nuclear translocation and in turn the EMT and aggressiveness in HPDE and HPDE/KRAS cells. Conclusions: We demonstrated that adipocytes could induce EMT and aggressiveness in models of pancreatic preneoplastic lesions by orchestrating a complex paracrine signaling of soluble modulators of the non-canonical WNT signaling pathway that determine, in turn, the activation and nuclear translocation of ROR2. This signaling pathway could represent a novel target for pancreatic cancer chemoprevention. Most importantly, these factors could serve as novel biomarkers to select a risk population among obese subjects for screening and, thus, early diagnosis of pancreatic cancer. Citation Format: Carmine Carbone, Geny Piro, Raffaela Santoro, Francesca Simionato, Valeria Merz, Camilla Zecchetto, Aldo Scarpa, Giampaolo Tortora, Davide Melisi. Adipocytes sustain pancreatic cancer progression through a non-canonical WNT paracrine network inducing ROR2 nuclear shuttling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3501.
Abstract 5842: Oxidative stress and protein carbonylation towards multi-drug resistance in cancer
Authors: Baikuntha P. Aryal, Jean-Pierre Gillet, V Ashutosh Rao
Journal: Cancer Research (2018)

Abstract Reactive oxygen species (ROS) are constantly produced under normal as well as stress conditions and play important roles in cell signaling and homeostasis. An elevated level of ROS has been reported in most cancers which may play a critical role in both cancer progression or cancer suppression. One proposed therapeutic strategy is to alter the oxidative stress from ROS-induced tumor promoting event to a ROS-induced apoptotic signaling. Most ROS inducing therapeutic agents initially induce ROS to kill cancer cells by apoptosis; however, prolonged exposure of drugs may result in reduced ROS level and an adaptive microenvironment that makes cancer cells resistant to the same ROS-inducing therapeutic drugs. Chronic exposure of ROS may also upregulate the multidrug resistance protein expression in cancer cells. We hypothesize that differences in oxidative stress and the antioxidant response between drug sensitive and drug resistance cells may play a key role in drug resistance to redox-active drugs. We used two pairs of cell lines, a mitoxantrone sensitive and resistance MCF7 human breast adenocarcinoma (MCF7/MCF7MX) and H460 non-small lung cancer cell lines (H460/H460MX) for our experiments. We employed western blot and ELISA assays to determine the total and specific protein oxidation by carbonylation. Both MCF7MX and H460MX showed slightly lower level of total protein carbonylation compared to their mitoxantrone sensitive counterparts. In western blot analysis, we observed two specific proteins that were differentially carbonylated in MCF7MX compared to and MCF7. Both cytoskeletal and multifunctional proteins were identified by mass spectrometry and confirmed by two-color western blot analysis. Investigation of the potential roles of these specific protein carbonylation in drug resistance will be presented. Citation Format: Baikuntha P. Aryal, Jean-Pierre Gillet, V Ashutosh Rao. Oxidative stress and protein carbonylation towards multi-drug resistance in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5842.
Abstract 139: Music Saves Lives: A Randomized Prospective Trial on Manikin Training
Authors: YoshihiroYamahata, BonOhta, JinIrie, KotaroTakebe, MakotoWatanabe
Journal: Circulation (2014)

Introduction: Some studies describe about the effectiveness of music during performing chest compressions. But they use the specific song such as “Stayin’ Alive” or “Nellie the Elephant”. But not all the people used to “Nellie the Elephant”, or one study points out some elderly people feel aversion against using “Stayin’ Alive”. In the previous occasion, we have reported the effectiveness of Music itself and the preferable rhythm and beat was 116 beat per minute (hereafter bpm) and 8 beats. Hypothesis: We assessed the hypothesis that the Music itself (not specific song) will be effective to master recommended chest compressions. Methods: This study followed a prospective design. The participants were seventy four newly hired nurses. Pre-training chest compression data of the participants were collected. The participants were randomly assigned into four groups, and took Cardio Pulmonary Resuscitation (hereafter CPR) training for ninety minutes with using different kinds of learning supports as follows: 1) ...
Abstract 743: ABT-806-derived antibody-drug conjugates (ADCs) inhibit growth of malignant mesothelioma <i>in vivo</i>
Authors: Puey Ling Chia, Diana Cao, Angela Rigopoulos, Hui Gan, Ed Reilly, Andrew Phillips, Thomas John, Andrew M. Scott
Journal: Cancer Research (2018)

Abstract Introduction: Malignant mesothelioma (MM) is an aggressive malignancy of the pleura with limited therapeutic options, and is associated with a poor prognosis. EGFR is known to be highly over-expressed in mesothelioma with reported EGFR overexpression between 44 to 97%. We have developed an anti-EGFR antibody (ABT-806), which is tumour specific and robustly inhibits EGFR-expressing tumours. We aimed to establish the validity and feasibility of targeting tumour expressed EGFR in MM using ABT-806 novel ADCs (ABT-414 and ABBV-221). Methods: We evaluated EGFR and mAb 806 immunohistochemistry in 4 MM cell lines (MSTO-211H, NCI-H2052, NCI-H28, NCI-H2452) and performed in-vitro cell proliferation assays (CPA) to evaluate the antineoplastic potential of mAb806-related ADCs. In-vivo therapeutic studies using the biphasic mesothelioma cell line (MSTO-211H) were conducted with treatment groups involving ABT-414, ABBV-221, ADC control, cisplatin chemotherapy. We also performed quantitative biodistribution and imaging of mAb806 ADC uptake (89Zr mAb806 ADC) to allow correlation of mAb806 ADC concentration in tumours. Results: mAb806 elicited strong binding to three of four MM cell lines (MSTO-211H, NCI-H2052 and NCI-H28). CPAs also demonstrated ABT-414 and ABBV- 221 had significant cell growth inhibition demonstrated in the range between 1 to 10ug/ml for MM cell lines. In MSTO-211H xenograft model significant anti-tumour response to both ABT-414 and ABBV-221 (p&amp;lt;0.01), was demonstrated. High, specific targeting of 89Zr-ch806 to MM tumour in-vivo was also shown. Conclusion: ABT-806 ADCs show potent anti-tumour activity in MM model, and warrant further exploration as a potential therapy for MM. Citation Format: Puey Ling Chia, Diana Cao, Angela Rigopoulos, Hui Gan, Ed Reilly, Andrew Phillips, Thomas John, Andrew M. Scott. ABT-806-derived antibody-drug conjugates (ADCs) inhibit growth of malignant mesothelioma in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 743.
Centrosome declustering agents: Potential interphase-targeting antimetastatic chemotherapeutics.
Authors: Vaishali Pannu, Padmashree C.G. Rida, Oi Wah S. Yap, Guilherme Henrique Cantuaria, Ritu Aneja
Journal: Journal of Clinical Oncology (2014)

1086 Background: The recent clinical failure of mitosis-targeted drugs has proven that cells in patient tumors divide infrequently, unlike cancer cells in cultures and xenograft models. Given the preponderance of interphase cells in clinical tumors, we asked whether targeting amplified centrosomes, held in tight clusters throughout interphase, presents a superior chemotherapeutic strategy that sabotages interphase-specific cellular activities such as directional migration. We utilized supercentrosomal N1E-115 murine neuroblastoma cells as a test-bed to study interphase centrosome declustering. Methods: We immunostained centrosomes and mitotic spindles in (i) paraffin-embedded clinical tumor samples of high-grade carcinomas of breast, prostate, bladder, head and neck, pancreas and colon, and (ii) cancer cell lines derived from a variety of tumor types, to determine the percentage of cells with amplified centrosomes and mitotic spindles. We analyzed how putative centrosome declustering agents [CDAs, viz., reduced 9-Bromonoscapine (RBN), Griseofulvin (GF) and PJ-34] disperse interphase centrosome clusters and compared them with Paclitaxel, a tubulin polymerizing drug currently in clinical use. Declustering potency of these drugs was ranked using a quantifiable declustering index (DI). Results: About 80% of patient tumor cells bear “supercentrosomal” clusters in interphase and mitosis; by contrast, cancer cells in culture exhibit a higher proportion of mitotic cells and lower levels of centrosome amplification. In cultured N1E-115 cells, RBN was the strongest declustering agent (DI=0.36), followed by GF (DI=0.28) and PJ-34 (DI=0.14). Dispersal of interphase centrosome clusters caused Golgi scattering, disrupted focal adhesion contacts, inhibited neurite formation by 70-80% and caused spindle multipolarity. Conclusions: CDAs (i) inhibit cell-substrate adhesion and polarized protrusion development, which are essential for directional migration in interphase cells, and (ii) induce catastrophic mitoses, suggesting that (a) disbanding the centrosome-Golgi axis is a potential anti-metastasis strategy and (b) interphase is a clinically important chemotherapeutic target.
Cytokine Gene Expression After Myocardial Infarction in Rat Hearts
Authors: KohOno, AkiraMatsumori, TetsuoShioi, YutakaFurukawa, ShigetakeSasayama
Journal: Circulation (1998)

Background—A large transmural myocardial infarction may initiate structural and geometric changes in the left ventricle that are commonly referred to as remodeling. Progressive, adverse remodeling of the myocardium may lead to ventricular dilatation and congestive heart failure. Recent studies have highlighted the effects of some cytokines on immune-mediated myocyte injury, postischemic myocardial inflammation, and cardiac function. However, studies of the involvement of cytokines in remodeling of the heart are few. Methods and Results—In a rat model of myocardial infarction, progressive dilatation of the left ventricular cavity and lack of appropriate hypertrophy of the surviving myocardium were confirmed by transthoracic echocardiography. The relative expression of mRNA for tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 in the infarcted and noninfarcted myocardium of these rats, as well as in a group of sham-operated animals, was assessed by the technique of quantitative polymerase chain r...
Abstract 99: An oncogenic role of Deleted in Liver Cancer 1 (DLC1) in metastatic melanoma
Authors: Xintao Yang, May Cheung, Hong-Lok Lung, Martin Cheung
Journal: Cancer Research (2018)

Abstract Melanoma is a type of skin malignancy originated from neural crest-derived melanocytes. Although the mortality rate has been significantly reduced due to early cancer diagnosis and treatment, distant metastasis still exhibits much inferior survival rates compared to the early stage of this disorder. Therefore, developing new target for therapy is of particular significance in combating metastatic melanoma. DLC1 is well known for its tumor suppressor role through activating small Rho-GTPases' (RHOA and CDC42) intrinsic capability to convert an active GTP to an inactive GDP-bound state, leading to inhibition of tumor growth and metastasis. So far, downregulation of DLC1 expression has been widely reported to associate with increased risk of various malignancies whereas elevation of its expression prevents tumor progression. In contrast to these studies, our pilot findings reveal that multiple melanoma cell lines exhibit higher levels of DLC1 than benign melanocytes and other cancer types, suggesting its unique expression profile in melanoma. Furthermore, in vitro functional assays demonstrate that silenced DLC1 inhibits proliferative, clonogenic, migratory and invasive capabilities of melanoma cells, whereas restoration of DLC1 rescue the oncogenic properties. More importantly, in lung metastasis model using nude mice, DLC1 knockdown suppresses melanoma cells colonizing to the lungs whereas their pulmonary metastases can be recovered with the reconstitution of DLC1. In addition, the manipulation of DLC1 expression does not alter the RHO-ROCK-MRLC signalling, indicating that its oncogenic effect is mediated through a RHO-independent manner. Thus, our results unravel an unprecedented paradigm-shift of DLC1 functioning as an oncogene instead of a tumor suppressor in metastatic melanoma, which may shed new light on disease pathogenesis and uncover novel therapeutic targets to treat this deadly cancer. Citation Format: Xintao Yang, May Cheung, Hong-Lok Lung, Martin Cheung. An oncogenic role of Deleted in Liver Cancer 1 (DLC1) in metastatic melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 99.
Abstract 1673: Ras degrading small molecules inhibit the transformation of colorectal cancer cells independently of beta-catenin signaling
Authors: Jeong-Ha Hwang, Eun Ji Ro, Wookjin Shin, Kang-Yell Choi
Journal: Cancer Research (2018)

Abstract Development of drugs controlling Ras is an emerging issue in cancer therapy; however, no clinically applicable drug is currently available. On the basis of the mechanism of Ras protein stability regulation via the Wnt/β-catenin signaling pathway, we previously identified small molecules inhibiting the proliferation and transformation of various colorectal cancer (CRC) cells via degradation of both β-catenin and Ras. Due to the absence of Ras degradation in cells expressing non-degradable mutation in β-catenin, and the need to determine an alternative mechanism for Ras degradation, we established a cell-based system to screen compounds that degrade Ras independently of the Wnt/β-catenin signaling pathway. A cell-based high-content screening (HCS) system monitoring the level of EGFP-K-RasG12V was established using HCT-116 cells harboring a non-degradable mutant β-catenin (ΔS45). Through HCS of a chemical library composed of 10,000 compounds, and by subsequent characterization of candidate compounds, we identified several compounds that degraded Ras without affecting β-catenin levels. KY7749, the most effective compound, inhibited the proliferation and transformation of CRC cells, including those resistant to the EGFR monoclonal antibody, cetuximab, due to KRAS mutations. Small molecules that degrade Ras independently of β-catenin would be a potential treatments for cancers caused by aberrant EGFR, Ras, and β-catenin. Citation Format: Jeong-Ha Hwang, Eun Ji Ro, Wookjin Shin, Kang-Yell Choi. Ras degrading small molecules inhibit the transformation of colorectal cancer cells independently of beta-catenin signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1673.
Abstract IA19: Emerging genetic mechanisms in undifferentiated round cell sarcomas
Authors: Cristina Antonescu
Journal: Clinical Cancer Research (2018)

Abstract Undifferentiated round cell sarcomas (URCS) occurring in pediatric and young adults are defined by a primitive morphology reminiscent of Ewing sarcoma, but lack the canonical EWSR1-ETS gene fusion. More than &amp;gt;90% of EWSR1-negative URCS are instead characterized by either a CIC-DUX4 fusion or a genetic abnormality involving BCOR. The latter group includes intra-chromosomal paracentric inversions (BCOR-CCNB3), inter-chromosomal fusions (BCOR-MAML3), or BCOR internal tandem duplications (ITD). Irrespective of their variable mechanism for dysregulation, the tumors share a similar phenotype and a BCOR upregulation at transcriptional and protein levels. In contrast, CIC-DUX4 URCS are characterized by a distinct transcriptional upregulation of PEA3 transcription factors (ETV1/4/5). For practical and treatment purposes, URCS have been regarded as “Ewing sarcoma-like” and have been managed similarly to the Ewing sarcoma family of tumors, despite their poor chemotherapy responses and aggressive clinical behavior. Alternatively these tumors are grouped by default in an “undifferentiated sarcoma category,” with their clinical management being often biased. Despite the wide spectrum of genetic abnormalities, the unifying concept is that the various gene partners or ITDs disrupt the C-terminal repressor domains of both CIC and BCOR, resulting in an oncogenic transcriptional activation of target genes. In URCS with BCOR ITD, the ITD sequences located at the C-terminal may affect the PUFD domain conformation of the BCOR protein, which might interfere with PCGF1 binding and thus could affect the PRC1-related epigenetic modifications. Citation Format: Cristina Antonescu. Emerging genetic mechanisms in undifferentiated round cell sarcomas [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr IA19.