tbuckley/cabot-search huggingface dataset:
Abstract 379: Effects on immunotherapy of EGFR mutation subtypes in non-squamous NSCLC
Authors: Haibo Tang, Xiaoning Li, Wenzhuan Xie, Mengli Huang
Journal: Cancer Research (2021)

Abstract Background: Genetic alternations of Epidermal growth factor receptor (EGFR) in lung cancer had shown associated with response or resistance to anti-PD-1 therapy. However, there is a lack of understanding of the clinical significance of EGFR mutation subtypes in non-squamous non-small cell lung cancer (NSCLC). Methods: We retrospectively analyzed 510 patients with non-squamous NSCLC treated with anti-PD-(L)1 monotherapy from four independent cohorts. The tumor tissues from the patients were subjected to MSK-IMPACT panel target sequencing or whole exome sequencing. The association between clinical features and specific EGFR alterations was analyzed. Results: EGFR positivity was 13.33% (68/510), which is close to the proportion in CheckMate-057 (14.09%), while is higher than in KEYNOTE-010 (8.33%). Compared with 68 EGFR alteration lung cancers, DCR, ORR and durable clinical benefit (DCB) were better in patients with EGFR wide-type (Chi-square test, p = 0.0021, 0.0436 and 0.0014, respectively), while the PFS and OS in EGFR wide-type group was not significantly longer than the EGFR positive group (Log-rank test, p =0.1310 for PFS and 0.7730 for OS). Among EGFR positivity, the incidence of L858R only, T790M only, L858R/T790M mixed and others were 23.53%, 19.12%, 11.76% and 45.59%, respectively. A significant difference in survival among the four subtypes of EGFR positive group was observed, mutation of T790M only showed a worse PFS and OS probability compared to the other subtypes (p&amp;lt;0.001 and p = 0.002), whereas mutation of L858R only showed a poorer PFS (p=0.05). Conclusion: Mutation of T790M in non-squamous NSCLC prospects worse survival than other EGFR mutations, while mutation of non-L858R and non-T790M subtypes was not a worse factor than EGFR wide-type group. The heterogeneity of EGFR alternations may be beneficial for establishing the uses of PD-(L)1 therapies for lung cancers. Citation Format: Haibo Tang, Xiaoning Li, Wenzhuan Xie, Mengli Huang. Effects on immunotherapy of EGFR mutation subtypes in non-squamous NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 379.
Abstract 1494: IgE receptor-activated human mast cells have potent anti-cancer properties
Authors: Chris Kepley, Mohammad Ferrydouni, Mona Motaghed, Kristen Dellinger
Journal: Cancer Research (2021)

Abstract The purpose of this study was to test the hypothesis that human mast cells (MC) have anti-tumor mediators that can be targeted to tumor specific antigens, induced to release these mediators, and cause cancer cell apoptosis. Breast cancer (BC) continues to be a significant cause of mortality for women in the United States. The oncogene HER2/neu is overexpressed in BC and is validated target for cancer therapeutics. New immunotherapy strategies and combinations of immune agents with non-redundant mechanisms of action are needed. The role of human tissue mast cells (MC) in the pathology of many cancers is not known. Nonetheless, high densities of MC are associated with favorable prognosis in certain types of cancer such as BC suggesting an anti-tumor effect. We previously reported that human adipose cells can be differentiated into autologous, fully functional MC (ADMC) capable of releasing mediators upon FcϵRI stimulation that induce BC cell death of cell suspensions of SK-BR3. Further data is presented demonstrating the anti-tumor effects of ADMC using BC tumor masses. The ADMC, sensitized with breast cancer-specific IgE anti-HER2/neu, bound to and were activated by, HER2/neu-positive human BC cells. The anti-HER2/neu IgE-sensitized ADMC bound to, infiltrated, and induced apoptosis of HER2/neu-positive BT-474 BC tumor masses as determined by time-lapse, live cell confocal imaging. Specific, HER2/neu IgE-mediated binding was also verified in vivo using immunocompromised xenograft models. Further studies are warranted to determine if tumor-targeted, autologous MC may be a new way to treat solid tumors. Citation Format: Chris Kepley, Mohammad Ferrydouni, Mona Motaghed, Kristen Dellinger. IgE receptor-activated human mast cells have potent anti-cancer properties [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1494.
Tackler and ball-carrier technique during moderate and severe injuries (≥8 days lost) compared with player-matched and team-matched injury-free controls in Elite Rugby Union
Authors: Vincent Meintjes, Pip Forshaw, Steve den Hollander, Lindsay Starling, Michael Ian Lambert, Wayne Viljoen, Clint Readhead, Sharief Hendricks
Journal: British Journal of Sports Medicine (2021)

To analyse tackler and ball-carrier technical proficiency during moderate and severe contact injuries (≥8 days lost) in professional rugby union, and compare it with injury-free event-matched controls from the same player and from the same team.Technical proficiency for 74 (n=74) (moderate and severe; ≥8 days lost) tackler and ball-carrier injuries during The Currie Cup (2014-2018) and 623 matched non-injury events (253 own controls, 370 team controls) were examined through video analysis using a standardised list of technical criteria.Mean technical proficiency score for injured tacklers during front-on tackles was 6.19/16 (arbitrary units (AU) 95% CI 4.89 to 7.48), which was significantly different to their own controls (8.90/16 AU, 95% CI 8.37 to 9.43, p<0.001, effect size (ES)=1.21, large) and team controls (9.93/16 AU, 95% CI 9.50 to 10.40, p<0.001, ES=1.71, large). Mean technical proficiency score for injured ball-carriers during front-on tackles was 5.60/14 AU (95% CI 4.65 to 6.55), which was significantly different to their own controls (8.08/14 AU, 95% CI 7.56 to 8.60, p<0.001, ES=1.16, moderate) and team controls (8.16/14 AU, 95% CI 7.75 to 8.57, p<0.001, ES=1.25, large).For the tackler and ball-carrier, for both front-on and side-on/behind tackles, overall technical proficiency scores were significantly lower for the injury-causing event, when compared with the player's own injury-free tackles and the team's injury-free tackles. Through analysing player and team controls, player technique deficiencies for the injured player and player technique deficiencies that expose all players to injury were highlighted, which may inform injury prevention strategies and policies, and assist coaches in optimising training to reduce tackle injury risk.
Abstract ND02: BT7480: A completely novel fully tumor antigen (Nectin-4) dependent agonist of the immune cell costimulatory receptor CD137
Authors: Nicholas J. Keen
Journal: Cancer Research (2021)

Abstract BT7480, a completely novel fully tumor antigen (Nectin-4) dependent agonist of the immune cell costimulatory receptor CD137. It is also the first example (to our knowledge) of a fully synthetic, low MW (~7.5kDa, less than 1/20th of an IgG), peptide-based approach to targeting either Nectin-4 or CD137. The costimulatory immune receptor CD137 has been recognized for its potential as a drug target in cancer alongside checkpoint inhibitors, but this promise has not been realized for patients due to toxicity (principally hepatic toxicity) and limited efficacy of current biologic based therapies. Thus, alternative approaches to this important target are warranted. Bicycles® are small, structurally constrained peptides discovered via phage display and optimized using structure-driven design and medicinal chemistry approaches. We have applied this disruptive technology to the problem, identifying CD137 binding Bicycles and chemically linking these to specific tumor antigen binding Bicycles to generate multifunctional “bi-specific” like molecules that induce tumor antigen dependent, tumor localized agonism of CD137. We termed these Tumor-targeted Immune Cell Agonists (TICAs™). BT7480 is a TICA that was designed to deliver highly potent CD137 agonism to Nectin-4 overexpressing tumor tissue. Nectin-4 is expressed at high levels in bladder, breast and lung tumors and at low levels in normal tissue and thus is an attractive target for localized immunotherapy. BT7480 binds potently to Nectin-4 expressing cells and engages CD137 expressed on immune cells in trans, leading to potent Nectin-4-dependent CD137 agonism in primary human PBMC/tumor cell co-culture assays. Treatment of Nectin-4 expressing tumors in immunocompetent mice with BT7480 induces complete tumor regressions and subsequent resistance to tumor re-challenge. Time-course examination of the treated tumors revealed a unique mechanism of action - rapid activation of myeloid cells (&amp;lt;24h) concomitant with a pulse of secretion of chemokines and cytokines peaking at 2-3 days, leading to a dramatic infiltration of cytotoxic T-cells on days 4-5. This is distinct from the reported behavior of checkpoint inhibitors such as PD1/PDL1 inhibitors. In the presentation we will describe the discovery work that led to the identification of BT7480, including a crystal structure of the CD137/Bicycle complex (the first reported low molecular weight ligand of this receptor), chemical optimization and structure of the molecule, it's PK and PD behavior, preliminary safety data and route to the clinic. Citation Format: Nicholas J. Keen. BT7480: A completely novel fully tumor antigen (Nectin-4) dependent agonist of the immune cell costimulatory receptor CD137 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr ND02.
Motixafortide and Pembrolizumab Combined to Nanoliposomal Irinotecan, Fluorouracil, and Folinic Acid in Metastatic Pancreatic Cancer: The COMBAT/KEYNOTE-202 Trial
Authors: Bruno Bockorny, Teresa Macarulla, Valerya Semenisty, Erkut Borazanci, Jaime Feliu, Mariano Ponz-Sarvise, David Gutierrez Abad, Paul Oberstein, Angela Alistar, Andres Muñoz, Ravit Geva, Carmen Guillén-Ponce, Mercedes Salgado Fernandez, Amnon Peled, Marya Chaney, Irit Gliko-Kabir, Liron Shemesh-Darvish, Debby Ickowicz, Ella Sorani, Shaul Kadosh, Abi Vainstein-Haras, Manuel Hidalgo
Journal: Clinical Cancer Research (2021)

Pancreatic ductal adenocarcinoma (PDAC) is largely unresponsive to checkpoint inhibitors. Blockade of the CXCR4/CXCL12 axis increases intratumoral trafficking of activated T cells while restraining immunosuppressive elements. This study evaluates dual blockade of CXCR4 and PD1 with chemotherapy in PDAC.Multicenter, single-arm, phase II study to evaluate the safety and efficacy of motixafortide and pembrolizumab combined with chemotherapy in patients with de novo metastatic PDAC and disease progression on front-line gemcitabine-based therapy (NCT02826486). Subjects received a priming phase of motixafortide daily on days 1-5, followed by repeated cycles of motixafortide twice a week; pembrolizumab every 3 weeks; and nanoliposomal irinotecan, fluorouracil, and leucovorin every 2 weeks (NAPOLI-1 regimen). The primary objective was objective response rate (ORR). Secondary objectives included overall survival (OS), progression-free survival (PFS), disease control rate (DCR), safety, and tolerability.A total of 43 patients were enrolled. The ORR according to RECISTv1.1 was 21.1% with confirmed ORR of 13.2%. The DCR was 63.2% with median duration of clinical benefit of 5.7 months. In the intention-to-treat population, median PFS was 3.8 months and median OS was 6.6 months. The triple combination was safe and well tolerated, with toxicity comparable with the NAPOLI-1 regimen. Notably, the incidence of grade 3 or higher neutropenia and infection was 7%, lower than expected for this chemotherapy regimen.Triple combination of motixafortide, pembrolizumab, and chemotherapy was safe and well tolerated, and showed signs of efficacy in a population with poor prognosis and aggressive disease.
Trends in Patient Volume by Hospital Type and the Association of These Trends With Time to Cancer Treatment Initiation
Authors: Zachary A. K. Frosch, Nicholas Illenberger, Nandita Mitra, Daniel J. Boffa, Matthew A. Facktor, Heidi Nelson, Bryan E. Palis, Justin E. Bekelman, Lawrence N. Shulman, Samuel U. Takvorian
Journal: JAMA Network Open (2021)

Increasing demand for cancer care may be outpacing the capacity of hospitals to provide timely treatment, particularly at referral centers such as National Cancer Institute (NCI)-designated and academic centers. Whether the rate of patient volume growth has strained hospital capacity to provide timely treatment is unknown.
Abstract 1657: Tumor selective immunotherapy to overcome checkpoint blockade resistance
Authors: Lingxiang Jiang, Paul J. Hergenrother, Xiumei Huang
Journal: Cancer Research (2021)

Abstract Most patients are resistant to PD-1/PD-L1 blockade therapy but mechanisms are not well defined. Defective innate sensing limits reactivation of T cells after the blockade. Patients with well-established solid tumors often generate complicated immunosuppressive networks and are generally refractory to immunotherapy. NAD(P)H:quinone oxidoreductase 1 (NQO1) is a two-electron oxidoreductase elevated (more than 100-fold) in most solid cancers and has emerged as a promising target for direct tumor-killing. Here, we demonstrate that novel NQO1 targeting drug-Isobutyldeoxynyboquinone (IB-DNQ) causes tumor-selective innate sensing leading to T cell dependent tumor suppression. IB-DNQ treatment increases PD-L1 expression in the tumor microenvironment. Upregulated PD-L1 within TME contributes to tumor relapse and provides therapeutic window for combination therapy of IB-DNQ with immune checkpoint blockade. We demonstrate that IB-DNQ or PD-1 blockade treatment alone leads to tumor rejection in mice bearing small but not large established tumors. However, combination therapy of IB-DNQ with anti-PD-L1 eradicates well-established and checkpoint blockade refractory tumors. Citation Format: Lingxiang Jiang, Paul J. Hergenrother, Xiumei Huang. Tumor selective immunotherapy to overcome checkpoint blockade resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1657.
Drug screening by uniform patient derived colorectal cancer hydro-organoids
Authors: Yong Hun Jung, Dong-Hee Choi, Kyungwon Park, Sat-byol Lee, Jonghun Kim, Hyunho Kim, Hyun-Woo Jeong, Ji Hun Yang, Jin-A Kim, Seok Chung, Byung Soh Min
Journal: Biomaterials (2021)
Cabazitaxel efficacy is strongly enhanced by continued Androgen Receptor Targeted Agents (ARTA) in Castration-Resistant Prostate Cancer (CRPC)
Authors: L. Mout, M.E. Van Royen, C.M.A. De Ridder, D. Stuurman, R.B. Marques, W.S. De Geer, H.J.G. Van De Werken, R.H.J. Mathijssen, R. De Wit, M.P. Lolkema, W.M. Van Weerden
Journal: European Urology (2021)
Abstract 2905: The relationship between peritoneal dissemination of gastric cancer &amp; exosome
Authors: Kazuya Kinoshita
Journal: Cancer Research (2021)

Abstract Introduction: In recent years, studies of exosomes have progressed rapidly, suggesting a connection to various physiological functions and pathogenesis. The exosomes are small extracellular vesicles with a diameter of 30 to 100 nm surrounded by lipid bilayers, and are attracting attention as a new cell-cell communication medium for carrying lipids, proteins, RNA, etc. in vivo. In addition, in exosomes released by cancer cells, it contains a large number of molecules related to angiogenesis and immunosuppression. It is believed to contribute to building microenvironments suitable for cancer cell growth and promoting cancer progression. Therefore, we focused on exosomes derived from gastric cancer cells, the action of gastric cancer cells, further constructed a gastric cancer peritoneal dissemination mouse model, the action of exosomes in gastric cancer peritoneal metastasis mechanism was examined in vitro, in vivo, respectively. Method: Exosome Isolation Kit was used to extract exosomes from each gastric cancer cell line MKN-1, MKN-45, MKN-45 GFP. The determination of exosomes was carried out using Nano-drop®. Cell adhesion in exosome-treated and non-administered groups were analyzed by colony forming assay. Cell proliferation ability was analyzed using cell proliferation assay method. In vivo, we examined whether the degree of peritoneal dissemination was made using live cell imaging using fluorescent cells. MKN-45 GFP was intraperitoneally administered to BALB/c-nu mice. On days 0, 5, 10, 15, 20, groups were prepared in which 25 µg/500 µl of exosome was administered intraperitoneally and groups in which the same amount of PBS was administered intraperitoneally. In addition, MKN-45 GFP was subcutaneously injected into BALB/c-nu mice to create MKN-45 GFP tumors, which were divided into small horns and transplanted to the stomach walls of BALB/c-nu mice. In the same way as the previous method, we prepared a group in which 25 µg/500 µl exosome was intraperitoneally administered on days 0, 5, 10, 15, 20 and a group in which the same amount of PBS was intraperitoneally administered. We performed a visual comparison of transplanted cancer cells and peritoneal dissemination of cancer. Results and Discussion: The results of the colony forming assay method suggest that exosomes derived from gastric cancer cells have the effect of promoting colony formation ability of cancer cells. We evaluate the results of peritoneal seeding model mice in this study, and further proceed with the analysis of miRNA extraction and analysis from exosomes derived from gastric cancer cells, and cell adhesion of cancer cells under high concentrations of exosomes. Citation Format: Kazuya Kinoshita. The relationship between peritoneal dissemination of gastric cancer &amp; exosome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2905.
Abstract 15843: Endothelial TRPV4 Deletion Protects Myocardium Against Pressure Overload Induced Hypertrophy via Preserved Angiogenesis and Reduced Cardiac Fibrosis
Authors: Ravi Adapala, Anantha K Kanugula, Vahagn A Ohanyan, Sailaja M Paruchuri, William M Chilian, Charles K Thodeti
Journal: Circulation (2019)

Microvascular dysfunction has been identified as one of the causes for progression of heart failure due to chronic pressure overload. However, the mechanosensor and mechanotransduction mechanisms u...
Reducing the risk of postoperative complications after robot-assisted radical prostatectomy in prostate cancer patients: results of a prospective audit and feedback intervention following the implementation of prospective data collection
Authors: G. Rosiello, G. Gandaglia, N. Fossati, A. Stabile, V. Cucchiara, S. Scuderi, F. Barletta, A. Martini, E. Mazzone, C.A. Bravi, D. Robesti, D. Cannoletta, L. Sciacqua, S. Comana, E. Camisassa, A. Gallina, F. Montorsi, A. Briganti
Journal: European Urology (2021)
Abstract 2084: Single-cell multimodal glioma analyses reveal epigenetic regulators of cellular plasticity and environmental stress response
Authors: Kevin C. Johnson, Kevin J. Anderson, Elise T. Courtois, Amit D. Gujar, Floris P. Barthel, Frederick S. Varn, Diane Luo, Martine Seignon, Eunhee Yi, Hoon Kim, Marcos R. Estecio, Ming Tang, Nicholas E. Navin, Rahul Maurya, Chew Yee Ngan, Niels Verburg, Philip C. De Witt Hamer, Ketan Bulsara, Michael L. Samuels, Sunit Das, Paul Robson, Roel G. Verhaak
Journal: Cancer Research (2021)

Abstract Glioma intratumoral heterogeneity enables adaptation to challenging microenvironments and contributes to universal therapeutic resistance. Here, we integrated 914 single-cell DNA methylomes, 55,284 single-cell transcriptomes, and bulk multi-omic profiles across 11 adult IDH-mutant or IDH-wild-type gliomas to delineate sources of intratumoral heterogeneity. We found that local DNA methylation instability, or epimutation burden, was elevated in more aggressive tumors, reflected intratumoral variability, linked with transcriptional disruption, and associated with environmental stress response. We show that the activation of cell-state specific transcription factors is impacted by epimutations and that loosened epigenetic control may facilitate cellular plasticity. We validated the impact that the common environmental stressor hypoxia has on the epigenetic stability and shifts in cell states through perturbation-based in vitro experiments coupled with single-cell genomics. Our analyses support that glioma cells under stress hijack epigenetic mechanisms that regulate cell state transitions to overcome challenges posed by nutrient-poor microenvironments and therapeutic insults. We confirmed the link between cellular stress and epigenetic instability by analyzing larger cohorts of bulk longitudinally collected and spatially separated DNA methylation data. Increased DNA methylation instability was associated with accelerated disease progression, and recurrently selected DNA methylation changes were enriched for environmental stress response pathways. Our work provides an integrative framework to better understand glioma evolution and highlights the importance of epigenetic heterogeneity in shaping therapeutic response. Citation Format: Kevin C. Johnson, Kevin J. Anderson, Elise T. Courtois, Amit D. Gujar, Floris P. Barthel, Frederick S. Varn, Diane Luo, Martine Seignon, Eunhee Yi, Hoon Kim, Marcos R. Estecio, Ming Tang, Nicholas E. Navin, Rahul Maurya, Chew Yee Ngan, Niels Verburg, Philip C. De Witt Hamer, Ketan Bulsara, Michael L. Samuels, Sunit Das, Paul Robson, Roel G. Verhaak. Single-cell multimodal glioma analyses reveal epigenetic regulators of cellular plasticity and environmental stress response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2084.
Retinopathy Predicts Future Cardiovascular Events Among Type 2 Diabetic Patients
Authors: Giovanni Targher, Lorenzo Bertolini, Roberto Tessari, Luciano Zenari, Guido Arcaro
Journal: Diabetes Care (2006)

We read with interest the recent article by van Hecke et al. (1) showing that diabetic retinopathy is associated with an increased risk of mortality and cardiovascular disease (CVD) incidence among type 1 diabetic patients.

Because the available data on associations between retinopathy and incident CVD in large population samples of type 2 diabetic patients are limited and conflicting (2–4), we would like to offer recent findings from our large observational study. We carried out a prospective, nested, case-control study in 2,103 …
Considerations in Comparing Proximal Tubule Cell Culture Models
Authors: Ora A. Weisz
Journal: Journal of the American Society of Nephrology (2021)

The use of immortalized and primary cell cultures to study the proximal tubule (PT) has significantly enhanced our understanding of how this nephron segment functions under normal and diseased conditions. The recent publication in JASN of a transcriptomic comparison of 14 available PT cell models