tbuckley/cabot-search huggingface dataset:
Abstract 1390: Inhibition of the catalytic activity of hUNG2 sensitizes multiple cancer cell lines to 5-FdUrd killing
Authors: Eric S. Christenson, Junru Cui, Anthony Gizzi, Mesfin Meshesha, James T. Stivers
Journal: Cancer Research (2020)

Abstract Previously reported shRNA knockdown studies have established that expression of the DNA repair enzyme human uracil DNA glycosylase (hUNG2) is protective against 5-flourodeoxyuridine (5FdUrd) cell killing in p53 mutated cancer cell lines, but not in cell lines with functional p53. Here we take a different approach to understanding the role of hUNG2 in 5FdUrd chemotherapy by selectively inhibiting the catalytic activity of hUNG2 using the small bacterial inhibitor protein UGI. UGI binds extremely tightly to the DNA binding and catalytic site of hUNG2, effectively mimicking the impact of a small molecule inhibitor and allowing us to explore the potential therapeutic vulnerabilities that loss of hUNG2 activity produces in p53 mutated and wild-type cancer cells. Accordingly, we used lentiviral transduction to introduce UGI, under control of a doxycycline-inducible promoter, into a large panel of cancer cell lines. In vitro hUNG2 activity measurements using cell extracts established that all lines had robust activity before induction of UGI and undetectable activity after induction. We find that some wild-type and mutant p53 cancer lines from different tissues show significant increases in drug sensitivity. For instance, the p53 wild-type MCF7 breast cancer line showed a 10,000-fold increase in sensitivity, while the p53 mutant HT29 colorectal cancer line showed a 50-fold increased sensitivity. Overall, the results do not support the proposal that p53 status itself determines whether a cancer cell will be sensitized to 5FdUrd in the presence of hUNG2 inhibition. Ongoing studies are focused on identifying the cellular factors that contribute to drug sensitivity under conditions of hUNG2 inhibition. Realizing the full therapeutic benefit of 5FdUrd requires identification of the cancer cell phenotypes that are sensitized upon hUNG2 inhibition. Citation Format: Eric S. Christenson, Junru Cui, Anthony Gizzi, Mesfin Meshesha, James T. Stivers. Inhibition of the catalytic activity of hUNG2 sensitizes multiple cancer cell lines to 5-FdUrd killing [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1390.
Evaluation of Cumulative Meta-analysis of Rare Events as a Tool for Clinical Trials Safety Monitoring
Authors: George C. M. Siontis, Adriani Nikolakopoulou, Orestis Efthimiou, Lorenz Räber, Stephan Windecker, Peter Jüni
Journal: JAMA Network Open (2020)

This meta-analysis evaluates the use of cumulative meta-analysis of rare events as a tool for safety monitoring of clinical trials using the example of coronary bioresorbable vascular scaffold–associated thrombosis.
Abstract 2723: XIAOPI formula inhibits breast cancer pre-metastatic niche formation <i>via</i> blocking TAMs/CXCL1 pathway
Authors: Zhiyu Wang, Yifeng Zheng, Neng Wang, Shengqi Wang, Bowen Yang, Yi Lin
Journal: Cancer Research (2020)

Abstract Recent findings suggested that premetastatic niche (PMN) is a prerequisite in mediating cancer metastasis. Previously we demonstrated that XIAOPI formula could inhibit breast cancer lung metastasis via inhibiting tumor associated macrophages (TAMs)-secreted CXCL1. Herein, we aimed to explore the effects of XIAOPI formula on preventing breast cancer PMN formation and its underlying molecular mechanisms. It was found that XIAOPI formula could inhibit the proliferation of M2 phenotype macrophages and reduce CXCL1 expression in a dose-dependent manner. TAMs/CXCL1 signaling was subsequently found to stimulate the recruitment of c-Kit+/Sca-1+ HSPCs and their differentiation into CD11b+/Gr-1+ MDSCs, which were symbolic events accounting for PMN formation. Moreover, XIAOPI formula was effective in inhibiting HSPCs activation and blocking the proliferation and metastasis of breast cancer cells 4T1 induced by HSPCs and TAMs co-culture system, implying that XIAOPI was effective in preventing PMN formation in vitro. Breast cancer xenograft experiments further demonstrated that XIAOPI formula could inhibit breast cancer growth and metastasis in vivo. More importantly, XIAOPI formula significantly delayed the time of cancer cell seeding in the lung tissues. Meanwhile, the populations of HSPCs in the bone marrow and MDSCs size in both tumor and lung tissues were all remarkably declined by XIAOPI formula treatment. However, the inhibitory effects of XIAOPI formula could be relieved by CXCL1 overexpression in the TAMs. Taken together, our study provided preclinical evidence supporting the application of XIAOPI formula in preventing breast cancer PMN formation, and highlighted TAMs/CXCL1 as a potential therapeutic strategy for PMN targeting therapy. Citation Format: Zhiyu Wang, Yifeng Zheng, Neng Wang, Shengqi Wang, Bowen Yang, Yi Lin. XIAOPI formula inhibits breast cancer pre-metastatic niche formation via blocking TAMs/CXCL1 pathway [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2723.
P254 Left ventricular global longitudinal strain and free wall strain of the right ventricle in respect to sex and systolic function among patients with acutely decompensated heart failure
Authors: Josip Anđelo Borovac, Zora Sušilović Grabovac, Anteo Bradarić, Duška Glavaš, Darko Duplančić, Joško Božić
Journal: European Journal of Heart Failure (2020)
US Congress investigates effects of $80bn private equity industry on government healthcare programme
Authors: Janice Hopkins Tanne
Journal: BMJ (2020)

A US government committee is to examine the role of private equity firms in Medicare, the government health insurance programme that covers 44 million Americans over 65.

Recent research has shown that investments by private equity firms in US healthcare increased from $23.1bn (£17.6bn; €19.5bn) in 2015 to $78.9bn in 2019.1 It found that while takeovers by private equity firms may improve some health outcomes, they can also improve profits—in part by increasing charges to insurers.

The Medicare Payment Advisory Commission is reviewing the evidence, holding public meetings, and interviewing stakeholders on the effects of private equity investments on Medicare after a request from the US House of Representatives Ways and Means Committee. It plans to report to Congress next June.2

The commission is looking at four matters: gaps in Medicare data that …
Abstract 4044: Pharmacological targeting of the circadian clock, a new frontier for cancer therapy
Authors: Gabriele Sulli, Jeremy Rich
Journal: Cancer Research (2020)

Abstract The circadian clock imposes daily rhythms in cell proliferation, metabolism, inflammation and DNA damage response. Perturbations of these processes are hallmarks of cancer. This raises the hypothesis that pharmacological modulation of the circadian machinery may be an effective therapeutic strategy for combating cancer. Indeed, targeting a circadian regulator could affect multiple cancer vulnerabilities, thus mimicking combination therapy. Here we show that pharmacological modulation of clock genes is specifically lethal to cancer cells and oncogene-induced senescent cells and have no effect on the viability of normal cells or tissues. This novel strategy can target multiple oncogenic drivers (such as HRAS, BRAF, PIK3CA, lack of p53 and others) and is effective under hypoxic conditions. Autophagy and de novo lipogenesis two crucial metabolic nodes for cancer survival are simultaneously blocked by chemical clock modulators. Notably, this approach impairs glioblastoma growth in vivo and improves survival without causing overt toxicity in mice. These results indicate that pharmacological modulation of circadian regulators is a novel antitumor strategy, identifying a class of anticancer agents with a wide therapeutic window. This new therapeutic paradigm could offer promising tools for the treatment of highly heterogeneous tumors that are unaffected by targeted therapy. The integration of circadian biology into cancer research therefore offers new options for making cancer treatment more effective and selective. Citation Format: Gabriele Sulli, Jeremy Rich. Pharmacological targeting of the circadian clock, a new frontier for cancer therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4044.
PNPLA3 rs738409 C&gt;G Variant Predicts Fibrosis Progression by Noninvasive Tools in Nonalcoholic Fatty Liver Disease
Authors: Grazia Pennisi, Rosaria Maria Pipitone, Calogero Cammà, Vito Di Marco, Vincenzo Di Martino, Federica Spatola, Rossella Zito, Antonio Craxì, Stefania Grimaudo, Salvatore Petta
Journal: Clinical Gastroenterology and Hepatology (2020)
Abstract 4002: Adipose tissue supernatant of overweight ER positive breast cancer patients promotes migration of MCF-7 breast cancer cells
Authors: Jie Ma, Hetty Timmer-Bosscha, Paul M. Werker, Carolina P. Schröder, Marlous Arjaans
Journal: Cancer Research (2020)

Abstract Introduction: Adipose tissue is a major component of the breast cancer microenvironment, and preclinical studies have suggested that adipose tissue might play a pivotal role in breast cancer progression. In this study we investigated the effect of adipose tissue from patients with ER positive breast cancer on migration of ER positive MCF-7 breast cancer cells. Materials and Methods: Adipose tissue samples were collected from patients with ER positive breast cancer undergoing a mastectomy. In total, adipose tissue samples from 3 normal weight (BMI: 18.5-24.9) and 7 overweight breast cancer patients (BMI: 25-29.9) were collected. Samples from the mastectomy specimens were minced in small pieces, incubated in RPMI-1640 and after 48 hours (h) the supernatant was harvested. The effect of adipose tissue supernatant on the migration of MCF-7 cells was monitored in real-time for 48 h with the xCELLigence cell invasion and migration plates expressed in delta cell index (DCI). In addition, effect of adipose tissue supernatant on migration was assessed by quantification of F-actin positive lamellipodia of MCF-7 cells in a scratch assay after 24 h. In all experiments, RPMI-1640 with 1% or 20% FCS was used as a negative or positive control respectively. Results: Supernatant of overweight patients significantly induced MCF-7 migration compared to supernatant of normal weight patients after 24 h (xCELLigence DCI: 1.22 ± 0.15 vs. 0.95 ± 0.19 (P=0.038)), 36 h (DCI 1.40 ± 0.21 vs. 0.91 ± 0.31 (P=0.019)) and 48 h (DCI 1.72 ± 0.23 vs. 0.98 ± 0.43 (P=0.007)). In addition, there was a significant difference between the overweight group and negative control at 36 h, and 48 h (DCI 1.40 ± 0.21 vs. 1.06 ± 0.12, P=0.038 and DCI 1.72 ± 0.23 vs. 1.11 ± 0.21, P=0.004 respectively). No significant difference between normal weight group and negative control was found at any of the time points. After 24 h MCF-7 cells incubated with supernatant of overweight patients developed significantly more F-actin positive lamellipodia compared to MCF-7 cells incubated with supernatant of normal weight patients (44.26 ± 3.26% vs. 25.47 ± 1.88% P&amp;lt;0.001). Conclusion: In this study, we showed that adipose tissue supernatant of patients with ER positive breast cancer can promote migration of MCF-7 breast cancer cells in a weight dependent manner. Whether this is the case in other breast cancer subtypes as well, and the potential clinical implication, is of interest for future studies. Citation Format: Jie Ma, Hetty Timmer-Bosscha, Paul M. Werker, Carolina P. Schröder, Marlous Arjaans. Adipose tissue supernatant of overweight ER positive breast cancer patients promotes migration of MCF-7 breast cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4002.
Abstract 908: BRAF inhibition and nanoparticle-delivered cytokine therapy for melanoma: A novel rational combined approach
Authors: Gabriele Romano, Roger Liang, Paradiso Francesca, John Miller, Francesca Taraballi, James Costello, Lawrence Kwong
Journal: Cancer Research (2020)

Abstract Although the advent of BRAF inhibitors plus MEK inhibitors has revolutionized BRAF-mutant melanoma therapy, most patients relapse within 16 months due to the persistence of minimal residual disease (MRD), a key obstacle in cancer therapy. In our inducible genetically engineered mouse model (iBIP), doxycycline withdrawal results in BRAFV600E extinction causing tumors to shrink, but not completely disappear, achieving a status of MRD. Time-course microarray analysis revealed a set of immune hallmarks with acute and strong initial activation after BRAFV600E extinction, then a decrease through to MRD, suggesting that the MRD might be immune suppressive/evasive. Systems biology analysis pinpointed the family of interferon inducible chemokines CXCL9/10/11 as central players in the orchestration of the process: CXCL9/10/11 are strongly induced within 8 hours of BRAFV600E extinction, but dissipate just prior to MRD, paralleling the more general immune signature. Data obtained in human samples and in other immunocompetent mouse models also show both a strong CXCL9/10/11 induction after BRAF inhibition and an immune evasive/suppressive microenvironment after eventual tumor relapse. Our preliminary data indicates resident macrophages as the main population responsible for CXCL9/10/11 production.. These data led us to hypothesize that sustaining CXCL9/10/11 expression might support superior tumor immune infiltration and activation to neutralize or eradicate the MRD. In a pilot study, we have observed significant tumor rejection in vivo with combined BRAF extinction plus intratumoral recombinant CXCL9 (rCXCL9) therapy in immunocompetent mice, which suggests that CXCL9 can therapeutically convert immunologically “cold” MRD back to “hot”. In order to improve the pharmacokinetics of cytokine therapy, we are currently developing a nanoparticle-based delivery that extends stability and half-life of rCXLC9 in vitro, with in vivo experiments as the next step. In this work, we utilized a confluence of in silico and in vivo data to guide the rational identification of a molecularly-driven cancer treatment based on immune drivers with predicted molecular synergy. Citation Format: Gabriele Romano, Roger Liang, Paradiso Francesca, John Miller, Francesca Taraballi, James Costello, Lawrence Kwong. BRAF inhibition and nanoparticle-delivered cytokine therapy for melanoma: A novel rational combined approach [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 908.
Gallstones, Body Mass Index, C‐Reactive Protein, and Gallbladder Cancer: Mendelian Randomization Analysis of Chilean and European Genotype Data
Authors: Carol Barahona Ponce, Dominique Scherer, Regina Brinster, Felix Boekstegers, Katherine Marcelain, Valentina Gárate‐Calderón, Bettina Müller, Gonzalo de Toro, Javier Retamales, Olga Barajas, Monica Ahumada, Erik Morales, Armando Rojas, Verónica Sanhueza, Denisse Loader, María Teresa Rivera, Lorena Gutiérrez, Giuliano Bernal, Alejandro Ortega, Domingo Montalvo, Sergio Portiño, Maria Enriqueta Bertrán, Fernando Gabler, Loreto Spencer, Jordi Olloquequi, Christine Fischer, Mazda Jenab, Krasimira Aleksandrova, Verena Katzke, Elisabete Weiderpass, Catalina Bonet, Tahereh Moradi, Krista Fischer, Willem Bossers, Hermann Brenner, Kristian Hveem, Niina Eklund, Uwe Völker, Melanie Waldenberger, Macarena Fuentes Guajardo, Rolando Gonzalez‐Jose, Gabriel Bedoya, Maria C. Bortolini, Samuel Canizales‐Quinteros, Carla Gallo, Andres Ruiz‐Linares, Francisco Rothhammer, Justo Lorenzo Bermejo
Journal: Hepatology (2020)

Background and Aims Gallbladder cancer (GBC) is a neglected disease with substantial geographical variability: Chile shows the highest incidence worldwide, while GBC is relatively rare in Europe. Here, we investigate the causal effects of risk factors considered in current GBC prevention programs as well as C‐reactive protein (CRP) level as a marker of chronic inflammation. Approach and Results We applied two‐sample Mendelian randomization (MR) using publicly available data and our own data from a retrospective Chilean and a prospective European study. Causality was assessed by inverse variance weighted (IVW), MR‐Egger regression, and weighted median estimates complemented with sensitivity analyses on potential heterogeneity and pleiotropy, two‐step MR, and mediation analysis. We found evidence for a causal effect of gallstone disease on GBC risk in Chileans ( P = 9 × 10 −5 ) and Europeans ( P = 9 × 10 −5 ). A genetically elevated body mass index (BMI) increased GBC risk in Chileans ( P = 0.03), while higher CRP concentrations increased GBC risk in Europeans ( P = 4.1 × 10 −6 ). European results suggest causal effects of BMI on gallstone disease ( P = 0.008); public Chilean data were not, however, available to enable assessment of the mediation effects among causal GBC risk factors. Conclusions Two risk factors considered in the current Chilean program for GBC prevention are causally linked to GBC risk: gallstones and BMI. For Europeans, BMI showed a causal effect on gallstone risk, which was itself causally linked to GBC risk.
Abstract 5032: Attenuated <i>Salmonella</i> blocks cancer metastasis by activating NK cells in an IFN-γ-dependent manner
Authors: Qiubin Lin, Li Rong, Jiandong Huang
Journal: Cancer Research (2020)

Abstract Introduction and objectives: The recent remarkable clinical results of cancer immunotherapies, such as immune checkpoint blockade and chimeric antigen receptor T cells (CAR-T), has sparked a great deal of enthusiasm in manipulating the immune response in the fight against cancer. Bacterial cancer therapies represent an alternative approach to targeting solid tumours for evoking anti-tumour immune responses. As a facultative anaerobic pathogen that can penetrate and colonize solid tumours, Salmonella typhimurium gained lot of interest in the investigation of bacterial cancer therapies and can exert its intrinsic antitumor activity by directly inducing systemic immune responses. However, most bacterial cancer therapies, including salmonella-based cancer therapies, have mainly focused on the suppression of already established tumours rather than metastasis. Metastasis accounts for 90% of cancer related deaths and blocking of metastatic cascade has critical clinical impact. However, the clinical drug development for cancer treatment, including cancer immunotherapies, is evaluated largely depending on their ability to cause tumour shrinkage and ignores the effect on metastasis as it has proven challenging to target. Therefore, there is an urgent need for novel therapeutic strategies and agents targeting metastasis. Experimental procedures and outcomes Using an attenuated Salmonella typhimurium strain YB1 engineered by our lab, we have found a potent suppressive effect of attenuated salmonella on cancer metastasis, regardless of cancer types and genetic background, by evoking strong anti-metastatic immune response. Further study showed that suppression of cancer metastasis by attenuated Salmonella only requires the innate immune response. Among the many induced cytokines, we identified IFN-γ as an indispensable factor for inhibiting cancer metastasis. Based on CyTOF (mass cytometry or cytometry by time of flight) analysis of the innate immune responses after Salmonella treatment and antibody-mediated cell depletion, we further demonstrated that NK cells are the major factor involved in Salmonella-provoked metastasis suppression. We found that IFN-γ was mainly produced by NK cells during early Salmonella infection, and in turn, IFN-γ promoted the accumulation, activation and cytotoxicity of NK cells. The IFN-γ-dependent NK cells directly eliminated newly accumulated cancer cells in the lung to block the cancer metastasis cascade in response to the Salmonella treatment. Citation Format: Qiubin Lin, Li Rong, Jiandong Huang. Attenuated Salmonella blocks cancer metastasis by activating NK cells in an IFN-γ-dependent manner [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5032.
Abstract 1832: A real-time extracellular ATP assay to identify modulators of the innate immune response
Authors: Andrew L. Niles, Kevin R. Kupcho, Dan F. Lazar, James J. Cali
Journal: Cancer Research (2020)

Abstract Damage-associated molecular patterns (DAMPs) liberated or exposed by dying cells after chemotherapeutic treatment augment innate immune responses and improve clinical outcomes as a result of the immunogenic cell death (ICD) phenotype. Extracellular ATP (eATP) is a potent DAMP that acts as a chemotactic agent for dendritic cells and as an immunomodulator for fine-tuning the inflammatory response. Current in vitro methods for identifying eATP inducers are procedurally difficult and laborious and are hampered by the instability of eATP in cell culture environments. To overcome these challenges, we have developed an easy-to-use, homogeneous, bioluminescent chemistry that can be introduced with test articles to measure dose-dependent ATP release kinetics and magnitudes of response in real time. We tested the assay using U20S and U937 cells dosed with serial dilutions of doxorubicin, idarubicin, mitoxantrone, and romidepsin. Luminescent data were continuously collected throughout the 24h exposure in 5- or 10- minute increments using a conventional multimode plate reader with CO2-independent medium, or with readers equipped with atmospheric control. When coupled with parallel cell health assays designed to measure either viability or loss of membrane integrity, the data can reveal agents that potentiate ATP release during early or late apoptosis. Our real-time data suggest the potency of eATP release is dependent upon cell model and agent and can be reproducibly and robustly measured in 96 and 384 well environments with kinetic resolution not possible by other methods. This new eATP measurement workflow may help define the capacity of new chemical entities to induce apoptosis and immunogenic cell death. Citation Format: Andrew L. Niles, Kevin R. Kupcho, Dan F. Lazar, James J. Cali. A real-time extracellular ATP assay to identify modulators of the innate immune response [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1832.