tbuckley/cabot-search huggingface dataset:
Trends in Low-Value Carotid Imaging in the Veterans Health Administration From 2007 to 2016
Authors: Timothy S. Anderson, Samuel Leonard, Alysandra J. Zhang, Erin Madden, Danielle Mowery, Wendy W. Chapman, Salomeh Keyhani
Journal: JAMA Network Open (2020)

<h3>Importance</h3> As part of the Choosing Wisely campaign, primary care, surgery, and neurology societies have identified carotid imaging ordered for screening, preoperative evaluation, and syncope as frequently low value. <h3>Objective</h3> To determine the changes in overall and indication-specific rates of carotid imaging following Choosing Wisely recommendations. <h3>Design, Setting, and Participants</h3> This serial cross-sectional study compared annual rates of carotid imaging before Choosing Wisely recommendations (ie, 2007 to 2012) and after (ie, 2013 to 2016) among adults receiving care in the Veterans Health Administration (VHA) national health system. Data analysis was performed from April 10, 2019, to November 27, 2019. <h3>Exposures</h3> Release of the Choosing Wisely recommendations. <h3>Main Outcomes and Measures</h3> Annual rates of overall imaging, imaging ordered for stroke workup, imaging ordered for low-value indications (ie, screening owing to carotid bruit, preoperative evaluation, and syncope). Indications were identified using a text lexicon algorithm based on electronic health record review of a stratified random sample of 1000 free-text imaging orders. The subsequent performance of carotid procedures within 6 months after carotid imaging was assessed. <h3>Results</h3> Between 2007 and 2016, 809 071 carotid imaging examinations were identified (mean [SD] age of patients undergoing imaging, 69 [10] years; 776 632 [96%] men), of which 201 467 images (24.9%) were ordered for low-value indications (67 064 [8.2%] for carotid bruit, 25 032 [3.1%] for preoperative evaluation, and 109 400 [13.5%] for syncope), 257 369 (31.8%) for stroke workup, and 350 235 (43.3%) for other indications. Imaging for carotid bruits declined across the study period while there was no significant change in imaging for syncope or preoperative evaluation. Compared with the 6 years before, during the 4 years following Choosing Wisely recommendations, there was no change in the trend for syncope, a small decline in preoperative imaging (post–Choosing Wisely trend, −0.1 [95% CI, −0.1 to &lt;−0.1] images per 10 000 veterans), and a continued but less steep decline in imaging for carotid bruits (post–Choosing Wisely trend, −0.3 [95% CI, −0.3 to −0.2] images per 10 000 veterans). During the study period, 17 689 carotid procedures were identified, of which 3232 (18.3%) were preceded by carotid imaging ordered for low-value indications. <h3>Conclusions and Relevance</h3> These findings suggest that Choosing Wisely recommendations were not associated with a meaningful change in low-value carotid imaging in a national integrated health system. To reduce low-value testing and utilization cascades, interventions targeting ordering clinicians are needed to augment the impact of public awareness campaigns.
Abstract 2883: A transformable delivery system for the effective treatment of pediatric central nervous system tumors
Authors: Tzu-yin Lin
Journal: Cancer Research (2020)

Abstract Malignancies of the central nervous system (CNS) are the most common type of solid tumor affecting children and a leading cause of cancer-related death in children. With the deterioration of brain tumors, blood-brain barrier (BBB)/blood-brain tumor barrier (BBTB) with poor permeability, and relatively weak enhanced permeability and retention effect become major obstacles in delivering therapeutics to brain tumors. Vincristine (VCR) is a mainstay of treatment of a variety of cancers including brain tumors due to its well-defined mechanism of action and demonstrated anticancer activity. However, the clinical application of VCR in brain tumors was limited by its neurotoxicity and inability to penetrate BBB/BBTB resulting in unsatisfactory anti-cancer efficacy. In this project, we developed a transformable nanoparticle, named Ninja-nanoparticle, which is capable overcoming several important barriers for drug delivery to CNS tumors resulting in better efficacy and toxicity profile. Ninja-NP was stable during circulation due to crosslinking and could transpass BBB/BBTB through glucose receptor-mediated transcytosis. Ninja-NP could further transform into smaller nanoparticle upon encountering acidic microenvironment and revealed hidden moiety to target tumor surface overexpressed sialic acid. Ninja-NP employed a unique strategy which could sequentially target BBB/BBTB and brain tumor cells. Our study confirmed that VCR loaded Ninja-NP significantly accumulated at the orthotopic brain tumor sites, and exhibited superior anti-cancer efficacy in orthotopic diffuse intrinsic pontine glioma (DIPG), the most deadly pediatric CNS tumor, then free VCR or Liposomal VCR with limited systemic toxicity. Ninja-NP addresses multiple challenges for CNS tumor treatment and exhibits great potential to be translated into an effective theranostic nano-platform which could be seamlessly integrated into standard human brain tumor management (imaging-guided drug delivery) with reduced long term toxicity. Citation Format: Tzu-yin Lin. A transformable delivery system for the effective treatment of pediatric central nervous system tumors [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 2883.
Abstract 2793: Application of conditionally reprogrammed cell in <i>in vitro</i> drug sensitivity test and PDX modeling
Authors: Yuan Long, Song Xi, Danyi Wen
Journal: Cancer Research (2020)

Abstract Tumor cell immortalization through conditional reprogramming, particularly from limited biopsy specimen, is an invaluable tool to generate propagating tumor cells for cell-based drug sensitivity assay and bio-banking in vitro. We have successfully reprogrammed primary tumor cells from a number of tumor types, including lung carcinoma, breast cancer and glioma .etc. The conditionally reprogrammed cells exhibited typical colonized growth, which is well maintained upon cryopreservation. In some cases, the cells can be passaged for multiple times and likely become sable cell lines. Like primary tumor cells, conditional reprogrammed tumor cells are reliable to test drug sensitivity in vitro. We attempt to extend conditional reprogrammed tumor cells to reconstitute and grow PDX models in vivo for testing drug efficacy. The conditional reprogrammed tumor cells could also be used in PDX establishment and the tumor formation rate is much higher than the primary tissue's. In summary, this study explores and expands application of conditional reprogrammed tumor cells in in vitro drug efficacy test and in vivo PDX Modeling. Citation Format: Yuan Long, Song Xi, Danyi Wen. Application of conditionally reprogrammed cell in in vitro drug sensitivity test and PDX modeling [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 2793.
Abstract 2447: Analyses of epigenetic marks and mechanisms in disease: your guide to a successful CUT and RUN assay
Authors: Fang Chen, Christopher R. Comeau, Jillian Mason, Carrie A. Brown, Christopher J. Fry
Journal: Cancer Research (2020)

Abstract Like the chromatin immunoprecipitation (ChIP) assay, Cleavage Under Targets &amp; Release Using Nuclease (CUT&amp;RUN) is a powerful and versatile technique used for probing protein-DNA interactions within the natural chromatin context of the cell. The CUT&amp;RUN assay can be combined with downstream qPCR or NG-seq to analyze histone modifications and binding of transcription factors, DNA replication factors, or DNA repair proteins at specific target genes or across the entire genome. CUT&amp;RUN provides a rapid, robust, and true low cell number assay for detection of protein-DNA interactions in the cell. Unlike the ChIP assay, CUT&amp;RUN is free from formaldehyde cross-linking, chromatin fragmentation, and immunoprecipitation, making it a much faster and more efficient method for enriching protein-DNA interactions and identifying target genes. CUT&amp;RUN can be performed in as little as one to two days, from live cells to purified DNA, and has been shown to work with as few as 500-1000 cells per assay (1,2). Instead of fragmenting all of the cellular chromatin as done in ChIP, CUT&amp;RUN utilizes an antibody-targeted digestion of chromatin, resulting in much lower background signal than seen in the ChIP assay. As a result, CUT&amp;RUN requires only 1/10th the sequencing depth that is required for ChIP-seq assays. Finally, the inclusion of simple spike-in control DNA allows for accurate quantification and normalization of target-protein binding between samples. This provides for effective normalization of signal between samples and between experiments. I will discuss the basics of the CUT&amp;RUN assay and important factors to consider when setting up your experiment. In addition, I will introduce Cell Signaling Technology's new CUT&amp;RUN Assay Kit and CUT&amp;RUN pAG-MNase enzyme, and present data showing the versatility of this assay for mapping various histone modifications, transcription factor, and transcription cofactor binding across multiple cell types. Citation Format: Fang Chen, Christopher R. Comeau, Jillian Mason, Carrie A. Brown, Christopher J. Fry. Analyses of epigenetic marks and mechanisms in disease: your guide to a successful CUT and RUN assay [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 2447.
Abstract 118: FCHSD2 controls oncogenic ERK1/2 signaling by regulating endocytic trafficking in non-small-cell lung cancer
Authors: Guan-Yu Xiao, Sandra Schmid
Journal: Cancer Research (2020)

Abstract Non-small-cell lung cancer (NSCLC) is the major cause of cancer deaths. The evolution of transformed NSCLC cells into metastatic tumors is, in part, driven by altered intracellular signaling downstream of receptor tyrosine kinases (RTKs). The surface levels and activity of RTKs are governed mainly through clathrin-mediated endocytosis (CME), endosomal recycling or degradation. We recently discovered that oncogenic signaling downstream of RTKs can reciprocally regulate CME and endocytic trafficking by creating feedback loops and that some of these mechanisms for crosstalk between signaling and endocytosis appear to be specific for, or co-opted by cancer cells to enhance tumor progression. We previously identified that FCHSD2 (FCH/F-BAR and double SH3 domain-containing protein) has a cancer-cell specific function in regulating CME downstream of ERK1/2 in NSCLC cells. It is now critical to further determine its role in RTK trafficking, signaling outcome and NSCLC progression. Here, we report that knockdown of FCHSD2 impacts recycling of the RTKs, EGFR and MET, and switches the RTK trafficking toward late endosome compartments and degradation. Notably, FCHSD2 loss results in active ERK1/2 signaling from late endosome and the nuclear translocation of ERK1/2 leading to upregulated EGFR and MET in NSCLC cells. We further identified the small GTPase, Rab7, as being essential for the FCHSD2 depletion-induced RTK upregulation. Loss of FCHSD2 activity in NSCLC cells leads to enhanced cell proliferation, survival and migration. Correspondingly, the expression level of FCHSD2 is negatively correlated with lung tumor grades and positively correlated with higher lung cancer patient survival rates, suggesting that FCHSD2 negatively affects cancer progression. Our study provides new insight into the molecular nexus for crosstalk between oncogenic signaling and RTK trafficking that can control cancer progression, opening the possibility of novel therapeutic strategies for lung cancer. Citation Format: Guan-Yu Xiao, Sandra Schmid. FCHSD2 controls oncogenic ERK1/2 signaling by regulating endocytic trafficking in non-small-cell lung cancer [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 118.
Abstract 1140: Declining awareness of HPV and HPV vaccination within the general US population
Authors: Onyema G. Chido-Amajuoyi, Inimfon Jackson, Robert Yu, Sanjay Shete
Journal: Cancer Research (2020)

Abstract Background: Programs aimed at boosting awareness on Human Papillomavirus (HPV) and HPV vaccination are considered one of the most effective strategies for increasing vaccination uptake and eliminating HPV-associated cancers. Several US states have demonstrated a strong commitment to this effort through legislation and dedicated funds, however the impact of this intervention over time remains poorly studied. Methods: Using a nationally representative population of US adults from the Health Information National Trends Survey (HINTS), we examined for awareness of HPV and HPV vaccination between 2009 and 2018. Prevalence estimates and confidence intervals were calculated for HPV and HPV vaccination awareness. Further, we assessed awareness status after stratifying by key sociodemographic characteristics. Results: Overall, the awareness of HPV and HPV vaccination declined over time. This finding was consistent across gender and socioeconomic strata. The lowest rates of awareness were found among those with educational level at or below high school completion, those who earned less than $35,000 per annum, rural residents, and male adults, aged 60 years and older. Declines in awareness of HPV or HPV vaccination between 2014 and 2018 were more than 10% among male adults, those with educational level at or below high school completion and those who earned less than $35,000 per annum. Only 36.1% of adults with high school education or lower had ever heard of HPV vaccine in 2018, a 15.6% reduction from 2009. In 2018 awareness of HPV and HPV vaccine was highest among non-Hispanic whites (65.8% and 66.5%) and female adults (70.5% and 71.4%), however these figures represented declines of at least 5% from rates observed in 2009. Discussion: Amid a background of sub-optimal HPV vaccination uptake and a growing incidence of HPV-associated cancers in the US, the awareness of HPV and HPV vaccination within the general population has declined over time. This calls for stricter enforcement of legislature aimed at boosting HPV awareness, as well as frequent evaluations of government-funded HPV awareness programs. Citation Format: Onyema G. Chido-Amajuoyi, Inimfon Jackson, Robert Yu, Sanjay Shete. Declining awareness of HPV and HPV vaccination within the general US population [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 1140.
Abstract 252: How the gatekeeper helix of the thioesterase domain of fatty acid synthase controls substrate recognition and initiation of cleavage of the proper substrate
Authors: Joseph Fromm, Peter Teriete, Piotr Cieplak, Laetitia Misson, Michael Burkart, Nicholas Cosford
Journal: Cancer Research (2020)

Abstract Since the initiation of multiple clinical trials of two chemically distinct small molecule fatty acid synthase (FASN) inhibitors for the treatment of Non-Alcoholic SteatoHepatitis (NASH), breast cancer, colon cancer, and non-small cell lung cancer, FASN has garnered a resurgent interest as a therapeutic target. However, little effort has been made to better understand this target to improve upon previous drug discovery efforts. Using both computational modelling and enzymatic analysis, we have identified specific residues from the thioesterase (TE) domain of FASN that are crucial for the enzymatic function of FASN-TE while independent of the catalytic triad. Introduction of point mutations to these residues hinder the protein's ability to cleave the proper substrate of FASN, effectively disrupting the de novo synthesis of fatty acids. We propose a mechanism-of-action by which FASN-TE measures and initiates the cleavage of the proper substrate of FASN and have shown that interfering with the residues involved in this mechanism cripples the activity of the protein. Building upon these findings regarding the substrate selection mechanism of FASN-TE will allow for the enhanced design and development of the next generation of potent and selective inhibitors of FASN for the treatment of a variety of cancer types and other metabolic diseases. Citation Format: Joseph Fromm, Peter Teriete, Piotr Cieplak, Laetitia Misson, Michael Burkart, Nicholas Cosford. How the gatekeeper helix of the thioesterase domain of fatty acid synthase controls substrate recognition and initiation of cleavage of the proper substrate [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 252.
Abstract LB-024: Development of a non-invasive clinically applicable real time cell tracking platform for evaluating cell-based cancer therapy using magnetic resonance imaging (MRI)
Authors: Johnny C. Akers, Zhao Wei, Hyungseok Jang, Eric Chang, Jiang Du, Mya S. Thu
Journal: Cancer Research (2020)

Abstract While advancement in chimeric antigen receptors (CARs) has greatly improved the anti-tumor activity of immune cell-based therapies utilizing modified T lymphocytes (CAR-T) and natural killer cells (CAR-NK), there remains a critical unmet need for diagnostic technologies to help evaluate their biological performance effectively and efficiently after injecting into the body.The ability to better understand the biodistribution of injected cells and devise dosing strategies are key determinants to the success or failure of cell therapy. However, clinicians are limited by the available technology for real time in-vivo tracking of cell therapy products in clinical settings. Here we present a clinically applicable novel magnetic agent that can effectively label a variety of cell types used in cancer cell therapy development including T cells, NK cells, and neural stem cells (NSCs), and when combined with the 3D ultrashort echo time Cones (3D UTE-Cones) sequence, can enable quantitative assessment of cell therapy products using MRI. In this study, we optimized loading of our tracking agent into T cells, NK cells, and NSCs, evaluated the morphology and viability of the labeled cells, and confirmed internalization of the labeling agent by Prussian blue staining and TEM. The in vitro MRI properties of the labeled cells were quantitated by the 3D UTE-Cones sequence. Ex vivo MRI analysis was performed by injecting labeled cells into harvested mouse livers and brains to ascertain their MRI visibility in tissues using a clinical MRI scanner. We confirmed that our magnetic labeling agent efficiently labeled each cell line tested, and the morphology or viability of the labeled cells were unaffected. The MRI detectability of labeled cells were confirmed by in vitro MRI phantoms. Further, using quantitative susceptibility mapping (QSM), T1, and T2* mapping based on 3D UTE-Cones sequences, we found near perfect correlations between cell density and MRI properties. By applying the parameters established in the MRI phantoms, we were able to detect and quantity the number of labeled cells injected into mouse livers and brains ex vivo. In summary, we have developed a clinically applicable imaging-based platform that empowers cell therapy researchers to better understand the results of their biodistribution and dosing studies through real-time cell tracking and quantitative assessments using MRI. Citation Format: Johnny C. Akers, Zhao Wei, Hyungseok Jang, Eric Chang, Jiang Du, Mya S. Thu. Development of a non-invasive clinically applicable real time cell tracking platform for evaluating cell-based cancer therapy using magnetic resonance imaging (MRI) [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 LB-024.
Abstract 1955: Inhibition of eIF4A by eFT226 blocks KRAS mutant tumor growth
Authors: Craig R. Stumpf, Vikas K. Goel, Joan Chen, Jocelyn Staunton, Emily M. Santori, Maria Barrera, Haleigh Howard, Kevin R. Webster, Gary G. Chiang, Peggy A. Thompson
Journal: Cancer Research (2020)

Abstract Mutations in KRAS are among the most common oncogenic lesions across a variety of human cancers. Activation of KRAS directs signaling via the MAPK and PI3K pathways to promote tumor growth. One outcome of enhanced KRAS signaling is the induction of mRNA translation by eIF4A, eIF4E, and eIF4G, which together comprise the eIF4F complex. eIF4A is an RNA helicase that functions to unwind elements in the 5'-untranslated region (UTR) of mRNAs to facilitate scanning of the 40S ribosomal subunit. eFT226 is a highly potent and selective inhibitor of eIF4A that functions by forming a ternary complex between eIF4A, eFT226 and specific polypurine motifs in the 5'-UTR of select mRNAs, thus blocking ribosome scanning and inhibiting mRNA translation. This polypurine sequence motif is highly enriched in the 5'-UTR of eFT226 target genes, many of which are known proto-oncogenes. Translational profiling revealed KRAS to be a target of eFT226 and 5'-UTR sequence analysis of KRAS mRNA identified the polypurine regulatory motif, which imparts sensitivity to eFT226 mediated inhibition of translation. In cell-based reporter assays used to monitor translation, mutation of the KRAS 5'-UTR polypurine motifs resulted in a 10-fold decrease in sensitivity to eFT226 relative to the wild-type sequence. In a cell panel screen for in vitro apoptosis induction by eFT226, the most sensitive models were enriched for cell lines driven by KRAS mutations. Consistent with these results, treatment with eFT226 decreased KRAS protein levels, repressed downstream MAPK signaling, inhibited cell proliferation, and induced apoptosis in a collection of non-small cell lung, colorectal and pancreatic KRAS mutant cancer cell lines. The ability of eFT226 to block tumor cell growth and induce apoptosis is independent of the specific KRAS mutation present (e.g. G12C/V, G13D, Q61H/L) suggesting that eFT226 could be broadly efficacious in treating tumors with activating KRAS mutations. Treatment of KRAS mutant solid tumor xenografts with eFT226 as a monotherapy significantly inhibited tumor growth. Together, these results highlight the ability of eFT226 to inhibit growth and promote apoptosis in KRAS mutant tumors and support the clinical development of eFT226 in KRAS driven tumors. A clinical trial evaluating eFT226 in patients with solid tumor malignancies has initiated. Citation Format: Craig R. Stumpf, Vikas K. Goel, Joan Chen, Jocelyn Staunton, Emily M. Santori, Maria Barrera, Haleigh Howard, Kevin R. Webster, Gary G. Chiang, Peggy A. Thompson. Inhibition of eIF4A by eFT226 blocks KRAS mutant tumor growth [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 1955.