tbuckley/cabot-search huggingface dataset:
Potentiation of Myocardial Contractility by Continual Premature Extra-activations
Authors: JanKoch-Weser
Journal: Circulation Research (1966)

Introduction of a premature activation into each interval between regular contractions of isolated kitten papillary muscles greatly increases isometric tension development. This premature extra-activation potentiation is a manifestation of the interval-strength relationship of ventricular myocardium and results both from the increase in the overall frequency of activation (frequency potentiation) and from the prematurity of the extra-activations (prematurity potentiation). A premature electrical stimulus which elicits a propagated action potential is always followed by a mechanically apparent activation of the contractile element. Potentiation of the regular contractions follows from the occurrence of premature, propagated action potentials, and/or the resulting activation processes. It does not depend on the extent to which the contractile element can respond to the premature activation. Prematurity potentiation results solely from an increase in the degree of activation of the contractile element. It in...
Detection of Coronary Artery Disease With Myocardial Contrast Echocardiography
Authors: SanjivKaul, RoxySenior, HowardDittrich, UshaRaval, RajKhattar, AvijitLahiri
Journal: Circulation (1997)

Background The purpose of this study was to determine whether myocardial contrast echocardiography (MCE) can be used to detect coronary artery disease (CAD) during rest and pharmacological stress in humans through the use of venous injections of contrast. Methods and Results Thirty patients with known or suspected CAD underwent MCE and 99mTc-sestamibi single-photon emission computed tomography (SPECT) at baseline and after dipyridamole (0.56 mg · kg−1) infusion. Ten myocardial segments (5 each in the apical two- and four-chamber views) from the two sets of images using both methods were scored for myocardial perfusion as follows: 1=normal, 0.5=mildly reduced, and 0=severely reduced. The information from baseline and postdipyridamole images was then used to determine whether an abnormal segment was irreversible (similar abnormal perfusion at baseline and after dipyridamole) or reversible (perfusion better at baseline compared with after dipyridamole). Concordance between segmental scores was 92% (κ=.99) fo...
Abstract 1081: <i>TCF12</i> regulates metastasis-promoting genes in pancreatic cancer
Authors: Michelle M. Maurin, Justin Y. Newberg, Mik A. Black, Devin J. Jones, Nancy A. Jenkins, Neal G. Copeland, Karen M. Mann
Journal: Cancer Research (2018)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease with poor patient outcome. While acquired oncogenic activation of KRAS is an initiating event, disease progression requires functional perturbation of additional genes and cellular pathways. We have taken a comparative genomics approach to identify progression drivers using a mouse model of metastatic PDAC driven by Sleeping Beauty (SB) insertional mutagenesis in the context of oncogenic Kras (SB PDAC). Statistical enrichment analysis of high read depth insertions from SB PDAC tumors defined 48 drivers predicted to contribute to disease progression. Among these drivers, Tcf12 was associated with increased metastatic incidence in the SB PDAC mouse model. We demonstrated significant increases in primary tumor burden and metastatic spread by single gene knockdown of TCF12 in an orthotopic mouse model of pancreatic cancer. TCF12 encodes a basic helix-loop-helix (bHLH) transcription factor that partners with other bHLH transcription factors in different cellular contexts, including TWIST, a transcription factor involved in epithelial-to-mesenchymal transition (EMT), PTF1A, a pancreas-specific transcription factor with essential roles in pancreas development and cancer, and SMAD3, a TGFß-related transcription factor involved in cellular migration. TCF12 resides in a chromosomal region (15q21) frequently lost in pancreatic cancer, and decreased TCF12 expression is associated with poor patient prognosis. RNASeq analysis identified genes with TCF12 consensus binding sites within 10 kb of their promoter regions that are differentially expressed upon TCF12 knockdown. A subset of these genes function in Wnt or TGF-beta signaling pathways and show consistent decreases in expression upon TCF12 knockdown in orthotopic tumors. ChipSeq analysis and functional validation studies are ongoing to confirm these genes are direct TCF12 transcriptional targets involved in pancreatic tumor metastasis. Citation Format: Michelle M. Maurin, Justin Y. Newberg, Mik A. Black, Devin J. Jones, Nancy A. Jenkins, Neal G. Copeland, Karen M. Mann. TCF12 regulates metastasis-promoting genes in pancreatic 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 1081.
Abstract 5690: Characterization of tumor growth and immune microenvironment in humanized NOG-EXL mice implanted with A549, MDA-MB-436 and A375 cells
Authors: Srimoyee Ghosh, Anne Fiore, Christoph Eberle, Sarah Wang, Keith Mikule, Kristen McEachern, Sujatha Kumar, David Jenkins, Geeta Sharma
Journal: Cancer Research (2018)

Abstract Syngeneic mouse models are the most extensively explored mouse models for evaluation of immune-oncology therapeutic modalities in preclinical settings. One of the major limitations with syngeneic models is that both the tumor and the immune system is murine and thus do not express any human targets. Also, this precludes the evaluation of human clinical product (antibody or protein) mandating the synthesis and use of murine surrogates. Therefore, development of models of human tumors in mice with competent human immunity became an urgent need. Tumor-bearing, humanized NOG-EXL mice are a new and valuable preclinical testing platform for immuno-oncology, to simulate trials, evaluate multiple drugs alone or in combination, and produce predictive data both in cell line derived (CDX) and patient derived (PDX) models. With the objective of understanding the tumor growth and basal immune microenvironment in Hu-NOG-EXL mice (NOG mice humanized using CD34+ cells isolated from cord blood), we implanted three different human tumor cell lines (A549: Human Lung Carcinoma; MDA-MB-436: Triple Negative Breast Cancer; A375: Human Melanoma) in Hu-NOG EXL mice procured from Taconic, NY. The tumors were collected at a tumor volume of 1000-1500mm3, and profiled for the lymphoid and myeloid compartments using flow cytometry. The corresponding splenic compartment was also profiled to monitor the correlation or lack thereof between the tumor and splenic compartments. Finally the tumors were compared and categorized based on their basal infiltrates. The results demonstrated that Hu-NOG-EXL mice could be an useful tool to dissect the immune response in human tumors. It was possible to identify and quantitate the myeloid cells which are absent in a model that has been implanted with human PBMNC's (Peripheral Blood Mono Nuclear Cells) instead of human CD34 stem cells. Citation Format: Srimoyee Ghosh, Anne Fiore, Christoph Eberle, Sarah Wang, Keith Mikule, Kristen McEachern, Sujatha Kumar, David Jenkins, Geeta Sharma. Characterization of tumor growth and immune microenvironment in humanized NOG-EXL mice implanted with A549, MDA-MB-436 and A375 cells [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 5690.
Abstract 3367: USP7 regulates CSB protein recovery after UV-induced DNA damage
Authors: Shengcai Wei
Journal: Cancer Research (2018)

Abstract Cockayne syndrome group B (CSB) protein functions in transcription-coupled repair (TCR), a sub-pathway of nucleotide excision repair (NER). We previously demonstrated that ultraviolet radiation (UVR) induces a valosin-containing protein (VCP)/p97-dependent ubiquitin-mediated CSB degradation. In this study, we further revealed that CSB protein is ubiquitinated immediately after ultraviolet-light irradiation and undergoes proteasomal degradation. The recovery of CSB protein level is dependent on USP7. Disruption of USP7 function sensitizes CSB degradation to lower UVR doses. We further demonstrated USP7's interaction with CSB in vivo by immunoprecipitation and in vitro by GST pulldown assays. Interestingly, in vitro CSB strongly binds to TRAF domain, which also interacts with UV stimulated scaffold protein A (UVSSA). Additionally, USP7 also interacts with VCP/p97 using its TRAF domain and C-terminal in in vitro. Furthermore, VCP/p97 was demonstrated to associates with USP7 in vivo. These results suggest that USP7 rescues CSB from ubiquitin-mediated proteolysis after (VCP)/p97-mediated CSB extraction from chromatin, preventing the CSB-ubiquitin conjugates being presented to proteasome for degradation. Citation Format: Shengcai Wei. USP7 regulates CSB protein recovery after UV-induced DNA damage [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 3367.
Abstract 1720: Analysis of multiplexed immunotherapy targets and secreted ligands using computational tumor microenvironment profiling
Authors: Jenifer Caldara, Brooke Hirsch, Joseph Krueger, Chris Bunker, Jeff Kim, Annelies Laeremans, Mohammed Qutaish, Allison Harney
Journal: Cancer Research (2018)

Abstract As the number and diversity of cellular and signaling pathway therapeutic targets in immuno-oncology increases, more therapy combinations are aimed at multiple cell types in the tumor microenvironment (TME). To develop rational combinations of therapies that will be effective in any individual patient, multivariate biomarker assays will be required to understand each patient's specific tumor and immune profile. Understanding the mechanistic effects of immunotherapy includes the tissue context of direct immunotherapy targets and downstream effector molecules such as secreted cytokines. Although the content of tumor-infiltrating immune cells and gene expression of the total tumor can be ascertained through several methods, spatial arrangements and proximity of cells and co-localization of biomarkers can only be achieved with tissue-based assays. Duplex chromogenic in situ hybridization assays using the RNAscope platform allows for the visualization of gene expression of mRNA targets directly in tissue for multiple cell types or biomarkers. Computational Tissue Analysis (cTA™) was used to quantify cellular spatial distributions including regional density maps, proximity measurements, and colocalization of biomarkers in both the tumor nests and the surrounding stroma that would be challenging by visual inspection of duplex RNAscope assays in non-small cell lung cancer (NSCLC) tissue microarrays (TMAs). Often, neither immune effector cells nor the therapeutic target is sufficient in isolation to understand blocked anti-tumor immune responses and therefore the potential efficacy of a single or combination therapeutic strategy. Multiplex RNAscope assays and cTA™ in combination allow the assessment of end points that measure spatial relationships between cell types expressing certain biomarkers. As these are performed in the context of the tissue microarchitecture within and across multiple tissue sections, they are a significant advancement over traditional tissue-based manual end points. Citation Format: Jenifer Caldara, Brooke Hirsch, Joseph Krueger, Chris Bunker, Jeff Kim, Annelies Laeremans, Mohammed Qutaish, Allison Harney. Analysis of multiplexed immunotherapy targets and secreted ligands using computational tumor microenvironment profiling [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 1720.
Abstract 1098: Innate immune response to primary breast cancer prevents metastasis-initiating cell colonization
Authors: Zafira Castano
Journal: Cancer Research (2018)

Abstract Current lack of insight into mechanisms governing breast cancer metastasis has precluded development of curative therapies. Previous reports, including our own, have demonstrated that metastatic success is due to tumor cell intrinsic properties as well as microenvironmental and systemic factors (Castano, et al., Cancer Discovery, 2013). The goal of our current study was to determine whether metastasis initiating cells (MIC), i.e., cells enriched for metastatic capacity, also rely on systemic cues. Using a preclinical model of the early phases of breast cancer metastasis, when cells are disseminated in the presence of the primary tumor (McAllister, et al., Cell 2008), we were surprised to find that certain primary tumors inhibit progression of disseminated MICs into overt tumors. In the presence of the primary tumor, MICs were maintained in a Zeb1hi/CDH1lo state and were less proliferative and poorly differentiated relative to those that formed in the absence of the primary tumor. We established that the primary tumor induces mobilization of IL1beta-expressing innate immune cells that are recruited to sites where MICs reside. At those sites, signaling via the IL1 receptor maintains MICs in the Zeb1hi/CDH1lo state, thus promoting disease indolence. Confirming our xenograft results, we established that expression of IL1beta in patient tumors is associated with metastasis free survival. Collectively, these data highlight the profound impact a primary tumor can exert on metastasizing cells - in this case, by altering the systemic environment to the detriment of secondary tumor growth-. Moreover, our data highlight a central role for IL1 pathway in modulating tumor cell plasticity and suggest it may provide a novel avenue for targeting recurrent disease. Citation Format: Zafira Castano. Innate immune response to primary breast cancer prevents metastasis-initiating cell colonization [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 1098.
Abstract 2677: A natural product-derived Compound A effectively targets both cancer stem and non-stem cells in NSCLC
Authors: Seung Yeob Hyun, Huong T. Le, Jaebeom Cho, Hye-Young Min, Ho-Young Lee
Journal: Cancer Research (2018)

Abstract Cancer stem-like cells (CSCs) contribute to tumor recurrence and chemoresistance. Hence, strategies eradicating CSCs are crucial for effective anticancer therapies. Here, we demonstrate transcriptional upregulation of the heat shock proteins (Hsp90 and Hsp70) and their co-chaperones and enhanced activities of the Hsp system in both non-CSCs and CSCs in non-small cell lung cancer (NSCLC) cells. Genetic and pharmacologic strategies targeting Hsps eliminated both CSCs and non-CSCs of NSCLC, suggesting the functional role of the Hsp system in the two populations in NSCLC. We further identified Compound A, a natural product-derived compound, as a novel Hsp70 inhibitor eliminating both the CSC and non-CSC populations in NSCLC. Compound A inhibited the sphere-forming ability of NSCLC CSCs by inducing apoptosis. Compound A also suppressed the viability and colony-forming abilities of NSCLC cells (non-CSCs) and their sublines carrying acquired chemoresistance by inducing apoptosis with minimal toxicity in normal cells derived from various organs. Mechanistically, Compound A disrupted Hsp70 function by binding to the ATP-binding pockets of Hsp70. These data suggest the rationale to target the Hsp system for controlling both CSCs and non-CSCs in NSCLC and the potential of Compound A as a natural Hsp70 inhibitor to eliminate the two populations with limited toxicities. Citation Format: Seung Yeob Hyun, Huong T. Le, Jaebeom Cho, Hye-Young Min, Ho-Young Lee. A natural product-derived Compound A effectively targets both cancer stem and non-stem cells in NSCLC [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 2677.
Abstract 5640: Development of a personalized pancreatic cancer vaccine
Authors: Darren R. Cullinan, Michael McLellan, Xiuli Zhang, Timothy M. Nywening, Chris A. Miller, S. Peter Goedegebuure, William G. Hawkins, William E. Gillanders
Journal: Cancer Research (2018)

Abstract Introduction: Cancer neoantigens result from mutations accumulated in an individual tumor. These mutations are usually private and yield high-affinity T-cells as they are not limited by mechanisms of self-tolerance. Neoantigens presented in the context of MHC class I can be recognized by anti-tumor CD8+ T-cells. Methods: Three consecutive patients with confirmed pancreatic ductal adenocarcinoma (PDAC) had DNA and RNA isolated from areas of high tumor cellularity. Comparative normal DNA was isolated from peripheral blood mononuclear cells (PBMC). Nonsynonymous mutations were identified by tumor/normal whole exome sequencing and expression in the tumor was verified by cDNA capture. HLA typing was inferred from exome sequencing. Candidate neoantigens were identified using multiple epitope prediction algorithms for MHC class I. Matched patient PBMC were cultured in serum-free media for 48 hours with synthetic mutated short peptides to determine the baseline immune response by interferon-gamma (IFNγ) enzyme-linked immunospot assay. Results: A KRAS driver mutation was identified in all three patients. Using KRAS variant allele frequency (VAF) as a surrogate for tumor purity, we achieved greater than 40% tumor purity for all three samples. This provides an adequate level of purity to proceed with neoantigen identification. In these samples, the mean number of nonsynonymous mutations identified was 27 (range: 18-32; DNA VAF cutoff 10%). Of these nonsynonymous mutations, a mean of 8.6 mutations (range: 7-10) were expressed (RNA VAF cutoff &amp;gt;10% and FPKM &amp;gt;1). Following confirmation of mutation expression, a mean of 5 mutations (range: 4-6) were predicted to bind to MHC class I using multiple prediction algorithms (binding affinity &amp;lt;500nM). IFNγ immunospot assay revealed a baseline immune response to one neoantigen in each patient (Patient A - SDHA: 75 spot forming units per millions cells (SFU/M) vs Negative: 12.5 SFU/M, p=0.01; Patient B - ZRANB1: 588 SFU/M vs Negative: 17.5 SFU/M, p&amp;lt;0.001; Patient C - ATAD3C: 340 SFU/M vs Negative: 75 SFU/M, p=0.002). Conclusion: Utilizing advanced genomic and bioinformatics tools we have successfully characterized the cancer neoantigens in a series of three consecutive patients with PDAC. From this data, we plan to open a phase I clinical trial to assess the safety and immunogenicity of a neoantigen DNA vaccine. Citation Format: Darren R. Cullinan, Michael McLellan, Xiuli Zhang, Timothy M. Nywening, Chris A. Miller, S. Peter Goedegebuure, William G. Hawkins, William E. Gillanders. Development of a personalized pancreatic cancer vaccine [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 5640.
Abstract 4827: Magnetic iron oxide nanoparticles induce apoptosis and autophagic cell death in prostate cancer cells treated with docetaxel via ROS generation and NF-KB signaling
Authors: Kanako Kojima, Sanai Takahashi, Shungo Saito, Tadashi Nittami, Eri Usugi, Kenichiro Ishii, Yoshifumi HIrokawa, Masatoshi Watanabe
Journal: Cancer Research (2018)

Abstract Patients with metastatic castration-resistant prostate cancer (mCRPC) have a poor prognosis. Docetaxel (DTX)-based therapy is one of current standard treatments for mCRPC since 2004 although cabazitaxel, abiraterone acetate, and enzalutamide are three agents recently approved for the treatment of mCRPC. Although DTX-based chemotherapy has been shown to improve the quality of life in patients with the advanced disease, this needs to be improved because of limitations by lack of specificity, toxicity, and progression of docetaxel-resistance. Thus, combination of docetaxel with other compounds or drugs is needed to overcome these problems. We have investigated usefulness of magnetic iron oxide nanoparticles (MNPs- Fe3O4) for cancer diagnosis and therapy, showing that MNPs- Fe3O4 may modify the effect of chemotherapy in prostate cancer cells in vitro. The purpose of this study was to analyze the combined effect of docetaxel and MNPs- Fe3O4 on prostate cancer cell lines, DU145 and PC-3 and clarify their mechanisms. Electron microscopy, flow cytometry and Western blotting were used to study apoptosis and autophagic cell death with/without an autophagic inhibitor. Our results showed that MNPs- Fe3O4 produced reactive oxygen species (ROS) and 8-OHdG, and the combination of docetaxel and MNPs- Fe3O4 inhibited cancer cell growth and induced apoptosis and autophagic cell death. Although docetaxel induced nuclear factor-kappaB (NF-KB) expression, combination of docetaxel and MNPs inhibited NF-KB expression. These results suggest that MNPs- Fe3O4 may enhance effect of docetaxel on prostate cancer cells via ROS generation and inhibition of NF-KB signaling, leading to new tumor ablation therapies.&amp;lt;!–EndFragment–&amp;gt; Citation Format: Kanako Kojima, Sanai Takahashi, Shungo Saito, Tadashi Nittami, Eri Usugi, Kenichiro Ishii, Yoshifumi HIrokawa, Masatoshi Watanabe. Magnetic iron oxide nanoparticles induce apoptosis and autophagic cell death in prostate cancer cells treated with docetaxel via ROS generation and NF-KB 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 4827.
Dehydroepiandrosterone Sulfate Does Not Predict Cardiovascular Death in Postmenopausal Women
Authors: ElizabethBarrett-Connor, DeborahGoodman-Gruen
Journal: Circulation (1995)

Background High levels of dehydroepiandrosterone sulfate (DHEAS) appear to be associated with a reduced risk of fatal cardiovascular disease (CVD) in men. We examined the association between baseline DHEAS levels and the 19-year CVD and ischemic heart disease (IHD) mortality rates in 942 postmenopausal women free of known heart disease at baseline. Methods and Results The 199 CVD deaths and 102 IHD deaths were not related to baseline DHEAS levels. DHEAS was not related to body mass index, fasting plasma glucose, or family history of coronary heart disease, but significantly higher DHEAS levels were found in women who had elevated total or HDL cholesterol or blood pressure, were current smokers, or were nonusers of estrogen replacement therapy. After we adjusted for age, cholesterol, blood pressure, smoking, estrogen replacement therapy, obesity, fasting plasma glucose, and family history of heart disease, the relative risk of fatal CVD and IHD was 1.11 (95% confidence interval, 0.81 to 1.23) and 0.92 (95%...
Abstract 10883: Ischemia-Modified Albumin in Acute Decompensated Heart Failure: IMA-HF Study
Authors: Yuksel Cavusoglu, Sule Korkmaz, Selda Demirtas, Erkan Gencer, Hatice Sasmaz, Birhan Yilmaz
Journal: Circulation (2012)

Purpose: Ischemia-modified albumin (IMA) is a sensitive marker of ischemia, even in the absence of myocardial damage. IMA has also been found to be elevated in the setting of oxidative stress, acid...