tbuckley/cabot-search huggingface dataset:
Angiomotin-Like Protein 1 Controls Endothelial Polarity and Junction Stability During Sprouting Angiogenesis
Authors: YujuanZheng, SimonaVertuani, StaffanNyström, StéphaneAudebert, InèzMeijer, TetyanaTegnebratt, Jean-PaulBorg, PerUhlén, ArindamMajumdar, LarsHolmgren
Journal: Circulation Research (2009)

Rationale: We have previously shown that angiomotin (Amot) is essential for endothelial cell migration during mouse embryogenesis. However, ≈5% of Amot knockout mice survived without any detectable vascular defects. Angiomotin-like protein 1 (AmotL1) potentially compensates for the absence of Amot as it is 62% homologous to Amot and exhibits similar expression pattern in endothelial cells. Objective: Here, we report the identification of a novel isoform of AmotL1 that controls endothelial cell polarization and directional migration. Methods and Results: Small interfering RNA–mediated silencing of AmotL1 in mouse aortic endothelial cells caused a significant reduction in migration. In confluent mouse pancreatic islet endothelial cells (MS-1), AmotL1 colocalized with Amot to tight junctions. Small interfering RNA knockdown of both Amot and AmotL1 in MS-1 cells exhibited an additive effect on increasing paracellular permeability compared to that of knocking down either Amot or AmotL1, indicating both protein...
Abstract 1122: MST4 phosphorylation of ATG4B regulates autophagic activity, tumorigenicity, and radio resistance in glioblastoma
Authors: Tianzhi Huang, Chung Kwon Kim, Angel A. Alvarez, Rajendra P Pangeni, Xuechao Wan, xiao song, Taiping shi, Yongyong Yongyong, Namratha Sastry, Craig Horbinski, Songjian Lu, Roger Stupp, John Kessler, Ryo Nishikawa, Ichiro Nakano, Erik Sulman, Xinghua Lu, Charles David James, Xiao-Ming Yin, Bo Hu, Shi-Yuan Cheng
Journal: Cancer Research (2018)

Abstract Autophagy-mediated intracellular catabolism sustains the rapid growth of established tumors and tumors in response to multiple stresses including genotoxic/cytotoxic therapies. Here we identify and validate ATG4B, a key regulator that stimulates autophagic process by promoting autophagosome through reversible modification of ATG8 as a novel substrate of mammalian sterile20-like kinase (STK) 26/MST4 that is less known for its function in cellular process (none in autophagy) and unknown authentic substrates in cancer. We show that MST4 phosphorylates ATG4B at serine residue 383, which stimulates ATG4B activity and increases autophagic flux. Inhibition of MST4 or ATG4B activities suppresses autophagic process and the tumorigenicity of glioblastoma (GBM) cells. Furthermore, radiation induces MST4 expression, ATG4B phosphorylation and autophagy. Inhibiting ATG4B in combination with radiotherapy in treating mice with intracranial GBM tumor xenografts markedly slows tumor growth and provides significant survival benefit to animal subjects. This study not only describes a novel regulatory mechanism by which the MST4-ATG4B axis accelerates autophagic process, regulates GBM tumorigenicity, and responses to radiotherapy (RT), but also explores imminent clinical utility of combination of ATG4B inhibition with RT to suppress orthotopic GBM tumor xenografts. This study should prove generalizable to other types of cancer and have positive impacts in advancing our knowledge of cancer biology and designing new cancer treatments. Citation Format: Tianzhi Huang, Chung Kwon Kim, Angel A. Alvarez, Rajendra P Pangeni, Xuechao Wan, xiao song, Taiping shi, Yongyong Yongyong, Namratha Sastry, Craig Horbinski, Songjian Lu, Roger Stupp, John Kessler, Ryo Nishikawa, Ichiro Nakano, Erik Sulman, Xinghua Lu, Charles David James, Xiao-Ming Yin, Bo Hu, Shi-Yuan Cheng. MST4 phosphorylation of ATG4B regulates autophagic activity, tumorigenicity, and radio resistance in glioblastoma [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 1122.
Abstract 13349: Long Term (4 Years) Clinical and Echocardiographic Results of Transcatheter Self-expanding Medtronic Corevalve Device in Patients With Aortic Stenosis
Authors: VassilisVoudris, SofiaThomopoulou, ManolisVavuranakis, MariaKariori, ChristosStefopoulos, GeorgeKaravolias, CarmenMoldovan, EfthychiaSbarouni, MarinaBalanika, MazenKhouri, ChristodoulosStefanadis
Journal: Circulation (2014)

Introduction: Transcatheter aortic valve implantation (TAVI) has emerged as an alternative to surgical aortic valve replacement for patients (pts) with severe aortic stenosis considered inoperable or at high operative risk. However, little is known about long-term outcomes following TAVI. In this study we assessed the 4-year clinical and echocardiographic outcomes of pts undergoing TAVI with the self expanding Medtronic CoreValve prosthesis. Methods: The 4-year outcomes following successful TAVI with the self-expanding aortic valve device (Medtronic CoreValve) were evaluated in 60 pts (mean age 79+6 years, male 47 %, Logistic Euroscore 28.43+10.93%). Principal outcome measures were death from any cause. An echocardiograpic examination was performed at prespecified intervals of 6 and 12 months, and every year afterwards. Categorical variables were compared using X2 test, and continuous variables using t test. Survival curves were also constructed. Results: All cause mortality at 1, 2, 3, and 4 years was 16...
Polymorphic Reentrant Ventricular Tachycardia in the Isolated Rabbit Heart Studied by High-Density Mapping
Authors: LucasBoersma, ZoltanZetelaki, JosepBrugada, MauritsAllessie
Journal: Circulation (2002)

Background— The role of dispersion of refractoriness and reentry for the genesis of polymorphic ventricular tachycardia (VT) has recently become emphasized. We investigated the mechanisms of polymorphic arrhythmias in a 2D preparation confining an area of prolonged refractoriness. Methods and Results— In 16 Langendorff-perfused rabbit hearts, a sheet of left ventricular epicardium was obtained by a cryoprocedure. Enhanced spatial heterogeneity in a refractory period was created by cooling a central region (diameter=12 mm). This markedly prolonged the refractory period (by 36±14 ms) inside but only slightly prolonged it (by 5±11 ms) outside the cooled area (n=6). During a control procedure, programmed stimulation with up to 3 premature stimuli induced an episode of monomorphic VT in only 1 of 10 hearts. During regional cooling, episodes of polymorphic VT with a maximum duration of 35 seconds could be induced in all hearts. High-resolution mapping (229 electrodes) of epicardial activation revealed that poly...
Prescription Drug Coverage and Outcomes of Myeloma Therapy Among Medicare Beneficiaries
Authors: Adam J. Olszewski, Stacie B. Dusetzina, Amal N. Trivedi, Amy J. Davidoff
Journal: Journal of Clinical Oncology (2018)

Purpose Novel parenteral (bortezomib) and oral (lenalidomide) therapies have improved survival in myeloma, but the standard Medicare benefit covers only parenteral drugs. We examined the association between prescription drug coverage, receipt of therapy, and survival among Medicare beneficiaries with myeloma. Methods Using SEER-Medicare data, we identified enrollment in a Medicare Part D plan (PDP) or other creditable prescription drug coverage (OCC) among 9,755 beneficiaries who were diagnosed with myeloma in 2006 to 2011. We examined the receipt of active myeloma therapy and that of classic cytotoxic agents or bortezomib as first-line regimen and overall survival. We report relative risk (RR) for binary outcome comparisons and 3-year restricted mean survival time (RMST) ratios, with 95% CI, adjusting for baseline patient- and disease-related characteristics. Beneficiaries with diffuse large B-cell lymphoma, a cancer that is uniformly treated with parenteral chemotherapy, served as a comparison cohort. Results Compared with beneficiaries without prescription drug coverage, PDP or OCC enrollees were more likely to receive active myeloma care, and PDP enrollees were less frequently treated with parenteral agents (adjusted RR, 0.86; 95% CI, 0.80 to 0.93) or classic cytotoxic agents in particular (RR, 0.62; 95% CI, 0.51 to 0.76). Overall survival was significantly better for beneficiaries with PDP coverage (adjusted RMST ratio, 1.16; 95% CI, 1.11 to 1.20) or OCC (RMST ratio, 1.16; 95% CI, 1.12 to 1.21). In contrast, we observed no survival differences by prescription drug coverage status in the control cohort with lymphoma. Conclusion Prescription drug coverage is associated with decreased use of classic cytotoxic chemotherapy and better survival among Medicare beneficiaries with myeloma, which suggests improved access to all existing treatment options. As oral targeted agents increasingly replace parenteral chemotherapy in oncology, adjustments in coverage policy are needed to ensure access to optimal treatment.
Abstract LB-330: Investigating how extracellular signals contribute to single cancer cell heterogeneity using near-infrared quantum dots
Authors: Phuong Le, Brian C. Baculis, Hee Jung Chung, Kristpher Kilian, Andrew M. Smith
Journal: Cancer Research (2018)

Abstract Cancer cells heterogeneity presents a major roadblock in clinical diagnostics and therapy. Investigations of tumor cell heterogeneity using single-cell analytical techniques have revealed not only the presence of multiple clonal subpopulations but also phenotypic variability among genetically identical cells. This heterogeneity plays a critical role in therapeutics, as population extrema, rather than cells near the ensemble mean, can dominate pathogenesis as well as drug resistance. To characterize single cell heterogeneity, multiple techniques quantifying single-cell gene expression have been developed. However, there's a lack of experimental techniques to measure how cellular decision-making processes underlying population variability derive from extracellular biochemical input signals, such as peptide growth factors, which cannot be measured at the single-cell level. Here, to digitally count growth factors in single cells, we develop a novel method combining fluorescent quantum dots and calibrated three-dimensional deconvolution microscopy (QDC-3DM). Using quantum dots with near-infrared emission to overcome intrinsic cellular autofluorescence, we were able to detect and accurately count individual quantum dots conjugated to epidermal growth factor (EGF) using their fluorescent intensities. Analyzing triple-negative breast cancer cells (MDA-MB-231) with QDC-3DM, we observed that single-cell heterogeneity in growth factor stimulation led to heterogeneity in receptor activation. When treating cells with increasing concentration of phamarcological inhibitor blocking receptor activation, we observed a proportional increase in receptor activation heterogeneity. Together, our results indicate that external stimulation contributes to signaling variation and drug response variation at the single-cell level. We anticipate that QDC-3DM can be applied to any peptidic ligands to study how extracellular signaling stimulation contributes to phenotypic variability to provide new insight into cancer cell heterogeneity that plays a critical role in therapeutic resistance. Citation Format: Phuong Le, Brian C. Baculis, Hee Jung Chung, Kristpher Kilian, Andrew M. Smith. Investigating how extracellular signals contribute to single cancer cell heterogeneity using near-infrared quantum dots [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 LB-330.
Cytosolic Aspartate Availability Determines Cell Survival When Glutamine Is Limiting
Authors: H. Furkan Alkan, Katharina E. Walter, Alba Luengo, Corina T. Madreiter-Sokolowski, Sarah Stryeck, Allison N. Lau, Wael Al-Zoughbi, Caroline A. Lewis, Craig J. Thomas, Gerald Hoefler, Wolfgang F. Graier, Tobias Madl, Matthew G. Vander Heiden, Juliane G. Bogner-Strauss
Journal: Cell Metabolism (2018)
Abstract 822: Predicting response to kinase inhibitors based on tumor genomics in NF1-related MPNSTs
Authors: Jamie Grit, Matt Pridgeon, Elizabeth Tovar, Zachary Madaj, Jackie Peacock, Julia Wulfkuhle, Emanuel Petricoin, Carrie Graveel, Matt Steensma
Journal: Cancer Research (2018)

Abstract Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are aggressive, chemoresistant sarcomas that develop in patients with the genetic disorder Neurofibromatosis Type 1 (NF1). Loss of TRP53 and amplification of the receptor tyrosine kinase (RTK) MET is observed 25-50% of cases. To investigate the role of MET and p53 in MPNST progression, we developed three MPNST mouse models: an NF1 null and MET overexpression MPNST model (NF1-MET), an NF1 and TRP53 heterozygous knockout model (NF1-p53), and a NF1 null model (NF1). Using orthotopic tumorgrafts from these models, we tested the efficacy of MET (capmatinib) and MEK (trametinib) inhibition on MPNST growth. Trametinib moderately inhibited tumor growth in all of the models; however, combined inhibition of MEK and MET was highly effective in both the NF1-MET and NF1 models. NF1-p53 tumors were the least responsive to combined inhibition and upregulated AKT signaling in response to single agent therapy. These data suggest that alternate RTK signaling pathways downstream of MET may compensate for MEK inhibition, and that p53 loss promotes kinome reprogramming in response to targeted inhibition in MPNSTs. To determine the effects of MEK, MET, PI3K, and mTOR inhibition on kinome signaling, we generated MPNST cell lines from each of our MPNST models. Western blot analysis revealed that NF1-MET MPNST cells are highly sensitive to MET inhibition, NF1-p53 MPNST cells maintain ERK and AKT activity in the presence of MET inhibition, and NF1-p53 MPNST cells uniquely upregulate MEK signaling in response to PI3K/mTOR inhibition. These results suggest p53 plays a unique role in kinome reprograming and resistance to kinase inhibitors. Currently, we are determining the effects of combined kinase inhibition on proliferation of MPNST cells and utilizing reverse phase protein arrays to evaluate the effect of MET and MEK inhibition on the phospho-proteome in our MPNST models. By understanding these complex signaling networks we will identify combinations of targeted therapies that can be used to effectively treat MPNSTs. Citation Format: Jamie Grit, Matt Pridgeon, Elizabeth Tovar, Zachary Madaj, Jackie Peacock, Julia Wulfkuhle, Emanuel Petricoin, Carrie Graveel, Matt Steensma. Predicting response to kinase inhibitors based on tumor genomics in NF1-related MPNSTs [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 822.
Abstract 971: Three-dimensional gene regulatory landscapes in normal and cancer cells
Authors: Brian J. Abraham, Yang Eric Guo, Denes Hnisz, Charles H. Li, Abraham S. Weintraub, Daniel S. Day, Jurian Schuijers, Tong Ihn Lee, Richard A. Young
Journal: Cancer Research (2018)

Abstract Key oncogenes can be misregulated in tumor cells by the acquisition of tumor-specific enhancers that direct gene expression through physical contacts (1,2). Identifying the full complement of enhancers regulating each oncogene could identify additional vulnerabilities in tumor expression programs, but remains challenging, because a given enhancer can regulate multiple genes and each of its targets may be genomically distant. Here we use DNA interaction data to construct gene regulatory landscapes for all expressed genes in a tumor cell and demonstrate that sets of enhancers can be assigned to these oncogenes using direct looping and insulated neighborhood data. A subset of these landscapes contains an exceptional amount of transcriptional apparatus, reminiscent of SEs (3), so we term this subset 3D-SEs. Well-characterized oncogenes, including c-Myc, acquire 3D-SEs in tumor cells where a c-Myc¬-associated linear SE was not identified, suggesting SE acquisition by c-Myc and other oncogenes has been underestimated. Each gene's regulatory network can also surprisingly extend beyond the confines of insulated neighborhoods and incorporate additional distal enhancers. Visualizing instances of 3D-SEs with microscopy demonstrates that they are components of liquid-liquid phase-separated bodies in cells, suggesting gene regulatory landscapes underpin these transcriptional condensates. The interactions comprising gene regulatory networks and their target genes thus extend previous interpretations of the targets of enhancers, signaling pathways, and disease-associated enhancer variants. References: 1. Hnisz, Abraham, Lee, et al. and Young, Cell 2013. 2. Mansour, Abraham, et al. and Young and Look, Science 2014. 3. Whyte, Orlando, Hnisz, Abraham, et al. and Young, Cell 2013. Citation Format: Brian J. Abraham, Yang Eric Guo, Denes Hnisz, Charles H. Li, Abraham S. Weintraub, Daniel S. Day, Jurian Schuijers, Tong Ihn Lee, Richard A. Young. Three-dimensional gene regulatory landscapes in normal and cancer 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 971.
Abstract 3167: Loss of HP1α alters the integrity of the nuclear lamina, thereby promoting invasion
Authors: Tracy K. Hale, Raoul Solomon
Journal: Cancer Research (2018)

Abstract Malignant cell invasion is accompanied by complex changes in nuclear morphology and chromatin patterning that have been utilized by pathologists to determine malignancy. Members of the HP1 family modulate chromatin plasticity, with the HP1α paralog required to maintain the condensation of transcriptionally silent heterochromatin and to sequester it at the nuclear periphery. While increased expression of HP1α is proposed to aid the onset of malignancy, the acquisition of an invasive phenotype correlates with the loss of this architectural protein in many solid tumors including those of the thyroid, kidney, colon and breast. We have shown in a Drosophila model of epithelial cell invasion that loss of HP1α synergistically enhances invasion in cells with an activated oncogenic pathway. In the poorly invasive MCF7 breast cells, loss of HP1α increases their invasive potential and promotes epithelial plasticity. These phenotypic changes are associated altered nuclear morphology including increased nuclear grooves and indentations, diffuse chromatin patterning and a loss of heterochromatin at the nuclear periphery. Since during metastatic invasion, the nucleus, the largest and most rigid cellular of organelle, becomes malleable enough to squeeze through interstitial spaces in the surrounding tissue. This lead us to propose that loss of HP1α causes a remodelling of nuclear periphery thereby increasing nuclear malleability. Here we demonstrate that HP1α knockdown in MCF7 cells decreases mechanical stability of the nuclei and altering the integrity of nuclear lamina. While total levels of Lamin A/C, Lamin B1 and Lamin B2 are unchanged within the cell, their solubility and thus localization within the nucleus is altered. We also demonstrate how this change in the lamina effects other proteins that function at the nuclear periphery. Together, these findings suggest that when loss of HP1α increases invasive potential there is a corresponding disruption to the nuclear periphery, creating a weakness in these cells that could be exploited for therapeutic benefit. Citation Format: Tracy K. Hale, Raoul Solomon. Loss of HP1α alters the integrity of the nuclear lamina, thereby promoting invasion [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 3167.
Abstract 5734: Interleukin-1 signaling is required for HNSCC tumor response to cetuximab
Authors: Madelyn M. Espinosa-Cotton, Rachel A. Dahl, Elana Fertig, Isaac Jensen, Ayana J. McLaren, Kenley Miller, Samuel N. Rodman, Sandra Schmitz, Andrean L. Simons
Journal: Cancer Research (2018)

Abstract Despite the incorporation of the epidermal growth factor receptor (EGFR) inhibitor cetuximab into the clinical management of head and neck squamous cell carcinoma (HNSCC), limited to no long-term changes in overall survival are observed in HNSCC patients even though EGFR is expressed at high levels in these tumors. Therefore, the identification of novel therapeutic approaches to enhance the clinical efficacy of cetuximab could lead to improved long-term survival for HNSCC patients. Our previous work suggests that cetuximab activates the interleukin-1 (IL-1) pathway via tumor release of IL-1 alpha (IL-1α), although the implications of activating this pathway are unclear. The IL-1 pathway plays a central role in immune response and displays both pro-tumor and anti-tumor activities. IL-1 may promote tumor growth by upregulating the secretion of pro-inflammatory mediators involved in angiogenesis and metastasis. On the other hand, IL-1 signaling may promote antitumor immunity specifically via natural killer (NK)-cell mediated antibody-dependent cell-mediated cytotoxicity (ADCC), which is also an important mechanism of action of cetuximab. The goal of our work is to determine how modulation of the IL-1 pathway affects HNSCC tumor response to cetuximab. We found that blockade of IL-1 signaling using an IL-1-receptor antagonist (IL-1RA, anakinra), neutralizing IL-1α/IL-1β antibodies, and genetic knockdown of the IL-1R all suppressed the anti-tumor efficacy of cetuximab, while IL-1α overexpression and treatment with recombinant IL-1α enhanced HNSCC tumor response to cetuximab in immunodeficient and immunocompetent HNSCC mouse models. Mechanistically, these results appear to be due to modulation of ADCC, as we found that IL-1 blockade significantly reduced cetuximab-mediated ADCC in vitro. Additionally, we found that HNSCC patients with high baseline circulating levels of IL-1 ligands (IL-1α, IL-1β) were significantly more likely to respond favorably to cetuximab monotherapy compared to patients with low or no baseline circulating IL-1 ligands. Altogether, these results suggest that IL-1 signaling is necessary for HNSCC tumor response to cetuximab. Therefore, IL-1α warrants further study as a novel therapeutic to enhance response to cetuximab and as an immunologic biomarker for cetuximab response. Citation Format: Madelyn M. Espinosa-Cotton, Rachel A. Dahl, Elana Fertig, Isaac Jensen, Ayana J. McLaren, Kenley Miller, Samuel N. Rodman, Sandra Schmitz, Andrean L. Simons. Interleukin-1 signaling is required for HNSCC tumor response to cetuximab [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 5734.
Relation of Electrolyte Disturbances to Cardiac Arrhythmias
Authors: Charlesfisch
Journal: Circulation (1973)

While a number of electrolytes play a role in the genesis of the transmembrane action potential (AP), the changes in the action potential most clearly related to arrhythmias are dependent to a large extent on K+. Potassium gradient is a major determinant of the magnitude of transmembrane resting potential (TRP), and secondarily the rate of rise (dV/dt) of phase 0, and consequently the speed of conduction. The cell membrane conductance for K+, or a decrease therein, is most likely the major determinant of spontaneous slow depolarization during phase 4. Thus K+ has a pronounced effect on both conduction and automaticity. Furthermore, these electrophysiologic properties are altered within levels of K+ encountered in clinical medicine, a situation which, with rare exceptions, is not seen with Ca++, Mg++, or Na–. These latter ions affect the action potential and induce experimental arrhythmias at concentrations which are unphysiologic and frequently incompatible with life. Consequently, of all the electrolytes...