tbuckley/cabot-search huggingface dataset:
Abstract 824: Targeting epidermal growth factor receptors and urokinase-type plasminogen activator receptors for sarcoma therapy
Authors: Ashley J. Graef, Jong-Hyuk Kim, Daniel A. Vallera, Jaime F. Modiano
Journal: Cancer Research (2018)

Abstract eBAT is a bispecific angiotoxin consisting of truncated, deimmunized Pseudomonas exotoxin fused to epidermal growth factor (EGF) and the amino terminal fragment of urokinase. This drug was designed to use epidermal growth factor receptors (EGFR) and urokinase-type plasminogen receptors (uPAR) as baits to deliver the lethal toxin into the cells, rather than as a means to interrupt signaling by the receptors. We previously showed that eBAT is remarkably safe, and that it reduced tumor burden in mice with established human rhabdomyosarcoma xenografts. It also was safe and showed a strong efficacy signal when used in the adjuvant setting in a clinical trial for dogs with splenic hemangiosarcoma. Nevertheless, the therapeutic mechanism of action of eBAT remains to be elucidated. Our goal is to identify patterns of uPAR expression in sarcomas that promote sarcoma growth and that mediate sensitivity for therapeutic activity by eBAT. We generated uPAR-knockout (KO) cells from MC1A-C1 mouse fibrosarcoma cell line using the CRISPR-Cas system to target exon 2 of the uPAR gene. The resulting cell lines D10 and H6 are clonal uPAR knockouts, whereas K02 and K06 represent mixtures where approximately 80% and 30% of the cells retain uPAR expression. uPAR expression in K02 and K06 has remained stable over numerous passages, indicating that loss of uPAR does not create selective pressure to enhance or inhibit cell growth in vitro. Furthermore, the growth kinetics of D10 and H6 are comparable to parental MC1A-C1 cells. eBAT treatment significantly inhibited proliferation of parental cells, but not of uPAR KO cells. In contrast, all of the cells were resistant to treatment with EGF- and uPA-monospecific toxins. The engraftment efficiency and tumor growth of uPAR KO cells in syngeneic hosts was substantially diminished when compared to K02 and K06 uPAR+ cells, suggesting that, even while uPAR-KO cells might be more resistant to eBAT therapy, uPAR expression appears to be necessary to create the tumor niche and/or to promote tumor growth in vivo. In our ongoing work, we are investigating how uPAR expression in stromal cells and in cells of the innate immune system influence sarcoma growth and the response to eBAT. Citation Format: Ashley J. Graef, Jong-Hyuk Kim, Daniel A. Vallera, Jaime F. Modiano. Targeting epidermal growth factor receptors and urokinase-type plasminogen activator receptors for sarcoma therapy [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 824.
Abstract 13846: Factor Xa Inhibition Prevents Cardiac Remodeling Induced by Intermittent Hypoxia in Sleep Apnea Model Mice
Authors: FumiYoshimura, ShotaTanikawa, ShogoHosako, RyujiKato, YoshioIjiri, YasukatsuIzumi, MinoruYoshiyama, TetsuyaHayashi
Journal: Circulation (2015)

Introduction: We have reported that intermittent hypoxia (IH) relevant to sleep apnea increases oxidative stress causing vascular remodeling and heart failure. The serine protease factor Xa in the coagulation cascade elicits inflammatory responses in endothelial cells. Hypothesis: We hypothesize that rivaroxaban might attenuate cardiac remodeling induced by IH in sleep apnea model mice. Methods: Male C57BL/6J mice at 8 weeks of age were exposed to IH (repeated cycles of 1.5 minute of 5% oxygen followed by 5 minutes of 21% oxygen) for 56 days with/without treatment by rivaroxaban (1.2 g riv./kg chow). After echocardiography, heart was examined by light and electron microscopy, immunohistochemistry, and RT-PCR. HPAECs were cultured under hypoxic conditions (37%, 1% O2, 5% CO2) with/without rivaroxaban (1 μM). Results: IH caused cardiac remodeling (Figure), associated with both systolic and diastolic dysfunction compared with those of normoxia (IH vehicle vs. Normoxia; EF: 51.8% vs. 59.4% and E/e’: 29.4 vs. ...
Abstract 20858: Australian’s Awareness of Heart Attack Symptoms and Action Improves With a Mass Media Warning Signs Campaign
Authors: Janet E Bray, Lahn Straney, Harry Patsamanis, Bill Stavreski, Judith Finn
Journal: Circulation (2016)

Introduction: Many Australians suffering heart attacks are still not recognising their symptoms and are delaying presenting to hospital. The Heart Foundation of Australia’s multimedia Warning Signs...
Response to Letter Regarding Article, “Mitomycin-Induced Pulmonary Veno-Occlusive Disease: Evidence From Human Disease and Animal Model”
Authors: FrédéricPerros, SvenGünther, BenoitRanchoux, LaurentGodinas, FabriceAntigny, Marie-CamilleChaumais, PeterDorfmüller, AurélieHautefort, NicolasRaymond, LaurentSavale, XavierJaïs, BarbaraGirerd, VincentCottin, OlivierSitbon, GeraldSimonneau, MarcHumbert, DavidMontani
Journal: Circulation (2016)
Right Heart Remodeling in Olympic Athletes During 8 Years of Intensive Exercise Training
Authors: Vincent L. Aengevaeren, Stefano Caselli, Cataldo Pisicchio, Fernando M. Di Paolo, Maria T.E. Hopman, Antonio Spataro, Thijs M.H. Eijsvogels, Antonio Pelliccia
Journal: Journal of the American College of Cardiology (2018)
Abstract 5837: Acquired resistance to anticancer drug of high glucose-exposed HepG2
Authors: Shuichi Kishimoto, Shoji Fukushima
Journal: Cancer Research (2018)

Abstract Reports show that diabetic patients with cancer tend to show resistance to anticancer drug treatment and have poor prognosis compared to non-diabetic patients. We observed that HepG2-HG, which is a derivative of the hepatocellular carcinoma cell line HepG2 exposed continuously to high glucose, shows high resistance to etoposide. In this study, we aimed to understand the involvement of excretion transporter and apoptosis regulatory factor in anti-cancer drug resistance in HepG2-HG. HepG2 was cultured in minimum essential medium (MEM) (with 5.5 mM glucose), and HepG2-HG was cultured in MEM supplemented with up to 25 mM glucose. Sensitivity to anticancer drugs was evaluated by the SRB assay. mRNA expression was assessed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) on Rotor-Gene Q using the KAPA SYBR FAST qPCR kit. Proteins extracted using the Ultra-RIPA kit were electrophoresed, transferred to a membrane by the iBlot 2 gel transfer device, reacted with antibodies, and evaluated for expression using enhanced chemiluminescence (ECL) prime reagent. IC50 values of etoposide in HepG2 and HepG2-HG were 0.59 µM and 17.5 µM, respectively. Comparison of the expression of the excretion transporter showed that the expression of p-glycoprotein (p-gp) was markedly enhanced in HepG2-HG compared to that in HepG2. Continuous contact of HepG2-HG with high glucose induced the expression of the glucose transporter GLUT1, which may provide a survival mechanism for cancer cells via escape from hypoxia-induced apoptosis. Furthermore, the expression of phospho-p70S6K was high in HepG2-HG, suggesting an increase in the activity of the mammalian target of rapamycin (mTOR). Therefore, we suggest that increased p-gp expression and mTOR activity in HepG2-HG provided resistance to etoposide by decreasing intracellular drug levels and suppressing the apoptotic mechanism. Estimation of the contribution of both mechanisms to etoposide resistance of HepG2-HG requires further examination. Citation Format: Shuichi Kishimoto, Shoji Fukushima. Acquired resistance to anticancer drug of high glucose-exposed HepG2 [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 5837.
Direct Inhibition of Expressed Cardiac L- and T-Type Calcium Channels by IgG From Mothers Whose Children Have Congenital Heart Block
Authors: Guang-QianXiao, KeliHu, MohamedBoutjdir
Journal: Circulation (2001)

Background—Congenital heart block (CHB) is a disease that affects the offspring of mothers with autoimmune diseases. We recently reported that maternal sera containing antibodies against SSA/Ro and SSB/La ribonucleoproteins (positive IgG) inhibited L-type Ca current in isolated cardiac myocytes and induced sinus bradycardia in a murine model of CHB. The direct interaction of positive IgG with L-type Ca channel proteins and the possible inhibition of T-type Ca current that could account for the sinus bradycardia remain unknown. Methods and Results—The 2-electrode voltage-clamp technique was used to record currents via L-type (IBa-α1C or IBa-α1C+β2a+α2/δ) and T-type (IBa-α1H) Ca channels, Na channels (INa-hH1), and K channels (IKs-minK+KvLQT1) expressed in Xenopus oocytes. Positive IgG (350 μg/mL) inhibited IBa-α1C by 50.6±4.7% (P<0.01) and IBa-α1C+β2a+α2/δ by 50.9±4.2% (P<0.01); IBa-α1H was reduced by 18.9±1.0% (P<0.01). Immunoblot data show cross-reactivity of positive IgG with α1C subunit. Pretreatment o...
Abstract 2329: Noncanonical mitophagy induced by Mieap and its role in tumor suppression via ferroptosis-like cell death
Authors: Yasuyuki Nakamura, Makoto Yamamoto, Hirofumi Arakawa
Journal: Cancer Research (2018)

Abstract Parkin/Pink1-mediated mitophagy plays a critical role in mitochondrial quality control, in which the damaged mitochondria are sequestered by autophagosomes, and degraded by fusion between autophagosomes and lysosomes. Here, we report Mieap-mediated noncanonical mitophagy as a new function of tumor suppressor p53. Mieap was originally identified as a p53-target gene. Overexpression of exogenous Mieap induces large vacuoles in cancer cells. Mieap-induced vacuoles are generated from the mitochondria, and directly eat and degrade the cancer mitochondria. UVRAG regulates the Mieap-mediated noncanonical mitophagy. Surprisingly, Mieap-mediated noncanonical mitophagy induces cell death via the iron-dependent production of reactive oxygen species (ROS). Introduction of exogenous Mieap strikingly suppresses in vivo tumor growth of Mieap-deficient colorectal cancer cells. Deficiency of endogenous Mieap dramatically promotes cancer development, malignancy, and aggressiveness in colorectal and gastric cancer model mice. The cell death induced by Mieap-mediated noncanonical mitophagy occurs via the ROS production in in vivo hypoxic tumor microenvironment. These results suggest that Mieap-mediated noncanonical mitophagy plays a critical role in tumor suppression via ferroptosis-like cell death. Citation Format: Yasuyuki Nakamura, Makoto Yamamoto, Hirofumi Arakawa. Noncanonical mitophagy induced by Mieap and its role in tumor suppression via ferroptosis-like cell death [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 2329.
Abstract 5850: Nrf2-mediated oxidative stress response is altered during acquired resistance to the proteasome inhibitor, oprozomib, in multiple myeloma
Authors: Snehal M. Gaikwad, Adriana Zingone, Aleksandra Michalowski, Susana Najera, Anaisa Quintanilla-Artega, Sayeh Gorjifard, John Simmons, Nick Watson, Ola Landgren, Jing Huang, Beverly Mock
Journal: Cancer Research (2018)

Abstract Multiple myeloma (MM) is a hematologic neoplasm characterized by malignant proliferation of plasma cells in the bone marrow. Proteasome inhibitors are widely used in treatment regimens for MM. Although initial responses to PI (e.g., bortezomib, carfilzomib) treatments have been promising, patients often develop resistance and become refractory to disease. Understanding molecular alterations in signaling cascades influenced by proteasome inhibitors and mechanisms underlying acquired resistance is needed. In this study, we have established a clinically relevant oproxomib-resistant subline (KMS28BMONYX) of the MM cell line KMS28BM. The KMS28BMONYX cell line is pan-resistant to PIs with a 10-fold increase in IC50 for oprozomib as compared to the parental line. To identify genes involved in modulating drug resistance, we analyzed gene expression profiles of both parental and resistant cell lines using the Affymetrix GeneChip Human Genome U133 Plus 2.0 array. Ingenuity Pathway Analysis of microarray data comparing the parental and resistant cells revealed an acute dependence on stress response proteins to maintain PI-resistance. Activation of nuclear factor-erythroid 2 (NF-E2)-related factor 2 (Nrf2; gene symbol NFE2L2) coupled with elevated levels of sequestosome 1/p62 (SQSTM1/p62) were prominent features of the KMS28BMONYX cell line. Altered levels of SQSTM1 correlated with resistance to oprozomib in several MM cell lines. Simultaneously, the KMS28BMONYX cell line showed increased expression of MYC and MCL1. Oprozomib treatment stabilized c-Myc expression in the KMS28BMONYX line. The Champion ChiP Transcription Factor Search Portal database DECODE predicted two c-Myc transcription factor binding sites in the SQSTM1 promoter. CHIP-seq data for MYC in MM1s cells also indicates strong binding in the promoter region of SQSTM1. Our data suggest that therapies targeting the SQSTM1/p62-Nrf2 pathway may help overcome proteasome inhibitor resistance in refractory MM patients. Citation Format: Snehal M. Gaikwad, Adriana Zingone, Aleksandra Michalowski, Susana Najera, Anaisa Quintanilla-Artega, Sayeh Gorjifard, John Simmons, Nick Watson, Ola Landgren, Jing Huang, Beverly Mock. Nrf2-mediated oxidative stress response is altered during acquired resistance to the proteasome inhibitor, oprozomib, in multiple myeloma [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 5850.
Distribution of Heart Potentials on the Thoracic Surface of Normal Human Subjects
Authors: Brunotaccardi
Journal: Circulation Research (1963)

The distribution of isopotential lines on the thoracic surface of 15 normal subjects aged 15 to 43 was determined at 10 to 20 instants of time during ventricular activation. At the beginning of the QRS interval a precordial maximum and a dorsal minimum of potential can be observed. Thereafter, the minimum migrates toward the right shoulder and appears then anteriorly in the right subclavicular fossa, while another minimum appears near the mid-sternal line. The two minima finally merge together, and the potential distribution becomes dipolar once again. During the last third of the QRS interval the maximum of potential moves toward the left axillary and dorsal region, while a new maximum appears near the upper end of the sternum. A tentative correlation between surface and intracardiac electrical events can be established on the basis of the most generally accepted descriptions of ventricular activation processes. During some phases of ventricular activation, the potential distribution on the surface of th...
Abstract 5155: The modulation of actin dynamics via atypical protein kinase-C activated cofilin regulates migration of colorectal cancer cells
Authors: S M Anisul Islam, Khandker Mohammad Khalid, Raja Reddy Bommareddy, Rekha Patel, Mildred Acevedo-Duncan
Journal: Cancer Research (2018)

Abstract Colorectal cancer (CRC) is the second most common cancer in both men and women in the United States. The exact mechanism of CRC cells migration is poorly understood. Actin polymerization is thought to be an initial step in cancer cells motility cycle which drives the formation of cell protrusions that defines the direction of migration and initiate cell crawling. Cofilin is a significant actin regulating molecule that can regulate the migration of cancer cells by the formation of lamellipodia and filopodia. In this study, the effect of atypical Protein Kinase C (aPKC) on cofilin in CRC was studied by using two inhibitors of aPKC: 1) ICA-I (5-amino-1-(2,3-dihydroxy-4-hydroxymethyl) cyclopentyl)-1H-imidazole-4-carboxamide) is a specific inhibitor of PKC-ι and 2) ζ-Stat (8-hydroxy-1, 3, 6-naphthalenetrisulfonic acid) is a specific inhibitor of PKC-ζ. The cell lines tested were CCD18CO normal colon fibroblast and LOVO &amp; RKO metastatic CRC cells. The inhibition of aPKC did not bring any significant toxicity in CCD18CO colon fibroblasts cells. However, our data showed that the inhibition of aPKC blocks the migration of CRC cells migration by increasing the level of cofilin phosphorylation at serine-3. Additionally, the aPKCs inhibition brought a significant reduction of CRC cells proliferation along with the reduction of survival markers. Our findings suggest that the PKC-ι and/or PKC-ζ may be responsible for the migration of CRC cells as well as carcinogenesis. These results suggest the possibility of utilizing aPKCs as the potential therapeutic targets for the CRC cells metastasis. Citation Format: S M Anisul Islam, Khandker Mohammad Khalid, Raja Reddy Bommareddy, Rekha Patel, Mildred Acevedo-Duncan. The modulation of actin dynamics via atypical protein kinase-C activated cofilin regulates migration of colorectal 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 5155.
Cardiac Involvement in Mitochondrial Diseases
Authors: RyuichiroAnan, MasanoriNakagawa, MasaakiMiyata, ItsuroHiguchi, ShoichiroNakao, MasahitoSuehara, MitsuhiroOsame, HiromitsuTanaka
Journal: Circulation (1995)

Background Mutations of mitochondrial DNA have been demonstrated as causes of human mitochondrial diseases. While these disorders typically involve multiple organs, the effect of mitochondrial mutations on the heart has not been systematically studied. Methods and Results We studied mitochondrial mutations and cardiac changes in 17 patients with Kearns-Sayre syndrome; ocular myopathy; myoclonus epilepsy with ragged red fibers (MERRF); and mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS). Cardiac involvement was evaluated by chest radiograph, ECG, His-bundle electrogram, and echocardiogram. All 3 patients with Kearns-Sayre syndrome had large deletions of mitochondrial DNA and disturbances in cardiac conduction. ECG abnormalities were found in 2 of 6 patients with ocular myopathy who showed large deletions of mitochondrial DNA. All 3 patients with MERRF had an A-to-G mutation at nucleotide position 8344; 2 had cardiomegaly, asymmetrical septal hypertrophy, and diffuse...
Peroxisome Proliferator–Activated Receptor Activators Inhibit Lipopolysaccharide-Induced Tumor Necrosis Factor-α Expression in Neonatal Rat Cardiac Myocytes
Authors: HiroyukiTakano, ToshioNagai, MasayukiAsakawa, TetsuyaToyozaki, ToruOka, IsseiKomuro, ToshihiroSaito, YoshiakiMasuda
Journal: Circulation Research (2000)

Abstract—Peroxisome proliferator–activated receptors (PPARs) are transcription factors belonging to the nuclear receptor superfamily. Recently, PPAR activators have been shown to inhibit the production of proinflammatory cytokines in macrophages or vascular smooth muscle cells. It has been reported that tumor necrosis factor-α (TNF-α) expression is elevated in the failing heart and that TNF-α has a negative inotropic effect on cardiac myocytes. Therefore, we examined the effects of PPARα and PPARγ activators on expression of TNF-α in neonatal rat cardiac myocytes. Northern blot analysis revealed expression of PPARα and PPARγ mRNA in cardiac myocytes. Immunofluorescent staining demonstrated that both PPARα and PPARγ were expressed in the nuclei of cells. When cardiac myocytes were transfected with PPAR responsive element (PPRE)-luciferase reporter plasmid, both PPARα and PPARγ activators increased the promoter activity. Cardiomyocytes were stimulated with lipopolysaccharide (LPS), and the levels of TNF-α i...
Phosphorylation of vimentin by Aurora A kinase: implications for the use of intermediate filaments as pharmacodynamic markers of Aurora A activity
Authors: Neil Rollins, Jessica Weiner, Eric Lightcap, Hua Liao, Douglas Bowman, Kara Hoar, Jeffrey Ecsedy, Anne Burkhardt
Journal: Cancer Research (2008)

4769  Intermediate filament proteins form extensive networks within the cytoplasm and inner nuclear membrane of vertebrate cells. Cytoskeletal intermediate filaments such as mesenchymal vimentin and epithelial keratins function in maintaining cell shape, structural integrity and organization of the cytoplasm. The structurally related intermediate filament proteins of the nucleus, the lamins, comprise a similar filamentous network underlining the inner nuclear membrane. Mitotic phosphorylation of specific sites within the head and tail domains of intermediate filament proteins results in the disassembly of these filamentous networks yielding filamentous bundles of protein length. Cdk1 plays a role in the disassembly of both the nuclear and cytoplasmic networks during mitosis; first by phosphorylating specific sites within the head and tail domains of lamin-B2 resulting in nuclear envelope breakdown (NEBD), followed by Cdk1 phosphorylation of vimentin Ser56 of the head domain which initiates dissolution of the vimentin cytoskeleton. Additional vimentin head domain sites of phosphorylation have been reported, including phosphorylation of Ser83 by PLK and Ser73 by Aurora B, among others. Although sites of phosphorylation within the tail domain of vimentin have been reported, the kinase(s) responsible for these events have yet to be described. We found that Aurora A phosphorylates vimentin Ser412 in certain cancer cells, a residue within the vimentin tail domain. In vitro, Aurora A phosphorylates vimentin Ser412, as determined by Mass Spectrophotometry and by Western Blotting using phospho-specific Ser412 (pSer412) antibodies. Analysis of vimentin isolated from nocodazole arrested cells confirmed the presence of phosphorylated Ser412 in mitosis. Immunofluorescence analysis using pSer412 antibodies determined that Ser412 is phosphorylated during mitosis and that phosphorylation is inhibited by treating cells with MLN8054, a selective Aurora A inhibitor. Protein sequence alignments identifies the vimentin Ser412 motif in additional intermediate filament proteins as well, including keratin 5, which is expressed in basal layer of epithelial skin tissue. This motif also maps to the region of Cdk1 phosphorylation in the lamin-B2 tail domain. These findings suggest a potential role for Aurora A in the disassembly of the cytoskeletal intermediate filament network during mitosis. Moreover, these findings provide the potential for using phosphorylated intermediate filaments as pharmacodynamic markers of Aurora A activity in clinical trials with Aurora A inhibitors.