tbuckley/cabot-search huggingface dataset:
Abstract 16441: Novel Calmodulin Mutations Cause Congenital Long QT Syndrome and Affect Calcium Current in Human Cardiomyocytes
Authors: Daniel C Pipilas, R. Gregory Webster, Jurg Schlaepfer, Florence Fellmann, Nicole Sekarski, Christopher N Johnson, Peter J Schwartz, Walter J Chazin, Lia Crotti, Zahurul A Bhuiyan, Alfred L George
Journal: Circulation (2015)

Calmodulin (CaM) mutations are associated with cardiac arrhythmia susceptibility including the congenital long QT syndrome (LQTS). We identified two novel CaM mutations in children with LQTS associated with cardiac arrest, and performed studies to elucidate the functional consequences of each molecular defect. The first mutation was discovered in a male infant with a ventricular septal defect and fetal bradycardia born to healthy parents. His ECG on postnatal day 1 revealed bradycardia and very prolonged QTc (651 msec). At age 2-days, he developed 2:1 AV block, profound bradycardia (50 bpm) and cardiogenic shock. He was resuscitated and received a pacemaker. Targeted DNA sequencing revealed a de novo mutation in CALM2 (D132H). A second novel mutation was discovered in a three year-old boy who suffered witnessed cardiac arrest. His initial rhythm was ventricular fibrillation, and after successful defibrillation an ECG recording revealed a QTc of 574 msec. The parents were healthy with normal QTc intervals. Exome sequencing of the parent-child trio demonstrated a de novo mutation in CALM1 (D132V). Both novel mutations affect the same conserved aspartate residue within the C-domain EF-hand-IV Ca2+ binding motif. Further studies elucidated biochemical and functional effects of the mutations. Measurements of Ca2+ binding affinity of CaM-D132H indicated extremely weak binding to the C-domain (Kd &gt; 150 μM) with significant structural perturbations. Voltage-clamp recordings of human induced pluripotent stem cell (iPSC) derived cardiomyocytes transiently expressing wildtype or mutant CaM demonstrated that both mutations caused impaired Ca2+-dependent inactivation (CDI) of voltage-gated Ca2+ current. Neither mutant affected voltage-dependent inactivation of Ba2+ currents. Our findings implicate impaired CDI in human cardiomyocytes as the plausible mechanism for LQTS associated with CaM mutations.
Normal Standards for Amplitude of Ballistocardiograms Calibrated by Force
Authors: Isaacstarr
Journal: Circulation (1955)

Normal standards for ballistocardiogram amplitude have been estimated by statistical methods from a series of 194 healthy men and women. The application of new knowledge of the genesis of ballistocardiograms has resulted in normnal standards with a smaller scatter than those previously formulated, and so the ability to detect cardiac abnormality has been correspondingly increased.
Density and Kinetics of IKr and IKs in Guinea Pig and Rabbit Ventricular Myocytes Explain Different Efficacy of IKs Blockade at High Heart Rate in Guinea Pig and Rabbit
Authors: ZhiboLu, KaichiroKamiya, TobiasOpthof, KenjiYasui, ItsuoKodama
Journal: Circulation (2001)

Background— Class III antiarrhythmic agents commonly exhibit reverse frequency-dependent prolongation of the action potential duration (APD). This is undesirable because of the danger of bradycardia-related arrhythmias and the limited protection against ventricular tachyarrhythmias. The effects of blockade of separate components of delayed rectifier K+ current (IK) may help to develop agents effective at high heart rate. Methods and Results— We assessed the density and kinetics of the 2 components of the delayed rectifier K+ current, IKr and IKs, in rabbit and guinea pig ventricular myocytes. The effects of their specific blockers (chromanol 293B for IKs and E-4031 for IKr) on the action potential was studied at different heart rates by use of whole-cell patch-clamp techniques. In guinea pig ventricular myocytes only, blockade of IKs causes APD prolongation in a frequency-independent manner, whereas blockade of IKs in rabbit ventricular myocytes shows reverse frequency dependence, as does blockade of IKr ...
Abstract 5201: Differences in tumor microenvironments between primary lung tumors and brain metastases in lung cancer patients: Therapeutic implications for immune checkpoint inhibitors
Authors: Ryul Kim, Bhumsuk Keam, Sehui Kim, Miso Kim, Se Hyun Kim, Jin Wook Kim, Yu Jung Kim, Tae Min Kim, Yoon Kyung Jeon, Dong-Wan Kim, Doo Hyun Chung, Jong Seok Lee, Dae Seog Heo
Journal: Cancer Research (2018)

Abstract Background: We aimed to compare intra- and extracranial responses to immune checkpoint inhibitors (ICIs) in lung cancer with brain metastases (BM), and to explore tumor microenvironments of the brain and lungs focusing on the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway. Methods: Two cohorts of lung cancer patients with BM were analyzed. Cohort 1 included 18 patients treated with nivolumab or pembrolizumab, and intra- and extracranial responses were assessed. Cohort 2 comprised 20 patients who underwent both primary lung surgery and brain metastasectomy. Specimens from cohort 2 were subjected to immunohistochemical analysis for the following markers: CD3, CD4, CD8, FOXP3, and PD-1 on tumor infiltrating lymphocytes (TIL) and PD-L1 on tumor cells. Results: Seven patients (38.9%) in cohort 1 showed progressive disease in both primary and intracranial lesions. Although the other 11 patients exhibited a partial response or stable disease in the primary lesion, eight showed a progression in BM. Interestingly, PD-1+ TILs were significantly decreased in BM (P=0.034). For fifteen patients with adenocarcinoma, more distinctive patterns were observed in CD3+ (P=0.078), CD8+ (P=0.055), FOXP3+ (P=0.016), and PD-1+ (P=0.016) TILs. Conclusions: There may be discordant responses to an ICI of lung cancer between primary lung lesion and BM based on discrepancies in the tumor microenvironment. The diminished infiltration of PD-1+ TILs in tumor tissue within the brain may be one of the major factors that hinder the response to anti-PD-1 antibody in BM. Citation Format: Ryul Kim, Bhumsuk Keam, Sehui Kim, Miso Kim, Se Hyun Kim, Jin Wook Kim, Yu Jung Kim, Tae Min Kim, Yoon Kyung Jeon, Dong-Wan Kim, Doo Hyun Chung, Jong Seok Lee, Dae Seog Heo. Differences in tumor microenvironments between primary lung tumors and brain metastases in lung cancer patients: Therapeutic implications for immune checkpoint inhibitors [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 5201.
Leptin Induces Endothelin-1 in Endothelial Cells In Vitro
Authors: PeterQuehenberger, MarkusExner, RauteSunder-Plassmann, KatharinaRuzicka, ChristianBieglmayer, GeorgEndler, ClaudiaMuellner, WolfgangSpeiser, OswaldWagner
Journal: Circulation Research (2002)

Leptin, a protein encoded by the obese gene, is produced by adipocytes and released into the bloodstream. In obese humans, serum leptin levels are increased and correlate with the individual’s body mass index and blood pressure. Elevated serum concentrations of endothelin-1 (ET-1), a potent vasoconstrictor and mitogen, were also observed in obese subjects. The pathomechanisms underlying this ET-1 increase in obesity are poorly understood. In the present study, we investigated the influence of the ob gene product leptin on the expression of ET-1 in human umbilical vein endothelial cells (HUVECs). Binding studies using 125I-radiolabeled leptin revealed high- and low-affinity leptin binding sites on HUVECs (Kd1=13.1±3.1 nmol/L and Kd2=1390±198 nmol/L, respectively), mediating a time- and dose-dependent increase of ET-1 mRNA expression and protein secretion after incubation of HUVECs with leptin. This leptin-induced ET-1 expression was inhibited by preincubation of HUVECs with 0.75 μmol/L antisense phosphorot...
Functional CRISPR screen identifies AP1-associated enhancer regulating FOXF1 to modulate oncogene-induced senescence
Authors: Ruiqi Han, Li Li, Alejandro Piñeiro Ugalde, Arieh Tal, Zohar Manber, Eric Pinto Barbera, Veronica Della Chiara, Ran Elkon, Reuven Agami
Journal: Genome biology (2018)

Functional characterization of non-coding elements in the human genome is a major genomic challenge and the maturation of genome-editing technologies is revolutionizing our ability to achieve this task. Oncogene-induced senescence, a cellular state of irreversible proliferation arrest that is enforced following excessive oncogenic activity, is a major barrier against cancer transformation; therefore, bypassing oncogene-induced senescence is a critical step in tumorigenesis. Here, we aim at further identification of enhancer elements that are required for the establishment of this state. We first apply genome-wide profiling of enhancer-RNAs (eRNAs) to systematically identify enhancers that are activated upon oncogenic stress. DNA motif analysis of these enhancers indicates AP-1 as a major regulator of the transcriptional program induced by oncogene-induced senescence. We thus constructed a CRISPR-Cas9 sgRNA library designed to target senescence-induced enhancers that are putatively regulated by AP-1 and used it in a functional screen. We identify a critical enhancer that we name EnhAP1-OIS1 and validate that mutating the AP-1 binding site within this element results in oncogene-induced senescence bypass. Furthermore, we identify FOXF1 as the gene regulated by this enhancer and demonstrate that FOXF1 mediates EnhAP1-OIS1 effect on the senescence phenotype. Our study elucidates a novel cascade mediated by AP-1 and FOXF1 that regulates oncogene-induced senescence and further demonstrates the power of CRISPR-based functional genomic screens in deciphering the function of non-coding regulatory elements in the genome.
Vascular Endothelial Growth Factor-A–Induced Chemotaxis of Monocytes Is Attenuated in Patients With Diabetes Mellitus
Authors: JohannesWaltenberger, JulianeLange, AndreaKranz
Journal: Circulation (2000)

Background—Vascular endothelial growth factor-A (VEGF-A) acts on endothelial cells and monocytes, 2 cell types that participate in the angiogenic and arteriogenic process in vivo. Thus far, it has not been possible to identify differences in individual responses to VEGF-A stimulation because of the lack of an ex vivo assay. Methods and Results—We report a chemotaxis assay using isolated monocytes from individual diabetic patients and from healthy, age-matched volunteers. The chemotactic response of individual monocyte preparations to VEGF-A, as mediated via Flt-1, was quantitatively assessed using a modified Boyden chamber. Although the migration of monocytes from healthy volunteers could be stimulated with VEGF-A (1 ng/mL) to a median of 148.4% of the control value (25th and 75th percentiles, 136% and 170%), monocytes from diabetic patients could not be stimulated with VEGF-A (median, 91.1% of unstimulated controls; 25th and 75th percentiles, 83% and 98%; P<0.0001). In contrast, the response of monocytes...
Thermosensitive biomimetic polyisocyanopeptide hydrogels may facilitate wound repair
Authors: Roel C. op ‘t Veld, Onno I. van den Boomen, Ditte M.S. Lundvig, Ewald M. Bronkhorst, Paul H.J. Kouwer, John A. Jansen, Esther Middelkoop, Johannes W. Von den Hoff, Alan E. Rowan, Frank A.D.T.G. Wagener
Journal: Biomaterials (2018)
Abstract 532: PELP1 and AIB1 (SRC-3) complexes promote cancer stem cell-associated phenotypes in ER+ breast cancer models
Authors: Thu H. Truong, Hsiangyu Hu, Nuri A. Temiz, Kyla M. Hagen, Brian J. Girard, Nicholas J. Brady, Kathryn L. Schwertfeger, Carol A. Lange, Julie H. Ostrander
Journal: Cancer Research (2018)

Abstract Proline, glutamic acid, and leucine rich protein 1 (PELP1) is overexpressed in approximately 80% of invasive breast tumors. PELP1 dynamically shuttles between the nucleus and cytoplasm, but is primarily nuclear in normal breast tissue. However, altered localization of PELP1 to the cytoplasm is an oncogenic event that promotes breast cancer initiation and progression. Herein, we sought to identify interacting partners unique to cytoplasmic PELP1 and determine the mechanisms by which these interactions promote oncogenic PELP1 signaling. We identified AIB1 (amplified in breast cancer 1; also known as SRC-3 or NCOA3) as a novel binding partner of cytoplasmic PELP1 in both estrogen receptor-positive (ER+) and ER-negative cell lines. Cytoplasmic PELP1 expression elevated basal phosphorylation levels (i.e., activation) of AIB1, enhanced ALDH+ tumorsphere formation, and upregulated specific target genes independently of hormone stimulation. Direct manipulation of AIB1 levels using shRNA abrogated cytoplasmic PELP1-induced tumorsphere formation and downregulated cytoplasmic PELP1-specific target genes. SI-2, an AIB1 inhibitor, inhibited the PELP1/AIB1 interaction and decreased cytoplasmic PELP1-induced tumorsphere formation. Similar results were observed in a murine-derived MMTV-AIB1 tumor cell line (J110). Furthermore, in vivo syngeneic tumor studies showed that PELP1 knockdown in J110 cells resulted in increased survival of tumor-bearing mice as compared to mice injected with control cells. These studies suggest that manipulating PELP1 location or levels has the potential to mitigate tumor progression, particularly in the context of AIB1-mediated tumorigenesis. Taken together, our data demonstrate that cytoplasmic PELP1/AIB1-containing complexes function to promote advanced cancer phenotypes, including outgrowth of stem-like cells, associated with estrogen-independent breast cancer progression. Citation Format: Thu H. Truong, Hsiangyu Hu, Nuri A. Temiz, Kyla M. Hagen, Brian J. Girard, Nicholas J. Brady, Kathryn L. Schwertfeger, Carol A. Lange, Julie H. Ostrander. PELP1 and AIB1 (SRC-3) complexes promote cancer stem cell-associated phenotypes in ER+ breast cancer models [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 532.
Progress in Late Results Among Pediatric Cardiac Surgery Patients
Authors: AlirezaRaissadati, HetaNieminen, EeroJokinen, HeikkiSairanen
Journal: Circulation (2015)

Background—Surgical treatment of congenital cardiac defects in Finland started >60 years ago. We analyzed the survival of all the pediatric cardiac surgery patients operated on before 2010. Methods and Results—Data were obtained retrospectively from a pediatric cardiac surgery database. Patient status was received from the Finnish Population Registry. Survival was determined with the Kaplan–Meier method, and the survival rate was compared with a sex- and age-matched general population. Between 1953 and 2009, 13 876 cardiac operations were performed on 10 964 pediatric patients in Finland. Follow-up coverage was 98%. The 60-year survival for the entire study was 70% versus 86% for the general population. The number and proportion of severe cardiac defects increased in the 2000s. The long-term survival of patients with severe defects improved significantly across decades. For instance, the 22-year survival rate of patients with transposition of the great arteries operated on in 1953 to 1989 and in 1990 to 2...
Abstract 1512: Regulation of the CDC42 signaling pathway by IKZF1 in T-cell acute lymphoblastic leukemia
Authors: Mario Soliman, Chunhua Song, Jonathon L. Payne, Zheng Ge, Chandrika Gowda, Yali Ding, Kimberly J. Payne, Sinisa Dovat
Journal: Cancer Research (2018)

Abstract The IKZF1 gene encodes Ikaros—a DNA-binding, Kruppel-like zinc finger protein that functions as a tumor suppressor in T-cell acute lymphoblastic leukemia (T-ALL). Ikaros regulates transcription of a large number of genes that are involved in control of cellular proliferation. However, the molecular mechanisms through which Ikaros regulates proliferation of T-ALL cells are still unknown. The use of quantitative chromatin immunoprecipitation (qChIP) showed that Ikaros binds to the promoter regions of CDC42 in vivo in primary T-ALL patient samples as well as in T-ALL cell lines. Ikaros overexpression in B-ALL cells via retroviral transduction results in decreased transcription of CDC42, as evidenced by qRT-PCR and Western blot. The luciferase reporter assay showed that Ikaros represses CDC42 transcription by directly binding to its promoter. The shRNA-mediated knock-down of Ikaros in T-ALL resulted in increased expression of CDC42. These results suggest that Ikaros functions as a transcriptional repressor of CDC42 in T-ALL. Next, we studied the upstream signaling pathways that regulate Ikaros-mediated control of CDC42 transcription in T-ALL. Because Ikaros activity in leukemia is regulated via direct phosphorylation by Casein Kinase II (CK2), we tested the effect of CK2 inhibition on Ikaros-mediated regulation of CDC42 expression. Treatment of T-ALL cells with a specific CK2 inhibitor, CX-4945, resulted in reduced expression of CDC42 in T-ALL cells. This was associated with an increase in DNA-binding of Ikaros to the promoter of the CDC42 gene. Ikaros knock-down restored high expression of CDC42 in T-ALL cells that were treated with CK2 inhibitors. These data suggest that transcriptional repression of the CDC42 gene by Ikaros is impaired in T-ALL due to increased CK2 activity and reduced Ikaros DNA-binding affinity toward the CDC42 gene promoter. Inhibition of CK2 restores Ikaros function and results in transcriptional repression of the CDC42 gene. In conclusion, our results suggest that Ikaros regulates CDC42 signaling pathway via transcriptional repression of the small GTPase, CDC42, in T-ALL. Ikaros-mediated repression of CDC42 in T-ALL is negatively regulated by CK2. These results suggest that regulation of CDC42 expression is one of the mechanisms through which Ikaros regulates cellular proliferation in T-ALL. Citation Format: Mario Soliman, Chunhua Song, Jonathon L. Payne, Zheng Ge, Chandrika Gowda, Yali Ding, Kimberly J. Payne, Sinisa Dovat. Regulation of the CDC42 signaling pathway by IKZF1 in T-cell acute lymphoblastic leukemia [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 1512.
Abstract 779: Integrative analysis reveals therapeutic targets to the DNA methyltransferase inhibitor SGI-110 in hepatocellular carcinoma
Authors: Minmin Liu, Toshinori Hinoue, Wanding Zhou, Hitoshi Ohtani, Anthony El-Khoueiry, John Daniels, Casey O'Connell, Tanya B. Dorff, Daniel J. Weisenberger, Gangning Liang
Journal: Cancer Research (2018)

Abstract Objective There is an urgent need for developing more effective therapies for Hepatocellular carcinoma (HCC) because of its aggressiveness. Guadecitabine (SGI-110) is a second-generation DNA methyltransferase inhibitor (DNMTi) currently in clinical trials for HCC and shows greater stability and performance over first generation DNMTi. The aim of this study is to identify potential therapeutic targets of SGI-110 for clinical trials. Design HCC cell lines (SNU398, HepG2 and SNU475) were used to evaluate effects of SGI-110 by an integrative analysis of DNA methylation, nucleosome accessibility and gene expression profiles following the transient SGI-110 treatment and its clinic relevant by comparing HCC clinic data from TCGA. Results These HCC cell lines represent the three DNA methylation subtypes of primary HCC tumors based on TCGA data. After SGI-110 treatment, all cell lines were sensitive to SGI-110 with prolonged anti-proliferation effects. Up-regulated genes including tumor suppressors were positively correlated with nucleosome accessibility and negatively correlated with gene promoter DNA methylation, while the down-regulated genes, such as oncogenes, were negatively correlated with nucleosome accessibility and positively correlated with gene body DNA methylation. Furthermore, SGI-110 down-regulated PRC2 complex genes by demethylating their gene bodies, resulting in re-activation of PRC2 repressed gene promoters which are independent on DNA methylation. In addition, SGI-110 up-regulated endogenous retroviruses (ERVs) to reactivate immune pathways. Finally, about 45% of frequently altered genes in primary HCC tumors can be re-shaped into a “normal like” expression status through the treatment. Conclusion Our integrative analysis has successfully linked the anti-tumor effects of SGI-110 to detailed epigenetic alterations in HCC cells and identified potential therapeutic targets. We also provide rationale of combination treatment with immune checkpoint therapies. Citation Format: Minmin Liu, Toshinori Hinoue, Wanding Zhou, Hitoshi Ohtani, Anthony El-Khoueiry, John Daniels, Casey O'Connell, Tanya B. Dorff, Daniel J. Weisenberger, Gangning Liang. Integrative analysis reveals therapeutic targets to the DNA methyltransferase inhibitor SGI-110 in hepatocellular carcinoma [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 779.
Endogenous Adrenomedullin Protects Against Vascular Response to Injury in Mice
Authors: JunsukeKawai, KatsuyukiAndo, AkihiroTojo, TatsuoShimosawa, KatsutoshiTakahashi, Maristela LikaOnozato, MasaoYamasaki, TeruhikoOgita, TakashiNakaoka, ToshiroFujita
Journal: Circulation (2004)

Background— In our previous study, adrenomedullin (AM) overexpression could limit the arterial intimal hyperplasia induced by cuff injury in rats. However, it remains to be elucidated whether endogenous AM plays a role against vascular injury. Methods and Results— We used the AM knockout mice to investigate the effect of endogenous AM. Compared with wild-type (AM+/+) mice, heterozygous AM knockout (AM+/−) mice had the increased intimal thickening of the cuff-injured femoral artery, concomitantly with lesser AM staining. In AM+/− mice, cuff placement increased both the production of superoxide anions (O2−) measured by coelentarazine chemiluminescence and the immunostaining of p67phox and gp91phox, subunits of NAD(P)H oxidase in the adventitia, associated with the increment of CD45-positive leukocytes, suggesting that the stimulated formation of radical oxygen species accompanied chronic adventitial inflammation. Not only the AM gene transfection but also the treatment of NAD(P)H oxidase inhibitor apocynin ...
Transcription factor Etv6 regulates functional differentiation of cross-presenting classical dendritic cells
Authors: Colleen M. Lau, Ioanna Tiniakou, Oriana A. Perez, Margaret E. Kirkling, George S. Yap, Hanno Hock, Boris Reizis
Journal: The Journal of Experimental Medicine (2018)

An IRF8-dependent subset of conventional dendritic cells (cDCs), termed cDC1, effectively cross-primes CD8+ T cells and facilitates tumor-specific T cell responses. Etv6 is an ETS family transcription factor that controls hematopoietic stem and progenitor cell (HSPC) function and thrombopoiesis. We report that like HSPCs, cDCs express Etv6, but not its antagonist, ETS1, whereas interferon-producing plasmacytoid dendritic cells (pDCs) express both factors. Deletion of Etv6 in the bone marrow impaired the generation of cDC1-like cells in vitro and abolished the expression of signature marker CD8α on cDC1 in vivo. Moreover, Etv6-deficient primary cDC1 showed a partial reduction of cDC-specific and cDC1-specific gene expression and chromatin signatures and an aberrant up-regulation of pDC-specific signatures. Accordingly, DC-specific Etv6 deletion impaired CD8+ T cell cross-priming and the generation of tumor antigen–specific CD8+ T cells. Thus, Etv6 optimizes the resolution of cDC1 and pDC expression programs and the functional fitness of cDC1, thereby facilitating T cell cross-priming and tumor-specific responses.