tbuckley/cabot-search huggingface dataset:
Comparison of Unitary Displacements and Forces Between 2 Cardiac Myosin Isoforms by the Optical Trap Technique
Authors: SeiryoSugiura, NaoshiKobayakawa, HideoFujita, HiroshiYamashita, Shin-ichiMomomura, ShigeruChaen, MasaoOmata, HaruoSugi
Journal: Circulation Research (1998)

Abstract—To provide information on the mechanism of cardiac adaptation at the molecular level, we compared the unitary displacements and forces between the 2 rat cardiac myosin isoforms, V1 and V3. A fluorescently labeled actin filament, with a polystyrene bead attached, was caught by an optical trap and brought close to a glass surface sparsely coated with either of the 2 isoforms, so that the actin-myosin interaction took place in the presence of a low concentration of ATP (0.5 μmol/L). Discrete displacement events were recorded with a low trap stiffness (0.03 to 0.06 pN/nm). Frequency distribution of the amplitude of the displacements consisted of 2 gaussian curves with peaks at 9 to 10 and 18 to 20 nm for both V1 and V3, suggesting that 9 to 10 nm is the unitary displacement for both isoforms. The duration of the displacement events was longer for V3 than for V1. On the other hand, discrete force transients were recorded with a high trap stiffness (2.1 pN/nm), and their amplitude showed a broad distri...
The effect of surface poly(ethylene glycol) length on in vivo drug delivery behaviors of polymeric nanoparticles
Authors: Ji-Long Wang, Xiao-Jiao Du, Jin-Xian Yang, Song Shen, Hong-Jun Li, Ying-Li Luo, Shoaib Iqbal, Cong-Fei Xu, Xiao-Dong Ye, Jie Cao, Jun Wang
Journal: Biomaterials (2018)
Abstract 5667: High-throughput analysis of MAPK and JAK-STAT signaling in CT26 tumors using a combination of immunophenotyping and phospho-flow cytometry
Authors: David Draper, Alden Wong, Philip Lapinski, Sheri R. Barnes, Maryland Rosenfeld Franklin, Scott C. Wise
Journal: Cancer Research (2018)

Abstract The development of robust platforms that enable the analysis of cell signaling proteins is crucial for small molecule drug development. Analysis of phospho-proteins in solid tumors is one area that remains a challenge due to the complex nature of the tissue. The most common approaches used to measure the effects of in vivo therapy are immunoblot and ELISA-based assays. However, these bulk analysis methods have drawbacks. This is primarily due to their inability to distinguish between phospho-protein levels in different cell subsets that exist in the tumor. Using the CT26 syngeneic model for colorectal cancer, we describe a novel high-throughput phospho-flow platform that can simultaneously analyze the phosphorylation status of up to 6 signaling proteins in both tumor cells and immune cells. To first validate the phospho-flow assay, splenocytes from naïve mice were treated in vitro with various stimuli that preferentially target distinct signaling proteins. We then tested the platform in vivo. To this end, CT26 tumor-bearing mice were dosed with the MEK inhibitor trametinib or vehicle. At the appropriate time point post-dosing, tumors were harvested and dissociated into single cell suspensions. Live tumor cells and CD8+ T cells were first identified by flow cytometry using antibodies against CD45, CD3, and CD8. Following fixation, MAPK and JAK-STAT signaling activity was analyzed by measuring the levels of phosphorylated MEK, ERK1/2, STAT1, STAT2, STAT5, and STAT6 proteins using phospho-flow. Our results demonstrated that trametinib triggered a reduction in both pMEK and pERK1/2 levels in tumor cells that was evident 24 hours after the final trametinib dose. We also found phosphorylated STAT1, STAT3, and STAT5 was readily detectable in tumor cells, while STAT6 phosphorylation was not obvious. In contrast, we found that the CD8+ T cell levels of pMEK and pERK1/2 were not affected by trametinib. Furthermore, when JAK-STAT signaling was analyzed, only phosphorylation of STAT3 was detected in CD8+ T cells, which was also unaffected by trametinib. These results demonstrate successful combination of immunophenotyping and phospho-protein analysis in solid tumor-derived cells using flow cytometry. This platform is a tool that can be used to provide valuable insight into the effects that small molecule inhibitors may have on distinct cell subsets within a heterogenous tumor microenvironment. Citation Format: David Draper, Alden Wong, Philip Lapinski, Sheri R. Barnes, Maryland Rosenfeld Franklin, Scott C. Wise. High-throughput analysis of MAPK and JAK-STAT signaling in CT26 tumors using a combination of immunophenotyping and phospho-flow cytometry [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 5667.
Abstract CT157: PANOVA-3: A phase III study of TTFields with nab-paclitaxel and gemcitabine for front-line treatment of locally-advanced pancreatic adenocarcinoma (LAPC)
Authors: Uri Weinberg, Ori Farber, Moshe Giladi, Zeev Bomzon, Gitit Lavy-Shahaf, Eilon D. Kirson
Journal: Cancer Research (2018)

Abstract Tumor Treating Fields (TTFields) are a non-invasive, regional antimitotic treatment modality, which has been approved for the treatment of patients with glioblastoma by the FDA. TTFields predominantly act by disrupting the formation of the mitotic spindle during metaphase. TTFields were effective in multiple preclinical models of pancreatic cancer. The Phase 2 PANOVA study was the first trial testing TTFields in pancreatic cancer patients, and demonstrated the safety of TTFields when combined with nab-paclitaxel and gemcitabine in both metastatic and LAPC. The Phase 3 PANOVA-3 trial (NCT03377491) is designed to test the efficacy of adding TTFields to nab-paclitaxel and gemcitabine combination in LAPC. Trial Design: Patients (N=556) with unresectable, LAPC (per NCCN guidelines) will be enrolled in this prospective, randomized trial. Patients should have an ECOG score of 0-2 and no prior progression or treatment. Patients will be stratified based on their performance status and geographical region, and will be randomized 1:1 to TTFields plus nab-paclitaxel and gemcitabine or to nab-paclitaxel and gemcitabine alone. Chemotherapy will be administered at standard dose of nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2 once weekly). TTFields (150kHz) will be deilvered at least 18 hours/day until local disease progression per RECIST Criteria V1.1. Follow up will be performed q8w, including a CT scan of the chest and abdomen. Following local disease progression, patients will be followed monthly for survival. Overall survival will be the primary endpoint and progression-free survival, objective response rate, rate of resectability, quality of life and toxicity will all be secondary endpoints. Sample size was calculated using a log-rank test comparing time to event in patients treated with TTFields plus chemotherapy with control patients on chemotherapy alone. PANOVA-3 is designed to detect a hazard ratio 0.75 in overall survival. Type I error is set to 0.05 (two-sided) and power to 80%. Citation Format: Uri Weinberg, Ori Farber, Moshe Giladi, Zeev Bomzon, Gitit Lavy-Shahaf, Eilon D. Kirson. PANOVA-3: A phase III study of TTFields with nab-paclitaxel and gemcitabine for front-line treatment of locally-advanced pancreatic adenocarcinoma (LAPC) [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 CT157.
IL-10 Production By CLL Cells Is Enhanced in the Anergic IGHV Mutated Subset and Associates with Reduced DNA Methylation of the IL-10 Locus
Authors: Samantha Drennan, Annalisa D'Avola, Yifang Gao, Eleni Chrysostomou, Andrew J Steele, Thorsten Zenz, Christoph Plass, Peter W Johnson, Anthony P Williams, Graham Packham, Freda K Stevenson, Christopher C. Oakes, Francesco Forconi
Journal: Blood (2015)
Abstract 18524: Heart Rate Variability and Cardiovascular Fitness are Lower in Non-hispanic Black versus Non-hispanic White Adolescents With Type 1 Diabetes
Authors: Melissa S Faulkner, Lauretta Quinn, Cynthia Fritschi
Journal: Circulation (2015)

Type 1 diabetes mellitus (T1D) is growing worldwide with the incidence peaking at puberty. Current population projections indicate that the numbers will nearly triple by 2050 with the prevalence primarily among minority racial/ethnic groups. Future diabetes-related morbidity, mortality and health care expenditures associated with poor cardiovascular (CV) outcomes are of paramount concern. In adolescents with T1D, heart rate variability (HRV) is noted to be lower when compared with healthy control subjects. Current research also supports a level of physical activity for adolescents with T1D that does not meet American Heart Association guidelines of 60 minutes of moderate-to-vigorous intensity per day, leading to decreased levels of physical fitness and elevated HbA1c. T1D Exchange (a large national epidemiological study) found that only 14% of Non-Hispanic Black (NHB) versus 34% Non-Hispanic White (NHW) youth met the American Diabetes Association HbA1c targets of &lt; 7.5%, potentially increasing the odds of poorer outcomes in NHB youth.The hypotheses were that HRV and CV fitness would be lower in NHB versus NHW adolescents with T1D and that those with poorer glycemic control would have lower HRV and CV fitness. Methods: A sample of 96 adolescents with T1D (n = 67 NHW; n = 29 NHB) participated. Using 24-hour holter recordings, both spectral and time domain measures of HRV were obtained. Cardiovascular fitness (V02peak) using a graded exercise test was completed. HbA1c was obtained using the Siemens/Bayer DCA 2000. Findings: There were no significant differences in age (15.4 ± 1.9 vs. 15.0 ± 1.9 years) or duration of diabetes (6.6 ± 3.8 vs. 5.3 ± 3.4 years). Resting diastolic BP, recent and average HbA1c (values averaged over 1 year) were significantly higher (p &lt; 0.05) and measures of HRV and fitness were significantly lower in NHB versus NHW adolescents (p &lt; 0.001). While average HbA1c was associated with lower CV fitness in both NHB and NHW groups (r = -.44 vs. -.25, p &lt; 0.05, respectively), lower measures of HRV were associated with poor glycemic control (HbA1c) only in NHBs (r = -.37 to -.43, p &lt; 0.05). Conclusions: Findings support the importance of early identification of CV health disparities in adolescents with T1D, particularly variation experienced in NHB youth.
Alternative Splicing of Titin Restores Diastolic Function in an HFpEF-Like Genetic Murine Model (TtnΔIAjxn)
Authors: MathewBull, MeiMethawasin, JoshuaStrom, PoojaNair, KirkHutchinson, HenkGranzier
Journal: Circulation Research (2016)

Rationale:Patients with heart failure with preserved ejection fraction (HFpEF) experience elevated filling pressures and reduced ventricular compliance. The splicing factor RNA-binding motif 20 (RBM20) regulates the contour length of titin’s spring region and thereby determines the passive stiffness of cardiomyocytes. Inhibition of RBM20 leads to super compliant titin isoforms (N2BAsc) that reduce passive stiffness. Objective:To determine the therapeutic potential of upregulating compliant titin isoforms in an HFpEF-like state in the mouse. Methods and Results:Constitutive and inducible cardiomyocyte-specific RBM20–inhibited mice were produced on a TtnΔIAjxn background to assess the effect of upregulating compliant titin at the cellular and organ levels. Genetic deletion of the I-band–A-band junction (IAjxn) in titin increases strain on the spring region and causes a HFpEF-like syndrome in the mouse without pharmacological or surgical intervention. The increased strain represents a mechanical analog of de...
Mechanism of action of vedolizumab: do we really understand it?
Authors: Gerhard Rogler
Journal: Gut (2018)

For many years, physicians had only antitumour necrosis factor (anti-TNF) antibodies as biologicals for the treatment of IBD. With the regulatory approval of vedolizumab, a completely new mechanism of action was introduced into the therapeutic armamentarium of IBD specialists: vedolizumab is an ‘integrin antagonist’ binding to the α4β7 integrin expressed on the surface of mononuclear cells such as T-lymphocytes.1 Circulating blood T-cells require binding of α4β7 integrin to mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expressed by the endothelial cells of the GI tract to be able to migrate into the mucosal layers.1 To prevent the migration of inflammatory mononuclear cells into the inflamed mucosa in patients with IBD, integrin antagonists have been developed. Several antagonists of integrin–adhesion molecule interactions are approved or under clinical development targeting either the α4β7 integrin heterodimer, the α4 integrin, the β7 integrin or MAdCAM-1 (such as etrolizumab, a β7 integrin antibody; and PF-00547659,17, an anti-MAdCAM-1 antibody).2 It is important to understand the mechanism of action of those therapies exactly to be able to adapt them to specific patient needs. …
Loading Sequence Plays an Important Role in Enhanced Load Sensitivity of Left Ventricular Relaxation in Conscious Dogs With Tachycardia-Induced Cardiomyopathy
Authors: ShinjiIshizaka, HidetsuguAsanoi, OsamuWada, TomokiKameyama, HiroshiInoue
Journal: Circulation (1995)

Background Left ventricular relaxation rate in the failing heart depends more on the systolic load than in the normal heart. To elucidate the mechanisms for the enhanced load sensitivity of left ventricular relaxation in heart failure, we examined the relative contributions of changes in end-systolic volume and loading sequence to the left ventricular relaxation rate. Methods and Results In seven conscious dogs, the time constant (Td) of left ventricular pressure decay, end-systolic volume, systolic circumferential force, and time to peak force during caval occlusion were compared before and after development of tachycardia-induced heart failure. Rapid ventricular pacing decreased the slope of the end-systolic pressure-volume relation from 4.5 to 2.8 mm Hg/mL (P<.01) and prolonged Td from 33 to 49 ms (P<.01). In normal conditions, caval occlusion reduced end-systolic force (−580 g, P<.01) and end-systolic volume (−7 mL, P<.01) but did not change Td or time to peak force. In heart failure, however, caval o...
Angiotensin IV Activates the Nuclear Transcription Factor-κB and Related Proinflammatory Genes in Vascular Smooth Muscle Cells
Authors: VanesaEsteban, MónicaRuperez, ElsaSánchez-López, JuanRodríguez-Vita, OscarLorenzo, HeidiDemaegdt, PatrickVanderheyden, JesúsEgido, MartaRuiz-Ortega
Journal: Circulation Research (2005)

Inflammation is a key event in the development of atherosclerosis. Nuclear factor-κB (NF-κB) is important in the inflammatory response regulation. The effector peptide of the renin angiotensin system Angiotensin II (Ang II) activates NF-κB and upregulates some related proinflammatory genes. Our aim was to investigate whether other angiotensin-related peptides, as the N-terminal degradation peptide Ang IV, could regulate proinflammatory factors (activation of NF-κB and related genes) in cultured vascular smooth muscle cells (VSMCs). In these cells, Ang IV increased NF-κB DNA binding activity, caused nuclear translocation of p50/p65 subunits, cytosolic IκB degradation and induced NF-κB–dependent gene transcription. Ang II activates NF-κB via AT1 and AT2 receptors, but AT1 or AT2 antagonists did not inhibit NF-κB activation caused by Ang IV. In VSMC from AT1a receptor knockout mice, Ang IV also activated NF-κB pathway. In those cells, the AT4 antagonist divalinal diminished dose-dependently Ang IV–induced NF...
Abstract 2458: The androgen receptor-regulated lncRNA landscape reveals a role forARlnc1in prostate cancer progression
Authors: Yajia Zhang, Sethuramasundaram Pitchiaya, Marcin Cieślik, Yashar S. Niknafs, Jean C. Tien, Yasuyuki Hosono, Lisha Wang, Yuanyuan Qiao, Xuhong Cao, Mats Ljungman, Hui Jiang, Rohit Mehra, Shuling Guo, Rohit Malik, Arul M. Chinnaiyan
Journal: Cancer Research (2018)

Abstract The androgen receptor (AR) signaling plays a key role in the development of the normal prostate as well as prostate cancer. While substantial efforts have been undertaken to study AR-regulated protein-coding genes in primary prostate cancer and castration-resistant prostate cancer, few studies have investigated the role of long noncoding RNAs. In this study, we employed transcriptome sequencing to delineate long noncoding RNAs (lncRNAs) associated with AR signaling in prostate cancer progression. ARlnc1 (AR-regulated lncRNA 1) was identified as being the top AR-induced, cancer-associated lncRNA in an integrative analysis of prostate cancer cell lines and tissues. Not only was ARlnc1 induced by AR, but ARlnc1 also was shown to sustain AR signaling by stabilizing the AR transcript via interaction with the AR 3' UTR. Knockdown of ARlnc1 suppressed AR expression, global AR signaling, and prostate cancer growth in vitro and in vivo. Taken together, these data support a role for ARlnc1 in maintaining a positive feedback loop that potentiates AR signaling during prostate cancer progression, and identifies ARlnc1 as a novel therapeutic target. Citation Format: Yajia Zhang, Sethuramasundaram Pitchiaya, Marcin Cieślik, Yashar S. Niknafs, Jean C. Tien, Yasuyuki Hosono, Lisha Wang, Yuanyuan Qiao, Xuhong Cao, Mats Ljungman, Hui Jiang, Rohit Mehra, Shuling Guo, Rohit Malik, Arul M. Chinnaiyan. The androgen receptor-regulated lncRNA landscape reveals a role for ARlnc1 in prostate cancer progression [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 2458.
MicroRNA-494 Targeting Both Proapoptotic and Antiapoptotic Proteins Protects Against Ischemia/Reperfusion-Induced Cardiac Injury
Authors: XiaohongWang, XiaoweiZhang, Xiao-PingRen, JingChen, HongzhuLiu, JunqiYang, MarioMedvedovic, ZhuoweiHu, Guo-ChangFan
Journal: Circulation (2010)

Background—MicroRNAs (miRs) participate in many cardiac pathophysiological processes, including ischemia/reperfusion (I/R)-induced cardiac injury. Recently, we and others observed that miR-494 was downregulated in murine I/R-injured and human infarcted hearts. However, the functional consequence of miR-494 in response to I/R remains unknown. Methods and Results—We generated a mouse model with cardiac-specific overexpression of miR-494. Transgenic hearts and wild-type hearts from multiple lines were subjected to global no-flow I/R with the Langendorff system. Transgenic hearts exhibited improved recovery of contractile performance over the reperfusion period. This improvement was accompanied by remarkable decreases in both lactate dehydrogenase release and the extent of apoptosis in transgenic hearts compared with wild-type hearts. In addition, myocardial infarction size was significantly reduced in transgenic hearts on I/R in vivo compared with wild-type hearts. Similarly, short-term overexpression of miR...
Abstract 15931: Glycogen Synthase Kinase-3α Plays a Critical Role in the Development of Cardiac Dysfunction During Obesity and Insulin Resistance Through Phosphorylation of Peroxisome Proliferator-Activated Receptor α
Authors: MichinariNakamura, PeiyongZhai, JunichiSadoshima
Journal: Circulation (2014)

Obesity and insulin resistance (IR) lead to impaired cardiac metabolism, resulting in cardiac dysfunction. However, the underlying mechanisms responsible for the development of cardiac dysfunction remain poorly understood. PPARα serves as a key regulator of fatty acid (FA) metabolism in the heart. GSK-3α, a serine/threonine kinase, was dephosphorylated at S21 and activated (2.0 fold, p<0.05) in the hearts of obese mice fed a high-fat diet (HFD) and ob/ob mice. To evaluate the functional significance of GSK-3α upregulation, wild-type (WT) and cardiac specific GSK-3α heterozygous knockout (cGSK-3α HKO) mice were fed a HFD for up to 14 weeks. There was no difference in the food intake or body weight change between WT and cGSK-3α HKO mice. However, cardiac hypertrophy and diastolic dysfunction observed in WT mice were significantly ameliorated in cGSK-3α HKO mice after HFD feeding (8.1± 0.6 and 6.5±0.5, LVW/TL; 24.8±0.9 and 16.6±0.8, deceleration time (DT), all p<0.05). FA oxidation (FAO) (0.81 fold) and ecto...
Abstract 5755: Cancer immunity contributes to genome stability by suppressing L1 retrotransposition in gastrointestinal cancers
Authors: Hyunchul Jung, Jung Kyoon Choi, Eunjung Alice Lee
Journal: Cancer Research (2018)

Abstract Long interspersed nuclear element-1 (L1) retrotransposons are normally suppressed in somatic tissues, mainly by DNA methylation and antiviral defense. However, L1s can be de-suppressed in cancers to act as insertional mutagens and cause genomic instability by creating DNA double-strand breaks and chromosomal rearrangements. Whereas the frequency of somatic L1 insertions varies greatly among individual tumors, much remains to be learned about underlying genetic, cellular, or environmental factors. Here, our pan-gastrointestinal cancer genome analyses for stomach, colorectal, and esophageal tumors identified multiple correlates of L1 activity. Clinical indicators of tumor progression, such as tumor grade and patient age, showed positive association. Potential L1 expression suppressors such as TP53 and DNMT1, a DNA methyltransferase, were inactivated in tumors with frequent L1 insertions. Importantly, tumors with high immune activity, for example, due to viral infection or high tumor-antigen load, tended to carry a low number of L1 insertions in their genomes with high expression levels of L1 suppressors such as APOBEC3s and SAMHD1. Our analysis of the transcriptional effects of intragenic retrotransposon insertions demonstrated an increased risk of gene disruption in retrotransposition-prone cancers. In particular, we found a splicing-disrupting L1 insertion in an exon of MOV10, a key L1 suppressor, which caused exon skipping with evidence of nonsense-mediated decay in a tumor with a high L1 insertion load. Our results indicate that cancer immunity may contribute to genome stability by suppressing L1 retrotransposition, particularly in gastrointestinal cancers. Citation Format: Hyunchul Jung, Jung Kyoon Choi, Eunjung Alice Lee. Cancer immunity contributes to genome stability by suppressing L1 retrotransposition in gastrointestinal cancers [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 5755.
Genetic Polymorphism of Methylenetetrahydrofolate Reductase and Myocardial Infarction
Authors: ChristianSchmitz, KlausLindpaintner, PetraVerhoef, J. MichaelGaziano, JulieBuring
Journal: Circulation (1996)

Background Elevated total plasma homocyst(e)ine (tHcy; the composite of homocysteine-derived moieties in their oxidized and reduced forms) levels are a risk factor for coronary heart disease, stroke, and venous thrombosis. tHcy plasma levels are influenced by folate, vitamins B6 and B12, as well as by hereditary factors. A point mutation (C677T) in the gene encoding methylenetetrahydrofolate reductase, an enzyme involved in homocysteine remethylation, has been reported to render the enzyme thermolabile and less active and has been associated with elevated tHcy in homozygous carriers (+/+ genotype) as well as with increased risk of premature cardiovascular disease. Methods and Results We investigated whether this mutation influences risk for myocardial infarction (MI) and plasma levels of tHcy and whether this effect may be modified by dietary folate intake in 190 MI cases and 188 control subjects from the Boston Area Health Study. Genotype frequencies were 37.8% for −/−, 47.8% for +/−, and 14.4% for +/+ i...