tbuckley/cabot-search huggingface dataset:
Liver X Receptor Activation Potentiates the Lipopolysaccharide Response in Human Macrophages
Authors: CoralieFontaine, ElenaRigamonti, AtsushiNohara, PhilippeGervois, ElisabethTeissier, Jean-CharlesFruchart, BartStaels, GiuliaChinetti-Gbaguidi
Journal: Circulation Research (2007)

Macrophages play a central role in host defense against pathogen microbes by recognizing bacterial components, resulting in the activation of an arsenal of anti-microbial effectors. Toll-like receptor (TLR)-4 mediates the recognition of lipopolysaccharide, a pathogen-associated molecular pattern from Gram-negative bacteria. Activation of the TLR-4 signaling pathway by lipopolysaccharide increases antibacterial effects by inducing secretion of cytokines that activate an immune inflammatory response and by generating bactericidal reactive oxygen species via the NADPH oxidase system. Liver X Receptors (LXRs) are nuclear receptors controlling cholesterol homeostasis and inflammation in macrophages. In addition, LXRs are critical for macrophage survival and play a role in the innate immune response in the mouse. In this study, we investigated whether LXR activation also regulates host defense mechanisms in human macrophages. In primary human macrophages, oxidized LDL and synthetic LXR ligands increased TLR-4 g...
Oscillatory Patterns in Sympathetic Neural Discharge and Cardiovascular Variables During Orthostatic Stimulus
Authors: RaffaelloFurlan, AlbertoPorta, FernandoCosta, JensTank, LemontBaker, RichardSchiavi, DavidRobertson, AlbertoMalliani, RogelioMosqueda-Garcia
Journal: Circulation (2000)

Background—We tested the hypothesis that a common oscillatory pattern might characterize the rhythmic discharge of muscle sympathetic nerve activity (MSNA) and the spontaneous variability of heart rate and systolic arterial pressure (SAP) during a physiological increase of sympathetic activity induced by the head-up tilt maneuver. Methods and Results—Ten healthy subjects underwent continuous recordings of ECG, intra-arterial pressure, respiratory activity, central venous pressure, and MSNA, both in the recumbent position and during 75° head-up tilt. Venous samplings for catecholamine assessment were obtained at rest and during the fifth minute of tilt. Spectrum and cross-spectrum analyses of R-R interval, SAP, and MSNA variabilities and of respiratory activity provided the low (LF, 0.1 Hz) and high frequency (HF, 0.27 Hz) rhythmic components of each signal and assessed their linear relationships. Compared with the recumbent position, tilt reduced central venous pressure, but blood pressure was unchanged. ...
CDK4/6 Inhibitors: What Is the Best Cocktail?
Authors: Marcos Malumbres
Journal: Clinical Cancer Research (2018)

CDK4/6 inhibitors have shown great potential in the new armamentarium against cancer. However, their effect as single agents is limited, and the hopes are on new combinatory strategies. Recent data suggest that inhibiting mTOR may significantly cooperate with cell-cycle arrest in a variety of cancers.See related article by Song et al., p. 403.
Lineage of Bone Marrow–Derived Cells in Atherosclerosis
Authors: HiroshiIwata, IchiroManabe, RyozoNagai
Journal: Circulation Research (2013)

Atherosclerosis is a chronic inflammatory disease driven by lipids and other atherogenic factors. It is characterized by a dynamic and complex pathological process of bone marrow–derived cells playing divergent roles. Recent studies have begun unraveling the contribution of growing varieties of subsets of immune cells and other bone marrow–derived cells to atherogenesis. For example, bone marrow–derived vascular progenitor cells have been shown to play an important role in the pathogenesis of atherosclerosis. This review provides an overview of the current understanding of contributions of bone marrow–derived cells to atherosclerosis. Particular focus is placed on myeloid cells and vascular progenitor cells. We also summarize the uncertainty surrounding cellular lineage identity and functions. Expansion of our understanding of pathological roles of various subsets of bone marrow–derived cells in atherosclerosis may lead to identification of novel cellular and molecular targets for development of therapeut...
Cerebral Microembolism Is Blocked by Tirofiban, a Selective Nonpeptide Platelet Glycoprotein IIb/IIIa Receptor Antagonist
Authors: UlrichJunghans, MarioSiebler
Journal: Circulation (2003)

Background— Microembolic signals (MES) as detected by transcranial Doppler ultrasound define an individual stroke risk in patients with carotid artery disease. To study the composition of MES in vivo, we used the glycoprotein IIb/IIIa (GPIIb/IIIa) receptor antagonist tirofiban, a highly selective platelet aggregation inhibitor. Methods and Results— Twenty-four patients with recent cerebral or retinal embolism of arterial origin and a MES rate >6 per hour on initial transcranial Doppler ultrasonography recording received the short-acting GPIIb/IIIa antagonist tirofiban. With tirofiban, the MES rate dropped from a median (range) of 38 (9 to 324) to zero in all patients. After cessation of infusion, the inhibitory effect of tirofiban was reversible, with a significant increase of MES (median 13.5; range, 0 to 35; n=16; P=0.001). Six patients received overlapping oral antiplatelet agents and remained MES-negative. Conclusions— Cerebral microembolism of arterial origin has the property of solid emboli, with pl...
Abstract 1273: Effect of a Western diet on colitis-associated colon tumor formation in BALB/c mice
Authors: Charlotte Groeschel, Samawansha Tennakoon, Abhishek Aggarwal, Enikoe Kallay
Journal: Cancer Research (2018)

Abstract Patients with inflammatory bowel disease (IBD) are at increased risk for inflammation associated colorectal cancer (CAC). The incidence of IBD is increasing in the Western industrialized world. Epidemiological studies suggest that a diet, high in fat but low in vitamin D, calcium, fibre and methyl donors is a risk factor for both, IBD and colorectal cancer (CRC). It has been shown previously that a ”New Western Diet”, caused development of sporadic colonic tumours in mice. Our study was performed to evaluate whether a Western Diet (WD) aggravates azoxymethane (AOM) /dextran sodium sulfate salt (DSS)-induced colitis-associated carcinogenesis in mice, and if a switch to the standard purified mouse diet AIN93G after cancer initiation is still able to ameliorate or delay the onset of the disease. Female BALB/c mice received either the WD (0.5 mg/g calcium, 2% fibre, 21 % butter fat, 0.23 μg/g folic acid) or AIN93G standard diet for 5 weeks until AOM was administered at a dose of 12.5 μg/kg intraperitoneally, followed by 3 cycles of DSS (2.5%). In one group the WD was switched to AIN93G diet one day before first administration of DSS. The mice were euthanized 80 days after AOM injection. One part of the colon, small intestine, kidney and liver were frozen in liquid nitrogen, the rest formalin fixed and paraffin embedded for mRNA and immunhistochemical analysis. Feeding constantly the WD shortened the colon (p&amp;lt;0.05) and increased the number (p&amp;lt;0.05) and size (p&amp;lt;0.01) of aberrant colonic crypt foci. The switch to the AIN93G diet ameliorated this effect, leading to reduced colitis and tumor promotion comparable with the AIN93G group. In colon ascendens of the WD group, Ki67 protein levels (p&amp;lt;0.001) and relative mRNA levels of the Wnt target genes c-myc (p&amp;lt;0.05) and axin2 (p&amp;lt;0.001) were reduced while mRNA levels of the vitamin D catabolizing enzyme cyp24a1 (p&amp;lt;0.001) and inos (p&amp;lt;0.05) were increased when compared with the AIN93G group. A healthy diet protects colonic mucosa against AOM/DSS-treatment and is an effective chemopreventive strategy to reduce chronic colonic inflammation and tumorigenesis. This project is funded by the Vienna Science and Technology Fund and the Austrian Research Fund. Citation Format: Charlotte Groeschel, Samawansha Tennakoon, Abhishek Aggarwal, Enikoe Kallay. Effect of a Western diet on colitis-associated colon tumor formation in BALB/c mice [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 1273.
3D printing of Mo-containing scaffolds with activated anabolic responses and bi-lineage bioactivities
Authors: Wentao Dang, Xiaoya Wang, Jiayi Li, Cuijun Deng, Yaqin Liu, Qingqiang Yao, Liming Wang, Jiang Chang, Chengtie Wu
Journal: Theranostics (2018)

When osteochondral tissues suffer from focal or degenerative lesions caused by trauma or disorders, it is a tough challenge to regenerate them because of the limited self-healing capacity of articular cartilage. In this study, a series of Mo-doped bioactive glass ceramic (Mo-BGC) scaffolds were prepared and then systematically characterized. The released MoO42- ions from 7.5Mo-BGC scaffolds played a vital role in regenerating articular cartilage and subchondral bone synchronously. Methods: The Mo-BGC scaffolds were fabricated through employing both a sol-gel method and 3D printing technology. SEM, EDS, HRTEM, XRD, ICPAES and mechanical strength tests were respectively applied to analyze the physicochemical properties of Mo-BGC scaffolds. The proliferation and differentiation of rabbit chondrocytes (RCs) and human bone mesenchymal stem cells (HBMSCs) cultured with dilute solutions of 7.5Mo-BGC powder extract were investigated in vitro. The co-culture model was established to explore the possible mechanism of stimulatory effects of MoO42- ions on the RCs and HBMSCs. The efficacy of regenerating articular cartilage and subchondral bone using 7.5Mo-BGC scaffolds was evaluated in vivo. Results: The incorporation of Mo into BGC scaffolds effectively enhanced the compressive strength of scaffolds owing to the improved surface densification. The MoO42- ions released from the 7.5Mo-BGC powders remarkably promoted the proliferation and differentiation of both RCs and HBMSCs. The MoO42- ions in the co-culture system significantly stimulated the chondrogenic differentiation of RCs and meanwhile induced the chondrogenesis of HBMSCs. The chondrogenesis stimulated by MoO42- ions happened through two pathways: 1) MoO42- ions elicited anabolic responses through activating the HIF-1α signaling pathway; 2) MoO42- ions inhibited catabolic responses and protected cartilage matrix from degradation. The in vivo study showed that 7.5Mo-BGC scaffolds were able to significantly promote cartilage/bone regeneration when implanted into rabbit osteochondral defects for 8 and 12 weeks, displaying bi-lineage bioactivities. Conclusion: The 3D-printed Mo-BGC scaffolds with bi-lineage bioactivities and activated anabolic responses could offer an effective strategy for cartilage/bone interface regeneration.
Abstract 17540: The Blood Urea Nitrogen to Creatinine Ratio Has Additive Prognostic Value to Hyponatremia in Patients With Acute Decompensated Heart Failure: Data From the Korean Heart Failure (KorHF) Registry
Authors: Jaewon Oh, Seok-Min Kang, Namki Hong, Jong-Chan Youn, Sungha Park, Sang-Hak Lee, Yangsoo Jang, Namsik Chung
Journal: Circulation (2013)

Background: The high blood urea nitrogen to creatinine ratio (BUN/Cr) recently was known to be related with poor clinical outcomes in patients (pts) with acute decompensated heart failure (ADHF). H...
Abstract 16005: OptiVol® Impedance Threshold Crossing Predicts Higher Mortality and Hospitalization Risk Among Medicare Recipients
Authors: Jason R Brown, Kenneth C Bilchick, Alvaro Alonso, Eduardo N Warman
Journal: Circulation (2016)

Introduction: The long-term prognostic value of Optivol® measurements on clinical events and mortality in a real-world cohort of cardiac resynchronization therapy defibrillator (CRT-D) patients with Medicare coverage is unknown. Hypothesis: We hypothesized that OptiVol® threshold crossings would be associated with increased adjusted risk of patient mortality and heart failure-related hospitalizations in Medicare patients. Methods: A cohort combining the Medicare Implantable Cardioverter-Defibrillator Registry data (implanted in 2005 and 2006), Medicare claims data, and data from Medtronic’s CareLink® Network were analyzed via an extended Cox model to assess the associations of impedance threshold crossings (OptiVol®) with both patient mortality and heart failure-related hospitalization. OptiVol® crossings were treated as time-dependent covariates. Results: N= 1,565 patients with OptiVol®-enabled CRT devices were included in this analysis. The median follow-up was 6.3 years. An OptiVol® crossing at any poi...
Abstract 12641: Absolute Change in Troponin Outperforms Relative Change in Troponin for Discrimination of Acute Myocardial Infarction: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Sameer Arora, Prashant Kaul, Patricia P Chang, Joseph S Rossi, Michael E Hall, Wayne D Rosamond, Melissa C Caughey
Journal: Circulation (2016)

Introduction: The rise or fall of cardiac troponin plays a central role in classification of acute myocardial infarction (AMI) by the Third Universal Definition. Clinical Practice Guidelines (CPG) advocate using a 20% change in serial troponin measurements for AMI detection. However, it is uncertain whether absolute or relative change in troponin has greater diagnostic accuracy. Hypothesis: Absolute and relative change in troponin will have differing abilities to detect AMI in patients hospitalized with chest pain and elevated troponin. Methods: Since 1987, the ARIC study has conducted surveillance of hospitalized events in 4 US communities. Clinical and laboratory data were abstracted, including troponin values from 1996 onward. AMI was classified by ARIC with a validated algorithm, using elevated biomarkers, presence of chest pain, and ECG evidence. Our analysis was based on patients with chest pain and serial troponin measurements (day 1 and day 2 of hospitalization), with elevated troponin on day 1. Patients undergoing revascularization procedures &lt;24 hours after event onset were excluded. The absolute and relative change in troponin between days 1 and 2 were calculated, and outcome discrimination was analyzed using the area under the receiver operating characteristic curve (AUC). All analyses were weighted by the inverse of the sampling probability. Results: A total of 6,232 hospitalizations spanning January 1 1996 - December 31, 2012 met our inclusion criteria. Most patients were white (64%) and male (60%), with a mean age of 63 years. Troponin I was more often assayed (93%) than troponin T. A total of 5,408 (87%) were classified as AMI by the ARIC algorithm, with 10% as STEMI. Absolute change in troponin outperformed relative change in troponin for detection of AMI (AUC: 0.69 vs. 0.64), NSTEMI (AUC: 0.68 vs. 0.64), and STEMI (AUC: 0.77 vs. 0.65); p &lt;0.001 for all comparisons. The recommended 20% cut-point endorsed by CPG diagnosed AMI, NSTEMI, and STEMI similarly, with a sensitivity of 75% and specificity of 44%. Conclusion: In patients hospitalized with chest pain and elevated troponin, absolute and relative change in serial troponin values detected AMI with moderate diagnostic accuracy; however, absolute change in troponin was a better discriminator.
Abstract 3205: Histone tyrosine phosphorylation determines glioblastoma cell survival
Authors: Mohammad Belayat Hossain, Rehnuma Shifat, Debora K. Kim, Yiesel Rivera-Molina, Francisco Puerta Martinez, Hong Jiang, Teresa Nguyen, David G. Johnson, Mark T. Bedford, Mien-Chie Hung, Erik P. Sulman, Frederick Lang, Raymond Sawaya, Juan Fueyo, Candelaria Gomez-Manzano
Journal: Cancer Research (2018)

Abstract Histone modification is crucial for cell signaling pathways and regulates predominantly chromatin functions related with DNA damage response (DDR) that lead cancer cells to survive upon different therapies. Receptor tyrosine kinases (RTKs) have been extensively studied in cancer progression and DDR and, recently, several reports described the role of RTKs in histone tyrosine modification. We have been focusing on the role of the receptor tyrosine kinase, TIE2, in gliomas. Our study identified the expression of TIE2 in human surgical glioma specimens in relation to malignancy, specifically in brain tumor stem cells. We have revealed that the unexpected membrane-to-nuclear trafficking of TIE2 is related with radioresistance of brain tumor stem cells, functioning as a genotoxic stress sensor to activate DNA repair machinery. Interestingly, TIE2 binds, upon IR stress, to DNA/protein complexes and phosphorylates several core histones. The tandem mass spectrum of H4 and H2B demonstrates that TIE2 directly phosphorylates not previously described H4pY51 and H2BY40 respectively, which reinvigorates TIE2's role in histone code modification. We screened for pY-readers using a SH2 domain array and found that H4pY51 and H2pY40 modifications are read by the proto-oncogenes ABL1 and CRK, respectively. Our data also showed that TIE2/H4pY54/ABL1 complex binds to DNA repair proteins, activating an NHEJ DNA repair mechanism. We summarize that upon IR stress TIE2 localizes to the nucleus where it is involved in key cellular functions by directly phosphorylating core histones, and recruiting SH2 domain proteins to the DNA damage sites, complexing to the DNA repair machinery, which in turns results in radioresistance. Our data highlight the role of epigenetics in modulating the DNA damage response of glioma radiation therapy and open new avenues to find novel targetable pathways for treatment of patients with glioblastomas. Citation Format: Mohammad Belayat Hossain, Rehnuma Shifat, Debora K. Kim, Yiesel Rivera-Molina, Francisco Puerta Martinez, Hong Jiang, Teresa Nguyen, David G. Johnson, Mark T. Bedford, Mien-Chie Hung, Erik P. Sulman, Frederick Lang, Raymond Sawaya, Juan Fueyo, Candelaria Gomez-Manzano. Histone tyrosine phosphorylation determines glioblastoma cell survival [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 3205.
Morphometry of the Human Pulmonary Arterial Tree
Authors: Siamsinghal, Roberthenderson, Keithhorsfield, Keithharding, Gordoncumming
Journal: Circulation Research (1973)

From a cast of a human pulmonary arterial tree, the diameter, length, order, and end branches of all intact branches down to those 0.8 mm in diameter were measured and corrections for broken branches were made. A sample of structures smaller than these (0.8-0.1 mm) was similarly measured. The values for branches less than 0.1 mm in diameter were found by extrapolation and comparison with known data for the precapillary vessels. Therefore, data or estimates for each order of branching in the pulmonary tree were obtained and calculations of cross-sectional area, volume, and flow were made.
Ras Induces Vascular Smooth Muscle Cell Senescence and Inflammation in Human Atherosclerosis
Authors: TohruMinamino, ToshihikoYoshida, KaoruTateno, HideyukiMiyauchi, YonzengZou, HaruhiroToko, IsseiKomuro
Journal: Circulation (2003)

Background— Vascular cells have a finite cell lifespan and eventually enter an irreversible growth arrest, cellular senescence. The functional changes associated with cellular senescence are thought to contribute to human aging and age-related vascular disorders. Ras, an important signaling molecule involved in atherogenic stimuli, is known to promote aging in yeast and cellular senescence in primary human fibroblasts. The aim of this study was to investigate the role of Ras-induced vascular smooth muscle cell (VSMC) senescence in atherogenesis. Methods and Results— We introduced an activated ras allele (H-rasV12) into human VSMCs using retroviral infection. Introduction of H-rasV12 induced a growth arrest with phenotypic characteristics of cellular senescence, such as enlarged cell shapes and increases in expression of cyclin-dependent kinase inhibitors and senescence-associated β-galactosidase (SA-β-gal) activity. Activation of Ras drastically increased expression of proinflammatory cytokines, in part t...
Abstract 3463: Crosstalk between PKCalpha and TGF-beta signaling suppresses inhibitor of DNA binding 1 (Id1) expression in intestinal epithelial cells
Authors: Xinyue Li, Michelle Lum, Adrian Black, Jennifer Black
Journal: Cancer Research (2018)

Abstract Inhibitor of DNA binding (Id) proteins (Id1-Id4) are dominant negative antagonists of basic helix-loop-helix (bHLH) transcription factors with recognized functions in development, stem cell self-renewal, and cell fate determination. Recent studies have identified Id proteins as master regulators of cancer-initiating cells and tumor aggressiveness, with critical roles in regulation of central hallmarks of cancer, including cell proliferation, survival, senescence, angiogenesis, migration, metastasis, and chemoresistance. In colorectal cancer (CRC), Id1 overexpression is associated with aggressive clinical behavior and poor prognosis, while decreasing sensitivity to chemotherapeutic agents. Protein kinase C α (PKCα) is a serine/threonine kinase that functions as a tumor suppressor in CRC. PKCα signaling induces cell cycle arrest in nontransformed IEC-18 intestinal epithelial cells via an ERK-dependent mechanism. A major target of PKCα negative control in these cells is Id1. To further characterize mechanisms underlying the tumor-suppressive effects of PKCα, we modulated PKCα expression and activation in CRC cells and nontransformed IEC-18 cells and performed RNA-seq analysis to identify changes in gene expression. This analysis identified transforming growth factor beta receptor 1 (TGFβR1) as an mRNA upregulated by PKCα signaling. Subsequent RT-PCR and Western blot analysis confirmed that PKCα upregulates TGFβR1 at both the mRNA and protein levels. The MEK inhibitors U0126 and PD98059 blocked PKCα upregulation of TGFβR1, pointing to an ERK-dependent mechanism. Notably, inhibition of TGFβR1 with GW788388 prevented PKCα-mediated Id1 downregulation, linking TGF-β signaling to the tumor-suppressive effects of PKCα. Further studies indicated that TGFβR1 activates a p38-mediated noncanonical pathway to downregulate Id1 in response to PKCα activity. Collectively, these findings identify a PKCα→Erk→TGFβR1→p38→Id1 signaling axis in intestinal epithelial cells. Both PKCα and TGF-β function as tumor suppressors in the intestinal epithelium and both pathways are inactivated during intestinal tumor progression. By providing a direct link between two tumor-suppressive signaling pathways with established effects on intestinal tumorigenesis, our findings broaden our understanding of CRC and open avenues for potential novel therapeutic approaches to this disease. (Supported by NIH grants DK60632, CA54807, CA036727 and CA191894.) Citation Format: Xinyue Li, Michelle Lum, Adrian Black, Jennifer Black. Crosstalk between PKCalpha and TGF-beta signaling suppresses inhibitor of DNA binding 1 (Id1) expression in intestinal epithelial 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 3463.