tbuckley/cabot-search huggingface dataset:
Role of Small GTPases in Endothelial Cytoskeletal Dynamics and the Shear Stress Response
Authors: EleniTzima
Journal: Circulation Research (2006)

Fluid shear stress caused by blood flow is a major determinant of vascular remodeling and arterial tone and can lead to development of atherosclerosis. The endothelial monolayer in vivo acts as a signal transduction interface for hemodynamic forces; these forces determine the shape, cytoskeletal organization, and function of endothelial cells, allowing the vessels to cope with physiological or pathological conditions. The Ras superfamily of GTPases have been revealed to be master regulators of many cellular activities. In particular, the GTPases RhoA, Rac1, and Cdc42 are known to regulate cell shape changes through effects on the cytoskeleton, but their ability to influence polarity, microtubule dynamics, and transcription factor activity is just as significant. Shear stress modulates the activity of small GTPases, which are critical for both cytoskeletal reorganization and changes in gene expression in response to shear stress. The goal of this article is to review what is known about Ras and more so abo...
Additional Evidence for High-Resistance Inter-calated Discs in the Myocardium
Authors: Nicksperelakis, JohnEgna
Journal: Circulation Research (1963)

Parallel-fibered strips of cardiac (cat papillary) and skeletal (frog sartorius) muscles were mounted in air and action potentials were externally recorded from the middle of the strip. Electric fields, oriented longitudinally with respect to the long axis of the cells, were applied. A pair of stimulating electrodes was located at each end of the strip to test for propagation. Under conditions of blocked propagation produced by addition of isotonic sucrose solution, the cells near the middle of the strip could be tested for direct response to longitudinal fields. In long-celled skeletal muscle, the sucrose solution produced simultaneously failure of electrical and mechanical response to stimulation across the strip as well as failure of propagation; stimulation at ten times threshold failed to elicit responses. However, in short-celled cardiac muscle, the sucrose solution produced failure of propagation first; electrical and mechanical responses to longitudinal field stimulation continued without a change...
Fluid Shear Stress Induces Lipocalin-Type Prostaglandin D2 Synthase Expression in Vascular Endothelial Cells
Authors: YojiTaba, ToshiyukiSasaguri, MegumiMiyagi, TakeoAbumiya, YoshikazuMiwa, ToshikoIkeda, MasakoMitsumata
Journal: Circulation Research (2000)

Abstract—Ligands for peroxisome proliferator–activated receptor γ, such as the thiazolidinedione class of antidiabetic drugs and 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), modulate various processes in atherogenesis. In search of cells that generate prostaglandin D2 (PGD2), the metabolic precursor of 15d-PGJ2, we identified PGD2 from culture medium of endothelial cells. To study how PGD2 production is regulated in endothelial cells, we investigated the role of fluid shear stress in the metabolism of PGD2. Endothelial cells expressed the mRNA for the lipocalin-type PGD2 synthase (L-PGDS) both in vitro and in vivo. Loading laminar shear stress using a parallel-plate flow chamber markedly enhanced the gene expression of L-PGDS, with the maximal effect being obtained at 15 to 30 dyne/cm2. The expression began to increase within 6 hours after loading shear stress and reached the maximal level at 18 to 24 hours. In contrast, shear stress did not alter the expression levels of PGI2 synthase and thromboxane A2 ...
Abstract B17: Gene therapy and chemotherapy cooperate to inhibit prostate cancer progression in an animal model
Authors: Rodrigo Esaki Tamura, Bryan Eric Strauss
Journal: Clinical Cancer Research (2018)

Abstract Patients with localized prostate carcinoma have a 5 year-survival rate of almost 100%; however, for patients with metastatic disease the rate is 31%, and mortality in 90% of these cases is the result of metastases. Clearly, there is a need for novel therapies and room for improving existing modalities. We propose that gene therapy and chemotherapy, when combined, may provide superior tumor cell killing. Our laboratory has developed a novel adenoviral vector expressing p53 under the control of a p53 responsive promoter; thus a positive feedback mechanism is established, providing high levels of p53, resulting in cell death of prostate cancer cells in vitro and in vivo. In previous assays, we have shown that our vector (AdRGDPGp53) is more effective than typical gene therapy approaches which employ a constitutive promoter (CMV) to control expression of p53. Here, we evaluate whether the union of gene therapy and chemotherapy applied to prostate cancer cell lines would promote a synergistic response in the induction of programmed cell death and reduction of tumor progression in an animal model. We combined AdRGDPGp53 along with the chemotherapy drugs used in the clinical treatment of prostate carcinoma, mitoxantrone, docetaxel, or cabazitaxel. Our results indicate that all drugs increase phosphorylation of p53, leading to improved induction of p53 targets. In vitro experiments indicate that AdRGDPGp53 sensitizes prostate cancer cells to each of the drugs tested, conferring increased levels of cell death. In a xenograft mouse model of in situ gene therapy, AdRGDPGp53 treatment, when combined with cabazitaxel, drastically reduced tumor progression and increased survival rates to 100%. Strikingly, we used a sub-therapeutic dose of cabazitaxel, thus avoiding leukopenia, yet still showed potent antitumor effects when combined with AdRGDPGp53 in this mouse model. The AdRGDPGp53 approach warrants further development for its application in gene therapy of prostate carcinoma. Citation Format: Rodrigo Esaki Tamura, Bryan Eric Strauss. Gene therapy and chemotherapy cooperate to inhibit prostate cancer progression in an animal model [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B17.
Abstract 308: Yeast Bax Inhibitor, <i>BXI1</i>, is involved in calcium homeostasis of the ER in <i>Saccharomyces cerevisiae</i>
Authors: Nicholas Andrews, Nicholas Mello, Liam McDonough, Joseph Alisch, David Eagan, James Mullin, Alfredo Gonzalez, Nicanor Austriaco
Journal: Cancer Research (2018)

Abstract Yeast Bax inhibitor-1 (BXI1/YBH3) encodes a protein that belongs to the Bax Inhibitor (TMBIM) family of proteins that all contain a transmembrane BAX inhibitor motif. The crystal structure of a prokaryotic member of the family, BsYetJ, has revealed that the Bax inhibitor proteins are pH sensitive calcium leaks. In mammals, the Bax inhibitor family of proteins has cytoprotective properties that are most evident in paradigms of endoplasmic reticulum (ER) stress. Our published studies have shown that yeast Bxi1p is localized to the endoplasmic reticulum and is involved in the unfolded protein response (UPR) that is triggered by ER stress. BXI1 is thought to act via a mechanism involving altered calcium dynamics. We now show that cells lacking BXI1 accumulate higher levels of calcium in their ER as compared to their wildtype counterparts. We have also over expressed Bxi1p in E.coli and have used a fura-2 based calcium assay to show that the protein facilitates the influx of extracellular calcium into the cell. Our preliminary data with Δbxi1 Δpmr1 double mutants suggest that Bxi1p and Pmr1p, the Golgi-ER calcium pump, function in an antagonistic manner. [Our laboratory is supported by grant NIGMS R15 GM110578, awarded to N. Austriaco.] Citation Format: Nicholas Andrews, Nicholas Mello, Liam McDonough, Joseph Alisch, David Eagan, James Mullin, Alfredo Gonzalez, Nicanor Austriaco. Yeast Bax Inhibitor, BXI1, is involved in calcium homeostasis of the ER in Saccharomyces cerevisiae [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 308.
Abstract 889: Metformin treatment inhibits proliferation and induces apoptosis in medulloblastoma cells
Authors: Kristen C. Payne, Abigail Hunter, W Paul Bowman, Jeffrey C. Murray, Riyaz Basha, Umesh T. Sankpal
Journal: Cancer Research (2018)

Abstract Medulloblastoma is the most common malignant brain tumor in children that typically requires a patient specific combination of surgical resection, chemotherapy, and radiation. Up to 80% of medulloblastoma patients respond to treatment and survive long-term. However, survivors often suffer from severe long term sequelae secondary to treatment that affects their neurocognitive and growth potential. Therefore, there is an urgency to develop less toxic, more focused treatment strategies that target specific pathways or molecules involved in medulloblastoma development and progression. Metformin is a widely used non-toxic anti-diabetic drug that has mild, generally well-tolerated side effects. Studies have shown that it can reduce cancer risk and improve the prognosis of certain malignancies. However, the mechanism underlying its anti-cancer effect is still unclear and varies depending on the type of cancer. There are reports that metformin can target the specificity protein 1 (Sp1) transcription factor. Sp1 regulates the expression of a variety of proteins involved in regulation of cancer cell proliferation including survivin, an Inhibitor of Apoptosis Protein family member. Expression of survivin is increased in medulloblastoma cells and often correlates with poor prognosis. We studied the anti-cancer activity of metformin on medulloblastoma using DAOY and D283 cells. Metformin treatment resulted in a dose and time dependent reduction in cell proliferation in both cell lines. This growth inhibition was accompanied by the induction of apoptosis as determined by annexin-V staining, PARP cleavage, and activation of caspase3/7. Metformin also induced cell cycle arrest in G0/G1 phase. Western blot analysis using extracts from cells treated with metformin revealed that the anti-proliferative and apoptotic effects of metformin in medulloblastoma were accompanied by a reduction in the expression of survivin protein. Overexpression of survivin is reported to be associated with chemo- and radio-resistance. This study suggests the use of metformin as a novel anticancer agent in combination with standard therapy for the treatment of medulloblastoma. Citation Format: Kristen C. Payne, Abigail Hunter, W Paul Bowman, Jeffrey C. Murray, Riyaz Basha, Umesh T. Sankpal. Metformin treatment inhibits proliferation and induces apoptosis in medulloblastoma 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 889.
Abstract 1993: Rapid clonal evolution of dormant micrometastatic disease in head and neck cancer
Authors: Angelica M. Lagunas, Jianchun Wu, David L. Crowe
Journal: Cancer Research (2018)

Abstract Head and neck cancer (HNC) is prone to locoregional recurrence which results in poor clinical outcome. Recent HNC clinical studies demonstrated that cervical lymph node dissection results in improved patient outcome even in early disease. These results suggest that dormant micrometastatic cancer occurs early in head and neck carcinogenesis. We used our established in vivo chemical carcinogenesis model of head and neck cancer to characterize dormant micrometastatic disease using genetic lineage tracing and null mutant mice. Histopathology was analyzed by hematoxylin and eosin staining. Telomere DNA damage response was determined by immunofluorescent 53BP1 localization at telomeres, and by ATM/ATR western blotting. Keratin expression and proliferation index were determined by immunohistochemistry. Apoptotic cells were determined by TUNEL analysis. Telomerase activity was determined by telomere repeat amplification protocol. Alternative lengthening of telomeres was determined by PML localization at telomeres, telomere circular DNA analysis, and chromosome orientation fluorescence in situ hybridization. Genomic instability was determined by high throughput sequencing. Cancer stem cells were sorted by flow cytometry and transplanted subcutaneously in Matrigel. Advanced HNC exhibited significant metastatic disease in the majority of lymph nodes. Early HNC and even premalignant lesions exhibited micrometastatic disease in most lymph nodes. These micrometastatic lesions contained multiple HNC clones that were dependent for proliferation on paracrine chemokine signaling from a tumorigenic keratin 15+ cancer stem cell population. In situ, the micrometastatic K15+ cancer stem cell population exhibited increased telomere DNA damage response including activated ATM and ATR which correlated with low proliferation index. Clonal evolution of K15+ micrometastatic cancer stem cells was dependent on extremely short telomeres. These cells expressed both telomerase and recombination-based alternative lengthening of telomeres (ALT) activities. K15+ micrometastatic cancer stem cells exhibited high levels of genomic instability resulting from telomere fusions and expressed metastasis-specific gene expression programs. These patterns of micrometastatic gene expression revealed targeted therapeutic vulnerabilities. These results indicate that dormant micrometastatic disease develops rapidly during head and neck carcinogenesis from normal epithelial cells with short telomeres and is sensitive to targeted therapies. Citation Format: Angelica M. Lagunas, Jianchun Wu, David L. Crowe. Rapid clonal evolution of dormant micrometastatic disease in head and neck cancer [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 1993.
Abstract 1171: Quantitative evaluation of hepatobiliary transporter density with microscopic fluorescence imaging using indocyanine green
Authors: Hui Meng, Yuan Gao, Lin Yin, Xibo Ma, Kun Wang, Jie Tian
Journal: Cancer Research (2018)

Abstract The sodium-dependent taurocholate cotransporter polypeptide (NTCP) has been identified as a predictive marker for post-surgery survival rate of hepatocellular carcinoma (HCC) patients. Previous studies indicated that the expression of NTCP was associated with tumor differentiation. The ability to quantify protein expression is imperative to ensure successful personalized medicine including treatment stratification and therapeutic monitoring. Current standards for transporter analysis are based on immunohistochemistry and immunofluorescence. These measurements are complicated and too time consuming. Here, we endeavored to identify the expression of NTCP by quantitative microscopic fluorescence imaging (MFI) features, that could be used for investigation of tumor heterogeneity. Quantitative image features including the intensity, texture and wavelet texture were extracted from microscopic fluorescence images. Using multiple xenograft tumor models with varying NTCP expression, we determined the NTCP density in each model with MFI using indocyanine green. The MFI-calculated transporter density was correlated with ex vivo immunohistochemistry. Overall, our results argue that MFI provides a promising measure of transporter expression equivalent to immune-staining, with implications for use in investigation of tumor heterogeneity. Citation Format: Hui Meng, Yuan Gao, Lin Yin, Xibo Ma, Kun Wang, Jie Tian. Quantitative evaluation of hepatobiliary transporter density with microscopic fluorescence imaging using indocyanine green [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 1171.
Ischemic Preconditioning Activates Phosphatidylinositol-3-Kinase Upstream of Protein Kinase C
Authors: HaiyanTong, WeinaChen, CharlesSteenbergen, ElizabethMurphy
Journal: Circulation Research (2000)

Abstract—The present study is designed to test whether phosphatidylinositol 3-kinase (PI3-kinase) has a role in the signaling pathway in ischemic preconditioning (PC) and whether it is proximal or distal to protein kinase C (PKC). Before 20 minutes of global ischemia, Langendorff-perfused rat hearts were perfused for 20 minutes (control); preconditioned with 4 cycles of 5-minute ischemia and 5-minute reflow (PC); treated with either wortmannin (WM) or LY 294002 (LY), each of which is a PI3-kinase inhibitor, for 5 minutes before and throughout PC; treated with 1,2-dioctanoyl-sn-glycerol (DOG), an activator of PKC for 10 minutes (DOG); treated identically to the DOG group except with WM added 10 minutes before and during perfusion with DOG; or treated with either WM or LY for 25 minutes. Recovery of left ventricular developed pressure (LVDP; percentage of initial preischemic LVDP), measured after 30 minutes of reflow, was improved by PC (72±2% versus 36±4% in control; P<0.001), and this was blocked by WM an...
INTERMACS Profiles and Outcomes Among Non–Inotrope-Dependent Outpatients With Heart Failure and Reduced Ejection Fraction
Authors: Ayman Samman-Tahhan, Jeffrey S Hedley, Andrew A McCue, Jonathan B Bjork, Vasiliki V Georgiopoulou, Alanna A Morris, Javed Butler, Andreas P Kalogeropoulos
Journal: JACC Heart Failure (2018)
Abstract 17101: Identification of Aortic Tissue at Risk for Dysfunction in Patients With Aortopathy Using 4D Flow MRI: Impact of Surgical Intervention
Authors: Emilie Bollache, Paul W Fedak, Pim van Ooij, Ozair Rahman, Alex Hong, Eric J Keller, S. Chris Malaisrie, Patrick M McCarthy, James Carr, Jeremy Collins, Michael Markl, Alex J Barker
Journal: Circulation (2016)

Introduction: Prophylactic resection for patients with aortopathy is based on diameter thresholds. However, rupture and acute dissection can occur below these thresholds and might be related to val...
Abstract 972: Defining the molecular context of MYC and WDR5 at chromatin
Authors: Alissa D. Guarnaccia, William P. Tansey
Journal: Cancer Research (2018)

Abstract MYC is an oncoprotein transcription factor that is overexpressed in the majority of malignancies and contributes to the deaths of ~100,000 Americans each year. The tumorigenic functions of MYC stem from its influence on the transcriptional program of a cell, promoting the expression of thousands of genes involved in cell cycle progression, growth, and metabolism. In order to understand how MYC promotes cancer, we must understand the mechanisms by which MYC selects its target genes. Epigenetic signatures, DNA sequence motifs, and protein-protein interactions have all been implicated to play a role in MYC target gene selection, but a deep molecular understanding of the determinants of target gene recognition by MYC is missing. Our laboratory discovered that the chromatin-associated scaffolding protein WDR5 directly interacts with MYC and co-localizes on chromatin at a majority of loci (Thomas et al., Mol. Cell, 58: 440-452, 2015). The MYC-WDR5 interaction is disrupted by point mutation of three charged residues in MYC. While this MYC mutant retains the ability to bind to naked DNA, the mutant does not bind target loci in the context of chromatin and is unable to form tumors in mice. From these findings we propose that WDR5 is a crucial factor for enabling MYC activity in cancer. Both MYC and WDR5 are known to be highly networked proteins with multiple simultaneous interactions. Our aim is to tease apart this complicated network and define the molecular context specifically for the MYC-WDR5 interaction. To do this, we are employing our WDR5-binding deficient MYC mutant as a tool to genetically distinguish MYC interactions that are dependent upon WDR5. Our approach is to use Stable Isotope Labeling of Amino acids in Cell Culture (SILAC) because it enables us to quantitatively compare wild-type and mutant MYC and reduces background noise common to non-quantitative MYC-centered proteomics. Once identified by SILAC, interacting proteins are validated with biochemical methods and by proximity ligation assay in cells. This dual validation confirms the interaction in two ways, and provides information on the sub-cellular localization of the interaction. Thus far we have identified a preliminary set of ~25 interacting proteins that are currently undergoing validation. Characterization of these new factors by genetic, genomic, and biochemical approaches will expand our understanding of MYC biology, and potentially identify new factors that can be therapeutically targeted in cancer. Citation Format: Alissa D. Guarnaccia, William P. Tansey. Defining the molecular context of MYC and WDR5 at chromatin [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 972.
Turnover of Cholesterol in the Artery Walls of Normal Chickens
Authors: Seymourdayton
Journal: Circulation Research (1959)

Studies of cholesterol metabolism in the walls of arteries of normal intact cockerels indicate that plasma cholesterol is the major precursor of the cholesterol in the artery wall, but that local synthesis may contribute a significant fraction. The fractional turnover of cholesterol in the wall of the abdominal aorta is faster than in either the thoracic aorta or the brachiocephalic arteries. However, considered in relation to endothelial surface area, the rate of cholesterol transfer from plasma is smallest in the abdominal aorta. The abdominal aorta also has a lower cholesterol concentration in this species than do the other large arteries.
Abstract 18594: Can Emergency Physician in Non-Pediatric-Specialty Hospitals Resuscitate Children With Out-of-Cardiac Arrest?
Authors: Natsumi Hata, Yoshinori Matsuoka, Daisuke Mizu, Koichi Ariyoshi
Journal: Circulation (2016)

Introduction: The concept of “pediatric readiness” has recently been advocated in the United States(US) recently. As in the US and other countries, most pediatric patients are received emergency treatment in non-pediatric-specialty hospitals in Japan and many children with out-of-hospital cardiac arrest (OHCA) are also resuscitated in general emergency departments (EDs). Hypothesis: We tested the hypothesis that emergency physician in general EDs may face a peculiar problem when resuscitating pediatric patients with OHCA. Methods: This study was a retrospective analysis of pediatric patients (age < 15 years) with OHCA who were brought to an urban tertiary ED of a non-pediatric-specialty hospital in Japan between 1999 and 2015.The primary outcome was the emergency physicians’ experience with pediatric patients with OHCA.Additional outcomes were causes of OHCAs, total mortality, survival status,neurological outcome at hospital discharge, and predictors of survival after OHCA. Results: Of all patients with O...