tbuckley/cabot-search huggingface dataset:
Pericytes Elicit Resistance to Vemurafenib and Sorafenib Therapy in Thyroid Carcinoma via the TSP-1/TGFβ1 Axis
Authors: Alessandro Prete, Agnes S. Lo, Peter M. Sadow, Swati S. Bhasin, Zeus A. Antonello, Danica M. Vodopivec, Soumya Ullas, Jennifer N. Sims, John Clohessy, Ann M. Dvorak, Tracey Sciuto, Manoj Bhasin, Joanne E. Murphy-Ullrich, Jack Lawler, S. Ananth Karumanchi, Carmelo Nucera
Journal: Clinical Cancer Research (2018)

The BRAFV600E oncogene modulates the papillary thyroid carcinoma (PTC) microenvironment, in which pericytes are critical regulators of tyrosine-kinase (TK)-dependent signaling pathways. Although BRAFV600E and TK inhibitors are available, their efficacy as bimodal therapeutic agents in BRAFV600E-PTC is still unknown.We assessed the effects of vemurafenib (BRAFV600E inhibitor) and sorafenib (TKI) as single agents or in combination in BRAFWT/V600E-PTC and BRAFWT/WT cells using cell-autonomous, pericyte coculture, and an orthotopic mouse model. We also used BRAFWT/V600E-PTC and BRAFWT/WT-PTC clinical samples to identify differentially expressed genes fundamental to tumor microenvironment.Combined therapy blocks tumor cell proliferation, increases cell death, and decreases motility via BRAFV600E inhibition in thyroid tumor cells in vitro. Vemurafenib produces cytostatic effects in orthotopic tumors, whereas combined therapy (likely reflecting sorafenib activity) generates biological fluctuations with tumor inhibition alternating with tumor growth. We demonstrate that pericytes secrete TSP-1 and TGFβ1, and induce the rebound of pERK1/2, pAKT and pSMAD3 levels to overcome the inhibitory effects of the targeted therapy in PTC cells. This leads to increased BRAFV600E-PTC cell survival and cell death refractoriness. We find that BRAFWT/V600E-PTC clinical samples are enriched in pericytes, and TSP1 and TGFβ1 expression evoke gene-regulatory networks and pathways (TGFβ signaling, metastasis, tumor growth, tumor microenvironment/ECM remodeling functions, inflammation, VEGF ligand-VEGF receptor interactions, immune modulation, etc.) in the microenvironment essential for BRAFWT/V600E-PTC cell survival. Critically, antagonism of the TSP-1/TGFβ1 axis reduces tumor cell growth and overcomes drug resistance.Pericytes shield BRAFV600E-PTC cells from targeted therapy via TSP-1 and TGFβ1, suggesting this axis as a new therapeutic target for overcoming resistance to BRAFV600E and TK inhibitors.
Abstract LB-193: TRAIL promotes entosis through Caspase-8
Authors: Emir Bozkurt, Heiko Dussmann, Jochen H. Prehn
Journal: Cancer Research (2018)

Abstract Despite its apoptosis-inducing activity, tumor necrosis factor-related apoptosis inducing ligand (TRAIL) also activates survival signaling pathways. Survival signaling not only interferes with apoptosis and causes resistance, but can also lead to gain of several tumor-promoting functions such as proliferation, invasion and metastasis. Here we demonstrate that colorectal cancer cells surviving from TRAIL treatment can initiate a cell-in-cell invasion process known as entosis. Entosis refers to a unique cell-in-cell phenomenon, in which one or more viable cells are actively internalized into another cell of the same type. After formation of cell-in-cell structures (CICs), internalized cells can divide inside the host cell or they can escape, however, the vast majority of cells undergo cell death inside their hosts, through a lysosome-dependent mechanism. Although the clinical relevance of entosis is highly context-dependent, the frequency of entosis has been shown associated with tumor grade and poor outcome in several malignancies. While monitoring single-cell response upon TRAIL stimulation, we noted that some cells internalized into their neighboring cells and died inside a vacuole. We confirmed CICs by fluorescence staining of cytoplasm, nucleus, lysosome and cell membrane, in addition to TEM. Further quantification revealed that TRAIL indeed increased the number of CICs in colorectal cancer cell lines (HCT116 and LS180) and spheroids. Moreover, both pre-treatment with ROCK inhibitor (Y-27632) and knockout of Caspase-8 resulted in a significant reduction in the number of TRAIL-induced CICs. After forming cell-in-cell structures, the majority of internalized cells appeared positive for lysotracker staining and underwent cell death inside their hosts. These cells showed an increase in IETD FRET probe cleavage, additionally, we observed increased levels of cleaved caspase-8, cleaved caspase-9 and cleaved caspase-3 in these cells in presence of TRAIL. Pre-treatment with z-VAD-fmk reduced the number of internalized cells undergoing cell death and Bax/Bak double knockout cells escaped from their hosts without undergoing cell death in response to TRAIL. Our findings demonstrate that entosis can be induced by TRAIL in a caspase-8-dependent manner, and may give new insights in understanding the death, survival and escape mechanisms in internalized cells. Citation Format: Emir Bozkurt, Heiko Dussmann, Jochen H. Prehn. TRAIL promotes entosis through Caspase-8 [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 LB-193.
Reciprocal Association of C-Reactive Protein With Adiponectin in Blood Stream and Adipose Tissue
Authors: NoriyukiOuchi, ShinjiKihara, TohruFunahashi, TadashiNakamura, MakotoNishida, MasahiroKumada, YoshihisaOkamoto, KojiOhashi, HiroyukiNagaretani, KenKishida, HitoshiNishizawa, NorikazuMaeda, HidekiKobayashi, HisatoyoHiraoka, YujiMatsuzawa
Journal: Circulation (2003)

Background— High-sensitive C-reactive protein (hs-CRP) is a well-known risk factor for coronary artery disease (CAD). Recently, we have demonstrated that adiponectin served as an antiatherogenic plasma protein which was secreted specifically from adipocytes. The present study investigated the association between adiponectin and CRP in the blood stream and adipose tissue. Methods and Results— We studied a total of 101 male patients, 71 of whom had angiographically documented coronary atherosclerosis. As a control group, 30 patients with normal coronary angiogram were included. The plasma hs-CRP levels were negatively correlated with the plasma adiponectin levels (r=−0.29, P<0.01). The plasma adiponectin concentrations were significantly lower and the hs-CRP levels were significantly higher in the CAD patients compared with control subjects. The mRNA levels of CRP and adiponectin were analyzed by quantitative real-time polymerase chain reaction method. We found that the CRP mRNA was expressed in human adipo...
Expression of NADH/NADPH Oxidase p22phox in Human Coronary Arteries
Authors: HiroshiAzumi, NobutakaInoue, SaoriTakeshita, YoshiyukiRikitake, SeinosukeKawashima, YoshitakeHayashi, HiroshiItoh, MitsuhiroYokoyama
Journal: Circulation (1999)

Background—NADH/NADPH oxidase is an important source of superoxide in the vasculature. Recently, we found that polymorphism of the gene p22phox, a critical component of this oxidase, is associated with a risk of coronary artery disease. The aim of this study was to investigate the localization of p22phox in human coronary arteries and to examine its difference in expression between nonatherosclerotic and atherosclerotic coronary arteries. Methods and Results—Using coronary artery sections from autopsied cases (n=11), the expression of p22phox was examined by immunohistochemistry and Western blotting. In nonatherosclerotic coronary arteries, p22phox was weakly expressed, mainly in the adventitia. In atherosclerotic coronary arteries, intensive immunoreactivity was detected in neointimal and medial smooth muscle cells and infiltrating macrophages in hypercellular regions and at the shoulder region. Semiquantitative analysis and Western blotting showed that the expression of p22phox in atherosclerotic corona...
Abstract 5728: DNA demethylating agents and interferons as modulators of Wnt/β-catenin signaling in colorectal cancer
Authors: Ilias Ettayebi, Parinaz Mehdipour, Rajat Singhania, Ankur Chakravarthy, Tiago Medina, Shu Yi Shen, Charles Ishak, David Roulois, Daniel De Carvalho
Journal: Cancer Research (2018)

Abstract p.p1 {margin: 0.0px 0.0px 0.0px 0.0px; font: 12.0px 'Times New Roman'} Colorectal cancer (CRC) is the second leading cause of death from cancer in men and the third in women in Canada. There is accumulating evidence suggesting that CRC is organized in a hierarchical manner, at the apex of which are the Cancer-Initiating Cells (CIC). Furthermore, results from xenograft models and human clinical trials indicate a selective enrichment of CICs in tumours that are resistant to therapy, suggesting that targeting CICs may represent a new paradigm in cancer treatment. We have previously reported the treatment with low dose of the DNA demethylating agent, 5-Aza-2'-deoxycytidine (5-AZA-CdR), can target CICs through the activation of the RIG1-MDA5 viral sensing sensing pathway, leading to an anti-viral response in cancer cells. Although it is now known that 5-AZA-CdR induces a state of “viral mimicry” in these cancer cells, the mechanism by which 5-AZA-CdR can specifically target CICs is not well understood. In this study, we propose a novel intersection between RIG1-MDA5-IRF7 and Wnt/β-catenin pathways. We found that treatment of CIC enriched cancer cells with both 5-AZA-CdR and type I and III interferons reduced canonical Wnt/β-catenin signalling. Furthermore, treatment with type I and III interferons showed a reduced CIC frequency in colorectal cancer cells in vitro. Mechanistically, we found that IRF7 and β-catenin interact in the nucleus, giving rise to a novel, non-canonical pathway that can modulate WNT signalling. These findings may explain a novel pathway by which 5-AZA-CdR can specifically target CIC enriched populations in colorectal cancer, and highlights the importance of innate immune pathways in epigenetic therapy. Citation Format: Ilias Ettayebi, Parinaz Mehdipour, Rajat Singhania, Ankur Chakravarthy, Tiago Medina, Shu Yi Shen, Charles Ishak, David Roulois, Daniel De Carvalho. DNA demethylating agents and interferons as modulators of Wnt/β-catenin signaling in colorectal 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 5728.
Abstract 3495: Trip13, a target of miR192, facilitates colorectal cancer progression through WNT/β-catenin signaling
Authors: Sumit Agarwal, Balabhadrapatruni V. Chakravarthi, Darshan S. Chandrashekar, Rong Jun Guo, Pran Datta, Sooryanarayana Varambally, Upender Manne
Journal: Cancer Research (2018)

Abstract Most colorectal cancers (CRCs) exhibit genomic instability or chromosomal instability (CIN) in the form of aneuploidy. These aberrations are associated with chromosomal gains or losses. In human malignances, levels of a member of the AAA-ATPases family, TRIP13, correlate with CIN. In the present study, we investigated the expression and biological function of TRIP13 in CRC. In silico gene expression profiling using the UALCAN (http://ualcan.path.uab.edu/) web portal showed elevated TRIP13 expression in CRCs as compared to normal/benign colonic epithelial tissues. Studies employing immunoblot analyses confirmed elevated expression of the TRIP13 protein in CRC tissues compared to their matched normal/benign colorectal tissues. Concurrent immunohistochemical analysis of tissue microarrays, containing normal and tumor tissues, further validated cytoplasmic TRIP13 expression in CRCs as compared to their contiguous normal/benign epithelial components. To understand the functional significance of TRIP13 in CRCs, particularly in regard to progression of cancer cells, experiments were performed by utilizing lentivirus-mediated TRIP13 silencing in CRC cell lines that express high levels of TRIP13. Depletion of TRIP13 impeded cell proliferation, colony formation, invasion, cell motility, and spheroid-forming capacity. TRIP13 depletion also showed suppression of EGFR activation and WNT/β-catenin signaling. Furthermore, bioinformatic analysis revealed that TRIP13 is a predicted target of miR192. Dual-luciferase reporter assays showed that miR192 binds to the 3' UTR of TRIP13. Also, overexpression of miR192 in HCT116 cells lowered TRIP13 expression and reduced cell proliferation, colony formation, and invasion, suggesting that it is a tumor suppressor. Thus, these findings demonstrate a function of TRIP13 in the progression of CRCs and indicate that TRIP13 inhibition by small molecules is a possible strategy for treatment of CRC. Citation Format: Sumit Agarwal, Balabhadrapatruni V. Chakravarthi, Darshan S. Chandrashekar, Rong Jun Guo, Pran Datta, Sooryanarayana Varambally, Upender Manne. Trip13, a target of miR192, facilitates colorectal cancer progression through WNT/β-catenin signaling [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 3495.
Rho-Associated Protein Kinase Contributes to Early Atherosclerotic Lesion Formation in Mice
Authors: ZiadMallat, AndreaGojova, VincentSauzeau, ValérieBrun, Jean-SébastienSilvestre, BrunoEsposito, RégineMerval, HervéGroux, GervaiseLoirand, AlainTedgui
Journal: Circulation Research (2003)

Members of the Rho family of small GTPases have been recently implicated in inflammatory signaling. We examined the effect of in vivo inhibition of Rho kinase on atherogenesis in mice. Low-density lipoprotein receptor (LDLR) knockout (KO) mice fed a cholate-free high-fat diet received daily intraperitoneal injection of saline (n=8, control group) or Y-27632 (30 mg/kg, n=9), a specific Rho kinase inhibitor. After 9 weeks, Y-27632 treatment resulted in significant in vivo inhibition of Rho kinase activity (P=0.004). Body weights, arterial blood pressures, and plasma cholesterol levels were comparable in both groups. Atherosclerotic lesion size in the aortic sinus and thoracic aorta of mice treated with Y-27632 was reduced by respectively 35% and 29% in comparison with the saline-treated animals (P=0.006 and P=0.03, respectively). This was associated with a significant reduction in T lymphocyte accumulation (P=0.035) and expression of p65 subunit of NF-κB within plaques (P<0.05). In vitro, treatment with Y-2...
Hydrogen Peroxide, an Endogenous Endothelium-Derived Hyperpolarizing Factor, Plays an Important Role in Coronary Autoregulation In Vivo
Authors: ToyotakaYada, HiroakiShimokawa, OsamuHiramatsu, TatsuyaKajita, FumiyukiShigeto, MasamiGoto, YasuoOgasawara, FumihikoKajiya
Journal: Circulation (2003)

Background— Recent studies in vitro have demonstrated that endothelium-derived hydrogen peroxide (H2O2) is an endothelium-derived hyperpolarizing factor (EDHF) in animals and humans. The aim of this study was to evaluate our hypothesis that endothelium-derived H2O2 is an EDHF in vivo and plays an important role in coronary autoregulation. Methods and Results— To test this hypothesis, we evaluated vasodilator responses of canine (n=41) subepicardial small coronary arteries (≥100 μm) and arterioles (<100 μm) with an intravital microscope in response to acetylcholine and to a stepwise reduction in coronary perfusion pressure (from 100 to 30 mm Hg) before and after inhibition of NO synthesis with NG-monomethyl-l-arginine (L-NMMA). After L-NMMA, the coronary vasodilator responses were attenuated primarily in small arteries, whereas combined infusion of L-NMMA plus catalase (an enzyme that selectively dismutates H2O2 into water and oxygen) or tetraethylammonium (TEA, an inhibitor of large-conductance KCa channe...
Remission of Human Type 2 Diabetes Requires Decrease in Liver and Pancreas Fat Content but Is Dependent upon Capacity for β Cell Recovery
Authors: Roy Taylor, Ahmad Al-Mrabeh, Sviatlana Zhyzhneuskaya, Carl Peters, Alison C. Barnes, Benjamin S. Aribisala, Kieren G. Hollingsworth, John C. Mathers, Naveed Sattar, Michael E.J. Lean
Journal: Cell Metabolism (2018)
Role of Myocyte Nitric Oxide in β-Adrenergic Hyporesponsiveness in Heart Failure
Authors: ShimakoYamamoto, HiroyukiTsutsui, HirofumiTagawa, KeikoSaito, MasaruTakahashi, HideoTada, MitsutakaYamamoto, MakotoKatoh, KensukeEgashira, AkiraTakeshita
Journal: Circulation (1997)

Background The positive inotropic response to β-adrenergic stimulation is attenuated at the isolated myocyte level in heart failure. Nitric oxide (NO) has a negative inotropic effect and attenuates the response to isoproterenol. It has been suggested that NO synthesis is increased in failing myocytes. However, the pathophysiological consequences after induction of NO in myocyte contractility are less clear in the setting of heart failure. Methods and Results We examined the effects of an NO synthase (NOS) inhibitor on contractile function in myocytes isolated from 11 dogs with rapid pacing–induced heart failure (ejection fraction, 29±2%) and 8 control dogs (ejection fraction, 74±3%). Sarcomere shortening velocity was measured as an index of contractility under four experimental conditions: at baseline, after adding isoproterenol (ISO; 1 nmol/L), after an NOS inhibitor (Nϖ-nitro-l-arginine methyl ester [L-NAME], 0.1 nmol/L), and after L-NAME plus ISO. L-NAME alone had no effects on basal sarcomere shorteni...
Evaluation of an alternative ruxolitinib dosing regimen in patients with myelofibrosis: an open-label phase 2 study
Authors: Moshe Talpaz, Susan Erickson-Viitanen, Kevin Hou, Solomon Hamburg, Maria R. Baer
Journal: Journal of Hematology & Oncology (2018)

Ruxolitinib improves splenomegaly and symptoms in patients with intermediate-2 or high-risk myelofibrosis; however, nearly half develop grade 3/4 anemia and/or thrombocytopenia, necessitating dose reductions and/or transfusions. We report findings from an open-label phase 2 study exploring a dose-escalation strategy aimed at preserving clinical benefit while reducing hematological adverse events early in ruxolitinib treatment. Patients with myelofibrosis received ruxolitinib 10 mg twice daily (BID), with incremental increases of 5 mg BID at weeks 12 and 18 for lack of efficacy (maximum, 20 mg BID). Symptom severity was measured using the Myelofibrosis Symptom Assessment Form Total Symptom Score (MFSAF TSS). Forty-five patients were enrolled, 68.9% of whom had a Dynamic International Prognostic Scoring System score of 1 to 2 (i.e., intermediate-1 disease risk). Median percentage change in spleen volume from baseline to week 24 was − 17.3% (≥ 10% reduction achieved by 26 patients [57.8%]), with a clear dose response. Median percentage change in MFSAF TSS from baseline at week 24 was − 45.6%, also with a dose response. The most frequent treatment-emergent adverse events were anemia (26.7%), fatigue (22.2%), and arthralgias (20.0%). Grade 3/4 anemia (20.0%) and dose decreases due to anemia (11.1%) or thrombocytopenia (6.7%) were infrequent. A dose-escalation approach may mitigate worsening anemia during early ruxolitinib therapy in some patients with myelofibrosis. ClinicalTrials.gov identifier, NCT01445769 . Registered September 23, 2011.
Abstract P100: Dietary Protein Intake and Chronic Kidney Disease in American Population with Hypertension and Diabetes
Authors: Jin-Liern Hong, Xia Li, Charles Poole
Journal: Circulation (2012)

Background: Dietary protein intake has been associated with renal disease progression in patients with chronic kidney disease (CKD). Little is known about the renal impact of protein intake in persons with hypertension or diabetes who are at high risk for CKD. Objectives: This study aims to evaluate protein intake in relation to CKD in a representative sample of US adults, stratified by hypertension and diabetes. Methods: A cross-sectional study was conducted using data from the US NHANES 2003-2008. Subjects were excluded if they were pregnant, with known weak kidney, or following on special diet. There were 9,284 eligible participants age 20-80 with data from two 24-hour dietary recall questionnaires. Protein intake was adjusted for energy intake and categorized into four evenly spaced groups. CKD was defined as an estimated glomerular filtration rate &lt;60mL/min/1.73m 2 . Logistical regression model was used to estimate the prevalence odds ratio (POR). Analyses were further stratified by hypertension and diabetes. Results: The median protein intake was 77 g/day (interquartile range, 66 to 89 g/day) in the study population, and was 59, 72, 83, and 100 g/day for the lowest to the highest quarter of protein intake, respectively. The prevalence of CKD was 4%. For a 25-g increase in protein intake, the POR was 1.18 (95% CI: 0.93 to 1.50), adjusting for age, sex, race, income adequacy, education level, energy intake, physical activity, cardiovascular disease, diabetes, and hypertension. The adjusted POR comparing the highest and the lowest quarter of protein intake was 1.12 (95%CI: 0.73 to 1.72). The stratified analysis showed the highest quarter is associated with CKD among persons with both hypertension and diabetes ( Table ). No association was found in persons with hypertension only, diabetes only, or neither. Conclusion: We observed a positive association between protein intake and CKD among American adults with both hypertension and diabetes. This finding adds to the concern of dietary protein intake in persons at high-risk for CKD. Table. Adjusted POR of CKD comparing the highest and the lowest quarter of protein intake. Disease Status Hypertension - + Diabetes - 1.05 (0.45 - 2.45) 0.80 (0.44 - 1.47) + 4.63 (0.33 - 65.70) 3.04 (1.13 - 8.19)
Abstract 3505: Tumor radiosensitization by suppression of hexosamine biosynthetic pathway
Authors: Elena V. Efimova, Oliver K. Appelbe, Steve Seung-Young Lee, Natalia Ricco, Aishwarya Ramamarthy, Nicolas Rymut, Tamica Collins, Donald J. Wolfgeher, Sara Warrington, Stephen J. Kron
Journal: Cancer Research (2018)

Abstract The elevation of glucose and glutamine metabolism characteristic of cancer has been ascribed to increased demand for metabolic intermediates that provide building blocks for rapid cell growth. However, recent discoveries have highlighted complementary effects mediated by metabolites serving as cofactors for chromatin modifying enzymes and providing metabolic intermediates for proteins posttranslational modification. Along with epigenetic regulation of gene expression, multiple chromatin modifiers modulate DNA damage repair, raising the question of whether metabolic reprogramming may thereby promote genomic instability and cell immortality. In our prior work, we uncovered a role for the glycolysis hexosamine biosynthetic pathway (HBP) in DNA repair, ionizing radiation induced foci (IRIF) resolution, and prevention of radiation induced cancer cell senescence. Here we report that the targeting of key enzymes in the HBP pathway, O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) or O-GlcNAcase (OGA/ MGEA5), have contrary effects on the DNA damage response in tumors. shRNA knockdown of OGA resulted in increased GlcNAc protein modification, protection of cancer cells from irradiation through improved double strand break (DSB) repair and IRIF resolution in tumor cells, increased proliferation, and prevented radiation-induced senescence. In turn, silencing of OGT diminished O-GlcNAc modification, prevented DSB repair, increased IRIF persistence, reduced proliferation, and promoted radiation-induced senescence in tumor xenografts. These findings reveal an important relationship between cancer cell metabolism, DSB repair, and senescence and provide a rationale for targeting metabolic reprogramming, specifically O-GlcNAc modification, to block cancer cell immortality and overcome resistance to genotoxic stress. Citation Format: Elena V. Efimova, Oliver K. Appelbe, Steve Seung-Young Lee, Natalia Ricco, Aishwarya Ramamarthy, Nicolas Rymut, Tamica Collins, Donald J. Wolfgeher, Sara Warrington, Stephen J. Kron. Tumor radiosensitization by suppression of hexosamine biosynthetic pathway [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 3505.