tbuckley/cabot-search huggingface dataset:
Abstract 5519: BAP1 modulates gene-environment interaction in carcinogenesis
Authors: Michele Carbone, Angela Bononi, Carlotta Giorgi, Simone Patergnani, Harvey I. Pass, Wei Jia, Paolo Pinton, Haining Yang
Journal: Cancer Research (2018)

Abstract We discovered that heterozygous germline BAP1 mutations (BAP1+/-) cause a novel cancer syndrome that we named “The BAP1 cancer syndrome” characterized by development of malignant mesothelioma (MM), uveal and cutaneous melanoma, and other cancers. We demonstrated how germline BAP1 mutations are transmitted over the centuries across generations and found that 100% of individuals who inherited germline BAP1 mutations have developed one or more malignancies in their lifetime. Very recently we demonstrated that the potent BAP1 tumor-suppressor activity is linked to its dual function in the nucleus, where it regulates DNA repair, and in the cytoplasm, where it regulates apoptosis by deubiquitylating and stabilizing the IP3R3 endoplasmic reticulum (ER) Ca2+ channel. In parallel we discovered that cells carrying heterozygous BAP1 mutations derive energy largely via aerobic glycolysis, Warburg effect. Now we have found the mechanisms regulated by BAP1 that are responsible for the changes in metabolism. We discovered that reduced BAP1 levels lead to reduced release of Ca2+ from the ER into the cytoplasm and reduced intra-mitochondrial Ca2+ levels. Reduced mitochondrial Ca2+ levels directly impair aerobic respiration and cells switch to glycolysis even in the presence of oxygen. We demonstrate that aerobic glycolysis can be induced in apparently any human cell type by reducing BAP1 levels using siRNAs or other strategies, and that in these cells glycolysis can be reverted to aerobic respiration upon re-establishing normal Ca2+ levels. In conclusion, our findings indicate how BAP1 deficiency regulates DNA repair and apoptosis and how low BAP1 levels induce the Warburg effect, an effect seen in all “normal” cell types from individuals born with inherited germline heterozygous BAP1 mutations. In these individuals aerobic glycolysis predates by many years malignant transformation. Citation Format: Michele Carbone, Angela Bononi, Carlotta Giorgi, Simone Patergnani, Harvey I. Pass, Wei Jia, Paolo Pinton, Haining Yang. BAP1 modulates gene-environment interaction in carcinogenesis [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 5519.
Imaging and therapy of ovarian cancer: clinical application of nanoparticles and future perspectives
Authors: Giovanni Di Lorenzo, Giuseppe Ricci, Giovanni Maria Severini, Federico Romano, Stefania Biffi
Journal: Theranostics (2018)

Despite significant advances in cancer diagnostics and treatment, ovarian cancers (OC) continue to kill more than 150,000 women every year worldwide.Due to the relatively asymptomatic nature and the advanced stage of the disease at the time of diagnosis, OC is the most lethal gynecologic malignancy.The current treatment for advanced OC relies on the synergistic effect of combining surgical cytoreduction and chemotherapy; however, beside the fact that chemotherapy resistance is a major challenge in OC management, new imaging strategies are needed to target microscopic lesions and improve both cytoreductive surgery and patient outcomes.In this context, nanostructured probes are emerging as a new class of medical tool that can simultaneously provide imaging contrast, target tumor cells, and carry a wide range of medicines resulting in better diagnosis and therapeutic precision.Herein we summarize several exemplary efforts in nanomedicine for addressing unmet clinical needs.
Clinical Genetic Testing for Familial Hypercholesterolemia
Authors: Amy C. Sturm, Joshua W. Knowles, Samuel S. Gidding, Zahid S. Ahmad, Catherine D. Ahmed, Christie M. Ballantyne, Seth J. Baum, Mafalda Bourbon, Alain Carrié, Marina Cuchel, Sarah D. de Ferranti, Joep C. Defesche, Tomas Freiberger, Ray E. Hershberger, G. Kees Hovingh, Lala Karayan, Johannes Jacob Pieter Kastelein, Iris Kindt, Stacey R. Lane, Sarah E. Leigh, MacRae F. Linton, Pedro Mata, William A. Neal, Børge G. Nordestgaard, Raul D. Santos, Mariko Harada-Shiba, Eric J. Sijbrands, Nathan O. Stitziel, Shizuya Yamashita, Katherine A. Wilemon, David H. Ledbetter, Daniel J. Rader
Journal: Journal of the American College of Cardiology (2018)
Abstract 5225: PAR1 signaling on tumor cells limits tumor growth by maintaining a mesenchymal phenotype in pancreatic cancer
Authors: Cansu Tekin, Kun Shi, Arnold Spek, Maarten F. Bijlsma
Journal: Cancer Research (2018)

Abstract Background: Pancreatic cancer is a dismal disease with limited treatment options. Importantly, in recent years an oncogenic role of protease-activated receptor 1 (PAR1) emerged in various cancer types, and PAR1 is generally accepted to promote tumor progression. PAR1 depletion in stroma limits cancer growth in an orthotopic pancreatic cancer model, suggesting that PAR1 would be a prognostic marker for PDAC. Aim: To determine PAR1 expression in tumor compartment of PDAC microenvironment and its contribution to tumor progression and invasion. Methods: Kaplan-Meier overall survival analysis for PAR1 expression on PDAC tumor expression sets was performed. In an orthotopic tumor model, short hairpin RNA mediated PAR1 (shPAR1) knockdown cells derived from p48-CRE/LSL-KRAS/p53flox/flox mice (KP cells) and Panc02 cells were used. Additionally, gene set enrichment analysis was done for EMT signatures on PDAC tumor and pancreatic cancer cell lines. Furthermore, in vitro migratory capacity and mRNA levels for emerging mesenchymal signatures were analyzed in PAR1 knockdown PANC-1 cell line. Results: PAR1 expression does not associate with the overall survival of PDAC patients. However, tumor cell-specific PAR1 silencing potentiates pancreatic tumor growth but decreases metastatic potential in subsequent murine orthotopic pancreatic cancer model. Further analysis of PAR1 expression in PDAC tumors and pancreatic cancer cell lines show positive correlation with mesenchymal signatures and epithelial to mesenchymal transition genes. Indeed, PAR1 knockdown results in well-differentiated pancreatic tumors in vivo, with enhanced epithelial characteristics both in vitro and in vivo. Furthermore, decreased PAR1 activity decreases migratory capacity and in vitro metastatic potential in vivo. Conclusion: Our results suggest that growth promoting effects of PAR1 in stromal cells are counterbalanced by the growth inhibitory contributions of PAR1 in tumor cells. Overall, tumor cell PAR1 is linked to the maintenance of a mesenchymal-like state and silencing PAR1 in this setup results in an increased epithelial phenotype of cancer cells with an increased proliferative index but a decreased metastatic potential. Citation Format: Cansu Tekin, Kun Shi, Arnold Spek, Maarten F. Bijlsma. PAR1 signaling on tumor cells limits tumor growth by maintaining a mesenchymal phenotype in pancreatic 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 5225.
Abstract MP41: Health-related Quality of Life and Risk of Hypertension in the Community: A Prospective Analysis from the Western New York Health Study
Authors: SaverioStranges, LisaRafalson, RichardDonahue
Journal: Circulation (2014)

Health-related Quality of Life and Risk of Hypertension in the Community: A Prospective Analysis from the Western New York Health Study Background: Measures of quality of life and health status are strong predictors of mortality and morbidity outcomes including cardiovascular disease (CVD). However, prospective epidemiological evidence from population-based studies on the potential impact of these measures on hypertension risk is scant. Objective: We sought to examine the independent role of measures of quality of life and health status on the risk of incident hypertension in a community-based sample from Western New York. Methods: A longitudinal analysis, over 6 years of follow-up, among 946 women and men (mean age 54.3 years) from the community, who were free of hypertension, CVD, and diabetes at the baseline examination, in the Western New York Health Study (WNYHS). Baseline variables included socio-demographics, anthropometrics, blood pressure, biomarker data, major behavioural risk factors, and measu...
Abstract 2480: Olig2-dependent reciprocal shift in PDGF and EGF receptor signaling regulates tumor phenotype and mitotic growth in malignant glioma
Authors: Fanghui Lu, Mei Xin, Qing Richard Lu
Journal: Cancer Research (2018)

Abstract Malignant gliomas exhibit extensive heterogeneity and poor prognosis. Diverse molecular characteristics in gliomas represent a significant hurdle for effective therapy. We uncover that a population of Olig2+ cells function as glioma-propagating cells and is critical for tumor initiation of primary gliomas in mice. Elimination of Olig2+ mitotic progenitors blocks tumor initiation and progression. Intriguingly, deletion of Olig2 resulted in tumors that grow, albeit at a decelerated rate. Genome occupancy and expression profiling analyses reveal that OLIG2 directly activates cell proliferation machinery to promote tumorigenesis. Olig2 deletion causes a tumor phenotypic shift from an oligodendrocyte precursor-correlated proneural toward an astrocyte-associated gene expression pattern, manifest in downregulation of PDGF receptor-alpha and reciprocal upregulation of EGFR. Olig2 deletion further sensitizes glioma cells to EGFR inhibitors and extends animal lifespans. Our observations reveal that OLIG2 is a molecular arbiter of tumor phenotype plasticity that may underlie drug resistance, suggesting new strategies for enhancing EGFR drug sensitivity in glioma treatment. Citation Format: Fanghui Lu, Mei Xin, Qing Richard Lu. Olig2-dependent reciprocal shift in PDGF and EGF receptor signaling regulates tumor phenotype and mitotic growth in malignant glioma [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 2480.
Abstract 16546: microRNA(miR)-451 Regulates Cardiac Growth and Myocardial Reactive Oxidative Species (ROS) Level via Nrf2 and AMPK Pathways
Authors: Young-Eun Cho, Chongxu Zhang, Ravi Ranjan, John W Christman, Lei Xiao, Qiong Zhao
Journal: Circulation (2015)

The role of miR-451 in certain cardiac diseases was recently reported including ischemia/reperfusion and hypertrophic cardiomyopathy. Oxidative stress is known to involve in the above diseases. Currently the relationship between miR-451 and cardiac oxidative stress is unknown. We thus hypothesize that miR-451 act as a key mediator for cardiac hypertrophy via regulating myocardial ROS level and antioxidant pathways. We first compared the heart/body weight (HW/BW) ratio between age- &amp; gender-matched miR-451 knockout (KO) and wild-type (WT) mice. Increase of HW/BW was found in KO mice (6.1±0.1 vs 4.8±0.1 mg/g in WT, p&lt;0.01). Expression of fetal genes ANF (2.9-fold↑) and β-MHC (4.0-fold↑) was also significantly increased in KO hearts, as well as the ROS level (2.3-fold↑, p&lt;0.05) in KO hearts. Consistently, both the protein expression and activation levels of the oxidation-regulating gene Nrf2 decreased the same extent (~33%↓, p&lt;0.05) in KO hearts. In contrast, the protein expression of the direct antioxidants HO-1 and SOD3 were found significantly increased in KO hearts, suggesting a compensatory mechanism to quench the increased cardiac ROS. Since we previously showed that phosphorylation (p) of AMPKα was inhibited in cardiac hypertrophy, thus the p-AMPKα level was tested and found significantly (76%↓, p&lt;0.05) decreased in KO heart, consistent with the hypertrophy in KO heart. In order to further explore the relationship between Nrf2 and AMPKα, cultured adult rat ventricular myocytes (ARVM) was treated with an Nrf2 activator sulforaphane, which induced 1.4-fold increase in p-AMPKα (p&lt;0.01); whereas the AMPK activator AICAR didn’t affect Nrf2 expression in ARVM, suggesting Nrf2 is upstream from AMPK. When miR-451 mimics were overexpressed in cultured cardiac myocytes, Nrf2 was significantly increased (2.3-fold↑, p&lt;0.05) with overexpression of miR-451 mimics vs control, suggesting miR-451 regulates Nrf2 expression. Taken together, our data show that miR-451 activates cardiac Nrf2 and its downstream AMPK signaling pathway; whereas antioxidants HO-1 and SOD3 act as compensatory mechanism for increased cardiac ROS when miR-451 is defect. miR-451 plays a novel protective role against cardiac oxidative stress, and also mediates cardiac hypertrophy.
Exercise Improves Flow-Mediated Vasodilatation of Skeletal Muscle Arteries in Rats With Chronic Heart Failure
Authors: RémiVarin, PaulMulder, VincentRichard, FabienneTamion, CorinneDevaux, Jean-PaulHenry, FrançoiseLallemand, GuyLerebours, ChristianThuillez
Journal: Circulation (1999)

Background—Flow-mediated dilatation (FMD) of the peripheral arteries may be impaired in chronic heart failure (CHF), and this could contribute to the increased peripheral resistance and exercise intolerance that occur with this disease. Physical exercise improves the FMD of large conduit arteries in CHF, but whether a similar impairment also occurs in smaller arteries is unknown. The mechanisms of the changes in FMD after CHF or exercise are also unknown. Methods and Results—FMD was assessed in isolated, perfused, and preconstricted gracilis muscle arteries from sham-operated rats or CHF rats (coronary artery ligation) who were either sedentary or exercised (30-minute swimming period twice a day for 10 weeks, starting 7 days after ligation). In animals with hemodynamic and echographic signs of CHF, FMD was abolished and converted into vasoconstriction (percent change in diameter after 370 μL/min flow: sham, 42±5%; CHF, −4±3%; P<0.05). Exercise partially restored FMD (18±3%; P<0.05 versus CHF). In sham rat...
Abstract 3127: Peripherally induced Tregs or pTregs are the potent tolerance inducer for the growth and metastasis of cancer
Authors: Upendra P. Hegde, Nitya G. Chakraborty
Journal: Cancer Research (2018)

Abstract Regulatory T cells act as the most important tolerance inducer for the growth and metastasis of cancer. It remains a wonder how Tregs induce tolerance for the development of cancer. Previously we have shown with melanoma patients that, increase in pTreg cell number in blood are related to the poor prognosis of the disease. pTreg and iTreg are remarkably similar and significantly different in functionality from tTreg. Here, we worked with four melanoma patients two HLA A2 + and two HLA A2 negative. PBL and tumor cells were obtained from the patients with informed consent. Treg cells were generated in four different culture conditions: isolated from tumor +PBL IVC or peptides, Mart-1 A2 or Flu A2 pulsed DC + PBL IVC, with purified CD4 cells stimulated with anti CD3 and antiCD28 plus IL-2 with or without TGF-b. Here we show some phenotypic and functional characteristics of the induced Treg cells in cultures from the patients' PBL derived CD4+CD5- cells and analyzed those in separate CTL generation assays. We observed that induced Treg cells under different conditions do not uniformly express CD25, FoxP3, PDL-1 or CTLA 4 as the known surface markers. When analyzed for their functionality, with adjusted number of cells, in suppressing the anti tumor CTL response, a significant difference was observed. The most effective Tregs cells were found to be those isolated from autologous tumor +PBL IVC or from Mart-1 peptide pulsed IVC. Those cells completely blocked the CTL induction and secreted huge amount of IL-10 upon re-stimulation. Further analysis with these different types of induced Treg cells in terms of various gene expressions will be useful to find a target molecule to block such expansion of pTregs cells for better therapeutic outcome. Citation Format: Upendra P. Hegde, Nitya G. Chakraborty. Peripherally induced Tregs or pTregs are the potent tolerance inducer for the growth and metastasis of 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 3127.
Abstract 15537: Ezetimibe in Combination With Simvastatin Reduces Remnant-cholesterol Without Affecting Biliary Lipid Concentrations in Gallstone Patients
Authors: Paolo Parini, Osman Ahmed, Ulf Gustafsson, Staffan Sahlin, Camilla Pramfalk, Mats Eriksson
Journal: Circulation (2015)

Introduction: Large genetic studies have recently recognized remnant-cholesterol, defined as cholesterol in triglyceride (TG)-rich lipoproteins, as a causal risk factor for ischemic heart disease and low grade inflammation, independently of HDL-cholesterol. NPC1L1 in the intestine is the target of ezetimibe, but its function in the liver is still unknown. Hypothesis: To clarify the function of hepatic NPC1L1 in humans we performed a randomized, single-blind, placebo-controlled study and investigated molecular changes in lipoprotein, lipid and carbohydrate metabolism secondary to combined inhibition of cholesterol synthesis and intestinal cholesterol absorption. Methods: Forty cholesterol gallstone patients (13 men and 27 women) received 80 mg/day simvastatin, 10 mg/day ezetimibe, or a combination of simvastatin and ezetimibe, or placebo for four weeks. Plasma, bile and liver biopsies were collected. Results: The first results showed that ezetimibe treatment alone or in combination with simvastatin did not increase the % molar concentration of cholesterol in bile nor blunted the decrease due to cholesterol synthesis inhibition. Combination therapy led to a 70% decrease in cholesteryl esters (p&lt;0.001) and a 50% decrease in TG (p&lt;0.01) in the core of TG-rich lipoproteins. Negative changes in fasting insulin, c-peptide, or glucose concentrations were not observed. The dramatic changes in the core of TG-rich lipoprotein were not seen in subjects treated with simvastatin or ezetimibe alone, and were not paralleled by changes in HDL-cholesterol. Conclusions: The expected increase in biliary cholesterol following treatment with ezetimibe does not occur in humans, suggesting different functions of NPC1L1 (or ezetimibe action) in the liver and intestine. The results also help to explain why ezetimibe associated to simvastatin was more effective in reducing CVD events in the diabetic patients (IMPROVE-IT), known to have increased levels of TG-rich lipoproteins.
Energetically Optimal Left Ventricular Pressure for the Failing Human Heart
Authors: HidetsuguAsanoi, TomokiKameyama, ShinjiIshizaka, TakashiNozawa, HiroshiInoue
Journal: Circulation (1996)

Background An energy-starved failing heart would benefit from more effective transfer of the mechanical energy of ventricular contraction to blood propulsion. However, the energetically optimal loading conditions for the failing heart are difficult to establish. In the present study, we analyzed the optimal left ventricular pressure to achieve maximal mechanical efficiency of the failing heart in humans. Methods and Results We determined the relation between left ventricular pressure-volume area and myocardial oxygen consumption per beat (Vo2), stroke work, and mechanical efficiency (stroke work/Vo2) in 13 patients with different contractile states. We also calculated the optimal end-systolic pressure that would theoretically maximize mechanical efficiency for a given end-diastolic volume and contractility. Left ventricular pressure-volume loops were constructed by plotting the instantaneous left ventricular pressure against the left ventricular volume at baseline and during pressure loading. The contract...
Importance of Atrial Compliance in Cardiac Performance
Authors: Hiroyukisuga
Journal: Circulation Research (1974)

Effects of changes in atrial compliance on cardiac performance were analyzed using a circulatory analog model. The atrium was assumed to be a noncontracting chamber with a constant compliance. It connected the venous return system, which was represented by mean circulatory filling pressure and a venous return resistance in accordance with Guyton's concept, with the ventricle, which was characterized by a time-varying elasticity. Atrial compliance was increased from near zero to a value at which atrial volume was twice ventricular stroke volume, while the parameters of ventricular contractility were kept unchanged. Cardiac output increased from 2,400 to 3,240 ml/min with increases in atrial compliance from 0.1 to 20 ml/mm Hg (venous return resistance 0.1 mm Hg sec/ml), whereas mean atrial pressure simultaneously decreased from 3.0 to 2.2 mm Hg. This result indicates that cardiac performance in terms of the cardiac output-mean atrial pressure relationship was markedly improved by increases in atrial complia...
Abstract 172: Collagen increases tumorigenic characteristics of papillary thyroid cancer cells harboring BRAFV600Emutations
Authors: Anna Sharabura, Jonathan Jenkins, Laura MacDonald
Journal: Cancer Research (2018)

Abstract Thyroid cancer is the most common endocrine cancer, and incidence is increasing worldwide. Thyroid cancer can be classified as either well differentiated or poorly differentiated. Of well-differentiated thyroid cancers, papillary thyroid cancer is most common, and is associated with activating BRAF mutations. While our understanding of the genetic basis for thyroid cancer is fairly extensive, less is known about how the tumor microenvironment alters characteristics of tumor cells. Recently, Jolly and others reported that papillary thyroid tumors derived from cells harboring BRAFV600E mutations and PTEN deletions are enriched with fibrillar collagen. Notably, overexpression of collagen was also associated with decreased survival and worse overall prognosis in patient samples. In this study, we investigated whether growth on collagen enhanced tumorigenic characteristics of papillary thyroid cancer cell lines with BRAFV600E mutations. Three distinct cell lines derived from mouse papillary thyroid cancer tumors were grown in the presence and absence of collagen and assessed for changes in morphology, proliferation, and drug resistance. Interestingly, our results suggest that growth on collagen contributes to a more mesenchymal morphology, increased proliferation, and decreased sensitivity to chemotherapy drugs. These and other results implicate an important role for collagen in the progression of thyroid cancer. Citation Format: Anna Sharabura, Jonathan Jenkins, Laura MacDonald. Collagen increases tumorigenic characteristics of papillary thyroid cancer cells harboring BRAFV600Emutations [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 172.