tbuckley/cabot-search huggingface dataset:
Abstract 12532: The Tandem Zinc Finger mRNA Binding Protein, Tristetraprolin, is a Novel Regulator of Cardiac Fatty Acid Metabolism Through its Effect on PPARa
Authors: Hsiang-Chun Chang, Tatsuya Sato, Konrad T Sawicki, Meng Shang, Chunlei Chen, Hossein Ardehali
Journal: Circulation (2016)

Introduction: Altered substrate utilization has been described in type II diabetes and heart failure (HF), but current therapies do not target the metabolic derangements in these disorders. Identification of novel pathways regulating cellular metabolism could facilitate the development of new therapies. Tristetraprolin (TTP) is a tandem zinc finger protein that binds to AU-rich regions in the 3’ untranslated region (UTR) of mRNA molecules and causes their degradation. Its expression is reduced in patients with diabetes, and its cellular level is regulated by mTOR, a key protein involved in cellular metabolism. Furthermore, the yeast homolog of TTP has been suggested to play a role in metabolism. Thus, we hypothesized that TTP regulates cardiac metabolism and plays a role in the development of HF through its effects on substrate utilization in the heart. Results: We first assessed the effects of TTP modulation on cellular substrate utilization, and found that TTP downregulation in cultured cardiomyocytes resulted in higher palmitate uptake and oxidation while its overexpression had the opposite effect. Since TTP regulates its targets at the mRNA level, we studied the mRNA levels of all genes involved in lipid metabolism, and found that only PPARα mRNA to be significantly increased with TTP downregulation. Furthermore, we demonstrated that TTP physically interacts with PPARα mRNA, and the activity of a luciferase reporter harboring full-length PPARα 3’UTR is increased with TTP downregulation. Additionally, PPARα mRNA is stabilized with TTP knockdown. We then studied the role of TTP in cardiac metabolism using mice with cardiac-specific TTP knockout. Although cardiac-specific TTP knockout mice had normal cardiac function at baseline, they displayed higher fatty acid utilization compared to wild type littermate control in an ex vivo heart perfusion setup. We also demonstrated a significantly higher TTP levels in failing human and mouse cardiac samples, suggesting that TTP levels are altered in HF. Conclusion: Our results demonstrate that TTP is a novel regulator of cardiac fatty acid metabolism through its effect on PPARα, and that its levels are increased in HF. Thus, modulation of TTP may be a viable therapeutic approach for HF.
Linking sustainability to the healthy eating patterns of the Dietary Guidelines for Americans: a modelling study
Authors: Nicole Tichenor Blackstone, Naglaa H El-Abbadi, Margaret S McCabe, Timothy S Griffin, Miriam E Nelson
Journal: The Lancet Planetary Health (2018)

BackgroundEvidence-based nutrition policy is a key mechanism to promote planetary health. In the USA, the Dietary Guidelines for Americans are the foundation of nutrition policy and guide more than US$80 billion in federal spending. Recent attempts have been made to incorporate sustainability into the development of the Dietary Guidelines. However, the sustainability of the 2015–20 Dietary Guidelines remains unclear; research has not yet assessed the environmental impacts of the distinct healthy patterns recommended by the policy.MethodsIn this modelling study done at the University of New Hampshire (Durham, NH, USA), we analysed the healthy US-style (US), healthy Mediterranean-style (MED), and healthy vegetarian (VEG) patterns recommended in the 2015–20 Dietary Guidelines for Americans. Food groups and subgroups consisted of 321 commonly consumed foods, with group composition predetermined by the US Department of Agriculture. We compiled and used multiple datasets to assign environmental burdens to foods, focusing on six impact categories of policy importance: global warming potential, land use, water depletion, freshwater and marine eutrophication, and particulate matter or respiratory organics. We did life cycle impact assessments for each of the three diet patterns and compared the six impact categories between the patterns. We also analysed the proportion contribution of the food groups to each impact category in each of the diet patterns.FindingsThe US and MED patterns had similar impacts, except for freshwater eutrophication. Freshwater eutrophication was 31% lower in the US pattern than the MED pattern, primarily due to increased seafood in the MED pattern. All three patterns had similar water depletion impacts, with fruits and vegetables as major contributors. For five of the six impacts, the VEG pattern had 42–84% lower burdens than both the US and MED patterns. Reliance on plant-based protein and eggs in the VEG pattern versus emphasis on animal-based protein in the other patterns was a key driver of differences, as was a lower overall protein foods recommendation in the VEG pattern.InterpretationThe recommended patterns in the Dietary Guidelines for Americans might have starkly different impacts on the environment and other dimensions of human health beyond nutrition. Given the scale of influence of the Dietary Guidelines for Americans on food systems, incorporating sustainability into their development has the potential to have great benefit in terms of long-term food security.FundingNone.
Importance of Variant Interpretation in Whole-Exome Molecular Autopsy
Authors: Garrett W. Shanks, David J. Tester, Jaeger P. Ackerman, Michael A. Simpson, Elijah R. Behr, Steven M. White, Michael J. Ackerman
Journal: Circulation (2018)

Potentially lethal cardiac channelopathies/cardiomyopathies may underlie a substantial portion of sudden unexplained death in the young (SUDY). The whole-exome molecular autopsy represents the latest approach to postmortem genetic testing for SUDY. However, proper variant adjudication in the setting of SUDY can be challenging.From January 2012 through December 2013, 25 consecutive cases of SUDY from 1 to 40 years of age (average age at death 27±5.7 years; 13 white, 12 black) from Cook County, Illinois, were referred after a negative (n=16) or equivocal (n=9) conventional autopsy. A whole-exome molecular autopsy with analysis of 99 sudden death-susceptibility genes was performed. The predicted pathogenicity of ultrarare, nonsynonymous variants was determined using the American College of Medical Genetics guidelines.Overall, 27 ultrarare nonsynonymous variants were seen in 16/25 (64%) victims of SUDY. Among black individuals, 9/12 (75%) had an ultrarare nonsynonymous variant compared with 7/13 (54%) white individuals. Of the 27 variants, 10 were considered pathogenic or likely pathogenic in 7/25 (28%) individuals in accordance with the American College of Medical Genetics guidelines. Pathogenic/likely pathogenic variants were identified in 5/16 (31%) of autopsy-negative cases and in 2/6 (33%) victims of SUDY with equivocal findings of cardiomyopathy. Overall, 6 pathogenic/likely pathogenic variants in 4/25 (16%) cases were congruent with the phenotypic findings at autopsy and therefore considered clinically actionable.Whole-exome molecular autopsy with gene-specific surveillance is an effective approach for the detection of potential pathogenic variants in SUDY cases. However, systematic variant adjudication is crucial to ensure accurate and proper care for surviving family members.
Abstract 4363: Pharmacologic targeting of Gq reveals new pathways in uveal melanoma
Authors: Michael D. Onken, Carol M. Makepeace, Shiqi Wang, Kevin M. Kaltenbronn, Stanley M. Kanai, Tom J. Broekelmann, John A. Cooper, Kendall J. Blumer
Journal: Cancer Research (2018)

Abstract Constitutively active G protein α-subunits are oncogenic drivers of several cancers, most notably in uveal (eye) melanoma (UM), which have constitutively activating mutations in GNAQ(Gαq) or GNA11(Gα11) in over 90% of tumors. Therapeutic intervention by targeted inhibition of constitutively active Gα subunits in cancer has yet to be achieved. Here we show that constitutively active Gαq in UM cells can be targeted by the cyclic depsipeptide FR900359 (FR). FR inhibits GDP/GTP exchange allosterically to trap constitutively active Gαq in inactive GDP-bound Gαβγ heterotrimers, and allosteric inhibition of other Gα subunits can be achieved by introduction of an FR binding site. In UM cells driven by constitutively active Gαq, FR inhibits second messenger signaling, arrests proliferation and reinstates melanocytic differentiation. At higher doses, FR also induces apoptosis. FR has no effect on BRAF-driven UM cells. FR promotes UM cell differentiation by reactivating polycomb repressive complex 2 (PRC2)-mediated gene silencing, antagonized by a heretofore unrecognized effector system of constitutively active Gαq in UM. Constitutively active Gαq and PRC2 therefore provide important therapeutic targets for UM. Further, the development of FR analogs specific for other Gα subunit subtypes may provide novel therapeutic approaches for diseases driven by constitutively active Gα subunits or multiple G protein-coupled receptors where targeting a single receptor is ineffective. Citation Format: Michael D. Onken, Carol M. Makepeace, Shiqi Wang, Kevin M. Kaltenbronn, Stanley M. Kanai, Tom J. Broekelmann, John A. Cooper, Kendall J. Blumer. Pharmacologic targeting of Gq reveals new pathways in uveal melanoma [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 4363.
Reduced Pulmonary Clearance of Endothelin-1 Contributes to the Increase of Circulating Levels in Heart Failure Secondary to Myocardial Infarction
Authors: JocelynDupuis, PeterCernacek
Journal: Circulation (1998)

Background—The pulmonary vascular bed is a major site for endothelin-1 (ET-1) clearance. A reduced clearance could contribute to the increase in circulating ET-1 levels found in heart failure (HF). We therefore evaluated the effect of HF on pulmonary ET-1 clearance and on plasma ET-1 concentrations. Methods and Results—Rats with myocardial infarction (n=24) were compared with sham-operated rats (n=22). The lungs were isolated and perfused at a constant flow rate of 10 mL/min. Pulmonary ET-1 clearance was measured by the single-bolus indicator-dilution technique with 125I-labeled ET-1. Infarct rats developed HF with mild pulmonary hypertension. ET-1 extraction was reduced by HF from 63±1.5% to 41±4.5% (mean±SEM, P<0.001). Mixed venous (MV) and aortic ET-1 levels doubled with HF. There was a plasma ET-1 gradient across the lungs of sham rats (MV−aortic levels, 0.21±0.12 pg/mL) but not in lungs of HF rats (0.01±0.17 pg/mL). Plasma ET-1 levels correlated closely and inversely with ET-1 extraction (P<0.001). C...
Noninvasive ventilation for acute respiratory failure: the next step is to know when to stop
Authors: Óscar Peñuelas, Andrés Esteban
Journal: European Respiratory Journal (2018)

Noninvasive ventilation (NIV) is commonly used in the acute care setting for critically ill patients with acute respiratory failure (ARF), and has gained much academic, research and clinical interest based on the marked decrease in clinical outcomes (intubation and mortality) compared with usual care in the intensive care unit (ICU) setting. A definitive decision to interrupt an attempt at noninvasive ventilation in critical patients presents a clinical challenge that modifies the outcome <http://ow.ly/Xrxo30l2D8E>
Abstract 2986: E-cadherin/ROS1 inhibitor synthetic lethality in breast cancer
Authors: Ilirjana Bajrami, Rebecca Marlow, Marieke van de Ven, Rachel Brough, Helen N. Pemberton, Jessica Frankum, Fei Fei Song, Rumana Rafiq, Asha Konde, Malini Menon, James Campbell, Aditi Gulati, Rahul Kumar, Stephen J. Pettitt, Mark D. Gurden, Marta Llorca Cardenosa, Irene Chong, Patrycja Gazinska, Fredrik Wallberg, Elinor J. Sawyer, Lesley-Ann Martin, Mitch Dowsett, Spiros Linardopoulos, Colm Ryan, Patrick W. Derksen, Jos Jonkers, Andrew N.J. Tutt, Alan Ashworth, Christopher J. Lord
Journal: Cancer Research (2018)

Abstract The E-cadherin (CDH1) tumour suppressor gene encodes a calcium-dependent cell-cell adhesion glycoprotein, which has roles in maintaining cell polarity, differentiation, cell migration and survival. E-cadherin dysfunction is a feature common to many epithelial tumours, with the highest incidence occurring in diffuse gastric cancer (50%) and lobular breast cancer (63%) and can occur via CDH1 mutation, deletion or epigenetic silencing. Although E-cadherin dysfunction is relatively common, precision medicine approaches that exploit this pathogenic alteration are not yet available. Using genetic and small-molecule perturbation screens in breast tumour cells with CRISPR-Cas9 engineered CDH1 mutations, we identified a synthetic lethal interaction between E-cadherin deficiency and inhibition of the tyrosine kinase ROS1. Using data from large-scale genetic screens in molecularly diverse breast tumour cell lines, we found that the E-cadherin/ROS1 synthetic lethality was not only robust in the face of considerable molecular heterogeneity but was also elicited with clinical ROS1 inhibitors including foretinib and crizotinib. ROS1 inhibitors induced mitotic abnormalities and multinucleation in E-cadherin defective cells, phenotypes that were associated with a defect in cytokinesis and aberrant p120-catenin phosphorylation and localisation. In vivo, ROS1 inhibitors produced profound anti-tumour effects in multiple, distinct, models of E-cadherin defective breast cancer. This data therefore provides the pre-clinical rationale for assessing ROS1 inhibitors such as the licensed drug crizotinib in appropriately stratified patients. Citation Format: Ilirjana Bajrami, Rebecca Marlow, Marieke van de Ven, Rachel Brough, Helen N. Pemberton, Jessica Frankum, Fei Fei Song, Rumana Rafiq, Asha Konde, Malini Menon, James Campbell, Aditi Gulati, Rahul Kumar, Stephen J. Pettitt, Mark D. Gurden, Marta Llorca Cardenosa, Irene Chong, Patrycja Gazinska, Fredrik Wallberg, Elinor J. Sawyer, Lesley-Ann Martin, Mitch Dowsett, Spiros Linardopoulos, Colm Ryan, Patrick W. Derksen, Jos Jonkers, Andrew N.J. Tutt, Alan Ashworth, Christopher J. Lord. E-cadherin/ROS1 inhibitor synthetic lethality in breast 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 2986.
Abstract 1384: The epigenetic modifier EZH2 represses antitumor immunity in melanoma
Authors: Jessamy Tiffen, Elena Shklovskaya, Stuart Gallagher, Dilini Gunatilake, Peter Hersey
Journal: Cancer Research (2018)

Abstract Despite major advances in immuno- and targeted therapies for metastatic melanoma, not all patients respond to such treatments and the development of therapy resistance remains a key obstacle. Novel targets are required and the epigenetic modifier EZH2 may represent such a solution. EZH2 methylates histones causing chromatin compaction and silencing of gene expression. Aberrant EZH2 in cancer results in the silencing of hundreds of tumor-suppressor genes that would normally constrain cancer growth, and 26% of patients in the Australian Melanoma Genome Project (AMGP) display such abnormal EZH2. Using ChIP-seq and microarrays to reveal downstream EZH2 target genes, we identified many tumor-suppressor genes including some that play a role in the antitumor immune response. Interestingly, xenografts in immune-deficient NOD SCID mice showed no significant inhibition in tumor growth when treated with an EZH2 inhibitor. However, growth inhibition was achieved when the same experiment was performed in nude mice, which retain some mediators of innate immunity. The effect of EZH2 overexpression in melanoma on immune-mediated rejection was studied in an inducible in vivo model. Subcutaneous B16 tumors expressing model antigen were initially rejected but relapsed in the majority of immunodeficient mice transferred with CD4 T cells. Long-term (120-day) survival was reduced from 40% to 22% if the tumors also overexpressed EZH2. Our studies suggest that aberrant EZH2 in melanoma drives aggressive disease via suppression of genes that would normally trigger the antitumor immune response. The progression of several preclinical, small-molecule inhibitors of EZH2 remains promising. Citation Format: Jessamy Tiffen, Elena Shklovskaya, Stuart Gallagher, Dilini Gunatilake, Peter Hersey. The epigenetic modifier EZH2 represses antitumor immunity in melanoma [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 1384.
Abstract 17: In situ immune expression signatures before and after ipilimumab therapy for relapsed acute myeloid leukemia after allogeneic stem cell transplantation
Authors: Pavan Bachireddy, Matthew S. Davids, Michael S. Rooney, Michaela Bowden, Chensheng W. Zhou, Scott J. Rodig, Vincent Ho, Joseph Antin, John Koreth, Edwin Alyea, Robert J. Soiffer, Catherine J. Wu
Journal: Clinical Cancer Research (2017)

Abstract Immune evasion may facilitate hematologic relapse after allogeneic hematopoietic stem cell transplantation (allo-SCT). We recently demonstrated that CTLA4 blockade with ipilimumab reinvigorates a graft-versus-leukemia effect to induce complete remissions of acute myeloid leukemia (AML) relapsing after allo-SCT. Here, we hypothesized that immune subpopulation dynamics and activation states inferred from in situ gene expression changes within the leukemic microenvironment are informative of clinical outcome. We undertook an in situ transcriptomic characterization of paired, pre/post ipilimumab leukemic biopsies from five samples with relapsed, extramedullary AML. We performed a response-to-treatment expression analysis for each patient and found three immune patterns corresponding to three clinical response patterns following ipilimumab (durable response, relapse, and primary resistance). Durable responses were characterized by a diverse infiltration of activated cytotoxic T lymphocytes, B cells, and macrophages. In contrast, primary resistance was associated with both marked infiltration of CD8 T cells deficient in T-cell receptor signaling, activation, or cytolytic activity and absent infiltration of other immune effectors. Interestingly, the sample with transient response and eventual relapse demonstrated pre- and post-treatment immunologically “inflamed” states that were strongly downregulated during clinical relapse. In situ gene expression analyses of leukemic biopsies before and after ipilimumab therapy suggest that specific patterns of immune population dynamics and activation states underlie diverse clinical outcomes. Citation Format: Pavan Bachireddy, Matthew S. Davids, Michael S. Rooney, Michaela Bowden, Chensheng W. Zhou, Scott J. Rodig, Vincent Ho, Joseph Antin, John Koreth, Edwin Alyea, Robert J. Soiffer, Catherine J. Wu. In situ immune expression signatures before and after ipilimumab therapy for relapsed acute myeloid leukemia after allogeneic stem cell transplantation [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr 17.
Egg Consumption and Risk of Heart Failure in the Physicians’ Health Study
Authors: LucDjoussé, J. MichaelGaziano
Journal: Circulation (2008)

Background— Reduction in dietary cholesterol is widely recommended for the prevention of cardiovascular disease. Although eggs are important sources of dietary cholesterol and other nutrients, little is known about the association between egg consumption and heart failure (HF) risk. Methods and Results— In a prospective cohort study of 21 275 participants from the Physicians’ Health Study I, we examined the association between egg consumption and the risk of HF. Egg consumption was assessed with the use of a simple abbreviated food questionnaire, and we used Cox regression to estimate relative risks of HF. After an average follow-up of 20.4 years, a total of 1084 new HF cases occurred in this cohort. Although egg consumption up to 6 times per week was not associated with incident HF, egg consumption of ≥7 per week was associated with an increased risk of HF. Compared with subjects who reported egg consumption of <1 per week, hazard ratios (95% confidence intervals) for HF were 1.28 (1.02 to 1.61) and 1.64...
Impaired Function of Cloth-Covered Starr-Edwards Mitral Valve Prosthesis
Authors: Ernestcraige, Peterhutchin, Richardsutton
Journal: Circulation (1970)

Malfunction of a cloth-covered Starr-Edwards mitral valve prosthesis (6300 series) was suspected because of phonocardiographic abnormalities. A prolonged interval from aortic closure to opening of the mitral ball suggested an impediment to movement of the ball. This was confirmed by catheterization and cinefluorography. At autopsy the impaired ball movement was found to be due to thrombus buildup on the outflow face of the mitral valve orifice. It is suggested that frequent postoperative phonocardiographic observations may be useful in detecting malfunction of valvular prostheses.
Risk Stratification After Acute Myocardial Infarction by Heart Rate Turbulence
Authors: PetraBarthel, RaphaelSchneider, AxelBauer, KurtUlm, ClausSchmitt, AlbertSchömig, GeorgSchmidt
Journal: Circulation (2003)

Background— Retrospective postinfarction studies revealed that decreased heart rate turbulence (HRT) indicates increased risk for subsequent death. This is the first prospective study to validate HRT in a large cohort of the reperfusion era. Methods and Results— One thousand four hundred fifty-five survivors of an acute myocardial infarction (age <76 years) in sinus rhythm were enrolled. HRT onset (TO) and slope (TS) were calculated from Holter records. Patients were classified into the following HRT categories: category 0 if both TO and TS were normal, category 1 if either TO or TS was abnormal, or category 2 if both TO and TS were abnormal. The primary end point was all-cause mortality. During a follow-up of 22 months, 70 patients died. Multivariately, HRT category 2 was the strongest predictor of death (hazard ratio, 5.9; 95% CI, 2.9 to 12.2), followed by left ventricular ejection fraction (LVEF) ≤30% (4.5; 2.6 to 7.8), diabetes mellitus (2.5; 1.6 to 4.1), age ≥65 years (2.4; 1.5 to 3.9), and HRT categ...