tbuckley/cabot-search huggingface dataset:
Abstract LB-080: Discovery of an unconventional form of cell-death in colorectal cancer
Authors: Amit K. Tiwari, Haneen Amawi, Karthikeyan Chandrabose, Paul Erhardt, Piyush Trivedi
Journal: Cancer Research (2018)

Abstract We recently discovered unique, structurally constrained 4-pyridinyl - containing compounds that induce a form of caspase-independent cell death in colorectal cancer (CRC) cells. This was characterized by the simultaneous induction of dysregulated macropinocytosis and macroautophagy, a type of cell death we have termed ‘methuophagy' (this neologism arises from the Greek ‘methuo', to drink to intoxication and ‘phagy', self-eating). Our new class of small molecular probes (BAPT analogues) do not induce cell death via activation of the well characterized classical apoptotic pathways. In contrast, our BAPT compounds cause methuophagy by inducing the formation and accumulation of fluid-filled, heterogeneous vacuoles and autophagosomes, resulting in metabolic failure, loss of membrane integrity, and detachment of cells from the substratum. Methuophagy produces extensive autophagy without cell shrinkage, chromatin condensation, alteration of mitochondrial membrane potential or nuclear membrane damage. The optimization of the BAPT structure led to the discovery of BAPT-27, which has nanomolar potency in inducing methuophagy in broad spectrum of CRC cell lines and may serve as a prototype for a new class of drugs. BAPT-27 produces methuophagy and surmounts MDR in CRC cells independent of Ras, p53 or other apoptotic protein (i.e. Bax, Bak) or expression of ATP-binding cassette (ABC) transporters. Furthermore, BAPT-27 is non-toxic in normal cells and zebrafish. Based on our findings, we postulate that the induction of methuophagy by BAPT-27 produces endolysosomal trafficking defects that prevent recycling of lysosomes and cause lysosome-to-nucleus signaling defect, a mechanism that disturb cellular clearance and energy metabolism. The selected compounds will allow us to understand the biology of methuophagy-induced cell death and will be particularly beneficial for treatment of patients with apoptotic-resistant and aggressive CRCs. Citation Format: Amit K. Tiwari, Haneen Amawi, Karthikeyan Chandrabose, Paul Erhardt, Piyush Trivedi. Discovery of an unconventional form of cell-death 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 LB-080.
Abstract 16504: Synergist Actions of the Bispecific Peptide, NPA7, and Furosemide in Experimental Heart Failure
Authors: Laura Meems, Yang Chen, Gail Harty, Jerry Harders, Seetha Iyer, Denise Heublein, John Burnett
Journal: Circulation (2017)

NPA7 represents a first-in-class dual-receptor activating designer peptide with cardiorenal protective and anti-renin-angiotensin-aldosterone system (RAAS) actions. We studied the renoprotective pr...
Abstract P046: What’s Good for the Heart is Good for the Mind: Neurocognitive Function and American Heart Association (AHA) Life’s Simple 7’s: Results from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL)
Authors: Hector M Gonzalez, Wassim Tarraf, Alvaro Camacho, Ellen Grober, Amber Pirzada, Tatjana Rundek, Clinton B Wright, Martha L Daviglus, Thomas H Mosley
Journal: Circulation (2013)

BACKGROUND: Favorable levels of 7 CVD risk factors or health behaviors: cholesterol, blood pressure, body mass index, glucose, not smoking, exercise, and healthy diet (aka: AHA Life’s Simple 7’s, L...
Neurological Symptoms in US Government Personnel in Cuba
Authors: Robert Emerson Bartholomew
Journal: JAMA (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Abstract 2155: Modeling therapeutic response in BRAF V600-mutant melanoma using patient-derived xenografts
Authors: Tianshu Feng, Javad Golji, Ailing Li, Xiamei Zhang, David Ruddy, Darrin Stuart, Matthew Meyer
Journal: Cancer Research (2018)

Abstract Approximately 50% of metastatic melanoma harbor oncogenic mutations of BRAF, resulting in constitutive activation of the MAPK signaling pathway. Treatment using BRAF and MEK inhibitor combination significantly improved survival in patients with BRAF V600-mutant melanoma. However, the duration of response remains limited as most patients develop resistance. Previously, our group established a collection of patient derived xenografts (PDXs), and conducted a PDX clinical trial using a 1x1x1 experimental design. The PDX clinical trial showed that BRAF V600-mutant melanoma models varied in their response to BRAF and MEK inhibitors, similar to observations in the clinical setting. Therefore, we sought to elucidate the mechanisms governing differential responses to MAPK inhibition in vivo. The PDX models were classified into complete and partial responders based on their sensitivity to BRAF and MEK inhibitors. Using this classification, we characterized the downstream signaling associated with therapeutic response. Whereas complete responders showed almost full suppression of MAPK signaling, partial responders showed heterogeneous levels of MAPK signaling upon BRAF and MEK inhibition. Ongoing work seeks to identify determinants of therapeutic response using biased and unbiased approaches, in an effort to inform combination strategies that improve survival in patients with BRAF V600-mutant melanoma. Citation Format: Tianshu Feng, Javad Golji, Ailing Li, Xiamei Zhang, David Ruddy, Darrin Stuart, Matthew Meyer. Modeling therapeutic response in BRAF V600-mutant melanoma using patient-derived xenografts [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 2155.
Abstract 3819: INCAGN02385 is an antagonist antibody targeting the co-inhibitory receptor LAG-3 for the treatment of human malignancies
Authors: David Savitsky, Rebecca Ward, Christina Riordan, Cornelia Mundt, Shawn Jennings, Joe Connolly, Mark Findeis, Michele Sanicola, Dennis Underwood, Horacio Nastri, Peggy Scherle, Gregory Hollis, Reid Huber, Robert Stein, Marc van Dijk, Nicholas S. Wilson
Journal: Cancer Research (2018)

Abstract Lymphocyte activation gene 3 (LAG-3) is a cell surface receptor that negatively regulates antigen-specific T cell responses. LAG-3 expression is generally restricted to populations of recently activated and chronically stimulated exhausted T cells, and is often correlated with general T cell dysfunction across several human malignancies. Accordingly, the LAG-3 pathway has been identified as a potential barrier to productive tumor-specific T cell immunity generated by PD-1/PD-L1 blockade. The antitumor activity from targeting the LAG-3 pathway in preclinical models has provided further rationale for pharmacologic modulation of the LAG-3 axis in cancer patients. INCAGN02385 is an Fc-engineered IgG1κ antibody chosen for development based on its high-affinity binding to human LAG-3, cross-reactivity with cynomolgus monkey LAG-3, and ability to potently block LAG-3 binding with its MHC class II ligand. INCAGN02385 also enhances T cell responsiveness to TCR stimulation alone or in combination with PD-1/PD-L1 axis blockade. Evaluation of INCAGN02385 in cynomolgus monkeys was well-tolerated and demonstrated the expected pharmacokinetic profile. Altogether, these data support assessment of INCAGN02385 in patients with advanced or metastatic solid tumors. Citation Format: David Savitsky, Rebecca Ward, Christina Riordan, Cornelia Mundt, Shawn Jennings, Joe Connolly, Mark Findeis, Michele Sanicola, Dennis Underwood, Horacio Nastri, Peggy Scherle, Gregory Hollis, Reid Huber, Robert Stein, Marc van Dijk, Nicholas S. Wilson. INCAGN02385 is an antagonist antibody targeting the co-inhibitory receptor LAG-3 for the treatment of human malignancies [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 3819.
Randomized trial of ibrutinib vs ibrutinib plus rituximab in patients with chronic lymphocytic leukemia
Authors: Jan A. Burger, Mariela Sivina, Nitin Jain, Ekaterina Kim, Tapan Kadia, Zeev Estrov, Graciela M. Nogueras-Gonzalez, Xuelin Huang, Jeffrey Jorgensen, Jianling Li, Mei Cheng, Fong Clow, Maro Ohanian, Michael Andreeff, Thomas Mathew, Philip Thompson, Hagop Kantarjian, Susan O’Brien, William G. Wierda, Alessandra Ferrajoli, Michael J. Keating
Journal: Blood (2018)
Evidence for Preconditioning by Isoflurane in Coronary Artery Bypass Graft Surgery
Authors: Denis Belhomme, Jacqueline Peynet, Moez Louzy, Jean-Marie Launay, Masafumi Kitakaze, Philippe Menasché
Journal: Circulation (1999)

Background —Experimentally, isoflurane, a commonly used volatile anesthetic agent, mimics the cardioprotective effects of ischemic preconditioning via a mechanism that could involve the activation of protein kinase C. The present study was designed to assess the clinical relevance of this observation in patients undergoing elective CABG. Methods and Results —Twenty patients were included in the study. In 10 of them, preconditioning was elicited after the onset of cardiopulmonary bypass via a 5-minute exposure to isoflurane (2.5 minimum alveolar concentration), followed by a 10-minute washout before aortic cross-clamping and cardioplegic arrest. Ten case-matched control patients underwent an equivalent period (15 minutes) of prearrest isoflurane-free bypass. Outcome measurements included troponin I and creatine kinase–MB isoenzyme (until the third postoperative day) levels and the activity of ecto-5′-nucleotidase, which contributes to adenosine production and is considered to be a reporter of protein kinase C activation, as assessed in right atrial biopsy samples taken before bypass and at the end of the preconditioning protocol (or after 15 minutes of bypass in control patients). Aortic cross-clamping times did not differ between the 2 groups: 52±14 and 48±14 minutes (mean±SD) in control and isoflurane-preconditioned patients, respectively. Likewise, prebypass values of ecto-5′-nucleotidase were similar in control (3.54±0.86 nmol · mg protein −1 · min −1 ) and isoflurane-treated (2.98±1.08 nmol · mg protein −1 · min −1 ) patients. The values subsequently remained unchanged in control patients (3.62±0.94 nmol · mg protein −1 · min −1 ), whereas they significantly increased after isoflurane preconditioning (4.74±0.50 nmol · mg protein −1 · min −1 ; P &lt;0.002 versus baseline values, P &lt;0.004 versus time-matched values in control patients). This was paralleled by a consistently smaller release of troponin I, which yielded an area under the curve and a peak value of 204±147 ng · mL −1 · min −1 and 3.98±2.83 ng/mL, respectively, versus 284±136 ng · mL −1 · min −1 and 5.88±3.64 ng/mL, respectively, in control patients. The release of creatine kinase–MB featured a similar pattern. There were no adverse effects related to isoflurane. Conclusions —These data support a cardioprotective effect of isoflurane and, more generally, demonstrate the feasibility of pharmacologically preconditioning the human heart during cardiac surgery.
SNAP23 regulates BAX-dependent adipocyte programmed cell death independently of canonical macroautophagy
Authors: Daorong Feng, Dulguun Amgalan, Rajat Singh, Jianwen Wei, Jennifer Wen, Tszki Peter Wei, Timothy E McGraw, Richard N Kitsis, Jeffrey E Pessin
Journal: Journal of Clinical Investigation (2018)

The t-SNARE protein SNAP23 conventionally functions as a component of the cellular machinery required for intracellular transport vesicle fusion with target membranes and has been implicated in the regulation of fasting glucose levels, BMI, and type 2 diabetes. Surprisingly, we observed that adipocyte-specific KO of SNAP23 in mice resulted in a temporal development of severe generalized lipodystrophy associated with adipose tissue inflammation, insulin resistance, hyperglycemia, liver steatosis, and early death. This resulted from adipocyte cell death associated with an inhibition of macroautophagy and lysosomal degradation of the proapoptotic regulator BAX, with increased BAX activation. BAX colocalized with LC3-positive autophagic vacuoles and was increased upon treatment with lysosome inhibitors. Moreover, BAX deficiency suppressed the lipodystrophic phenotype in the adipocyte-specific SNAP23-KO mice and prevented cell death. In addition, ATG9 deficiency phenocopied SNAP23 deficiency, whereas ATG7 deficiency had no effect on BAX protein levels, BAX activation, or apoptotic cell death. These data demonstrate a role for SNAP23 in the control of macroautophagy and programmed cell death through an ATG9-dependent, but ATG7-independent, pathway regulating BAX protein levels and BAX activation.
Abstract 2020: SAHA and EGCG affect metastatic potential to varying degrees in three triple-negative breast cancer cell lines
Authors: Kayla A. Lewis
Journal: Cancer Research (2018)

Abstract Although triple-negative breast cancers (TNBC) have distinct molecular aberrations, tumors of the same histological grade may have dramatically different responses to the same therapy. TNBC tumors are basal-like, aggressive, and harbor a proclivity to metastasize to the brain and lungs. By modifying the cancer epigenome we have shown it is possible to reduce the metastatic potential of triple-negative breast cancer. Suberoylanilide hydroxamic acid (SAHA, clinically Vorinostat) is a histone deacetylase (HDAC) inhibitor, and epigallocatechin-3-gallate (EGCG) is a green tea polyphenol that acts as a DNA methyltransferase (DNMT) inhibitor. In combination, we found that 3 μM SAHA and 5 μM EGCG alter mammosphere formation, and the expression of E-cadherin and N-cadherin, which are genes involved in the epithelial-to-mesenchymal transition (EMT). Epigenetic enzyme activity was also assessed to determine if SAHA and EGCG were capable of modulating the functionality of DNMTs and HDACs. Because our previous work has identified a decrease in cellular viability with the combination of SAHA and EGCG, we aimed to investigate the effect on cell cycle arrest and genes involved in cell cycle progression. Our prior findings have indicated that the combination of SAHA and EGCG decreases the expression level of miR-221/222, which is known to directly inhibit translation of p27 and PTEN. p27 is involved in regulating the transition from G1 to S phase, and with the combination of SAHA and EGCG the expression of p27 was significantly increased, suggesting potential cell cycle arrest between G1 and S phase. Because the PTEN/Akt pathway plays a role in progression from G1 to S phase through p-Akt, we also investigated changes in the expression of PTEN with SAHA and EGCG. Together our findings are reflective of tumor heterogeneity; despite the same breast cancer subtype they respond differently to chemotherapeutics. Further studies will include research into specific epigenetic modifications associated with the epithelial-like reversion seen in this project. Citation Format: Kayla A. Lewis. SAHA and EGCG affect metastatic potential to varying degrees in three triple-negative breast cancer cell lines [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 2020.
Aneurysm Global Epidemiology Study
Authors: DavidSidloff, PhilipStather, NikeshDattani, MatthewBown, JohnThompson, RobertSayers, EdwardChoke
Journal: Circulation (2014)

Background—Contemporary data from Western populations suggest steep declines in abdominal aortic aneurysm (AAA) mortality; however, international trends are unclear. This study aimed to investigate global AAA mortality trends and to analyze any association with common cardiovascular risk factors. Methods and Results—AAA mortality (1994–2010) using International Classification of Diseases codes were extracted from the World Health Organization mortality database and age standardized. The World Health Organization InfoBase and International Mortality and Smoking Statistics provided risk factor data. Nineteen World Health Organization member states were included (Europe, 14; Australasia, 2; North America, 2; Asia, 1). Regression analysis of temporal trends in cardiovascular risk factors (1946–2010) was done independently for correlations to AAA mortality trends. Global AAA mortality trends show substantial heterogeneity, with the United States and United Kingdom recording the greatest national decline, where...
Abstract 18805: Prediction of Pre-procedural TIMI Flow Grade and Post-procedural Cardiac Troponin Elevations by 320-raw Multidetector Computed Tomography Myocardial Perfusion Imaging
Authors: MakotoAraki, TakayukiNiida, JunjiMatsuda, AsamiSuzuki, TadashiMurai, TetsuminLee, YoshitoIesaka, TsunekazuKakuta
Journal: Circulation (2014)

Backgrounds: Computed tomography perfusion imaging (CTPI) is feasible, and the findings may be used as a diagnostic tool for predicting coronary TIMI flow grade or cardiac marker elevation after percutaneous coronary intervention (PCI) in patients with non-ST segment elevation acute coronary syndrome (NSTE-ACS). We sought to investigate if detection of qualitative CTPI abnormality combined with CT coronary angiography (CTCA) findings can stratify the risk of NSTE-ACS patients before PCI. Methods: The coronary CTCA and CTPI datasets of 130 NSTE-ACS patients (NSTEMI: 85, UA: 45) using 320-raw CT before percutaneous coronary intervention (PCI) were visually evaluated for the presence of coronary artery stenosis and perfusion defects. All patients underwent PCI within 48 hours from admission and CT examination. We excluded patients with cardiogenic shock, severe congestive heart failure, renal insufficiency. We also excluded patients without identifiable culprit lesions and/or suitable lesions for PCI. Perfus...
Growth Hormone Improves Cardiac Performance in Experimental Heart Failure
Authors: RenhuiYang, StuartBunting, NancyGillett, RossClark, HongkuiJin
Journal: Circulation (1995)

Background Growth hormone has been shown to increase maximum isometric active force of the left ventricular papillary muscle of rats in vitro. Administration of growth hormone causes an increase in myocardial contractility in normal humans. Our preliminary study suggests that treatment with growth hormone results in increased ventricular contractility in rats with left ventricular dysfunction. In the present study, the effects of growth hormone on cardiac function, including cardiac output, stroke volume, and peripheral vascular resistance, were determined in a rat model of heart failure. Methods and Results Ligation of the left coronary artery or sham operation was performed; 4 weeks after surgery, recombinant human growth hormone (2 mg/kg per day SC) or vehicle then was administered for 15 days. The animals were catheterized after 13 days of the treatment. Cardiac output, measured by a thermodilution method, and other hemodynamic parameters were measured in the conscious animals 2 days after catheteriza...
Abstract 4621: Risk stratification and biomarker discovery in HPV-positive oropharynx squamous cell carcinoma determined by HPV and human gene expression profile associations
Authors: Frederico O. Gleber-Netto, Xiayu Rao, Kelly Erikson, Keiko Akagi, Faye M. Johnson, Jing Wang, Joseph Califano, Maura L. Gillison, Jeffrey N. Myers, Curtis R. Pickering
Journal: Cancer Research (2018)

Abstract Determining which HPV+ oropharyngeal squamous cell carcinoma (OPSCC) patients will respond to therapy is of utmost important for implementation of treatment de-escalation to reduce morbidity or testing of novel therapeutic approaches. Due to the lack of reliable indicators of treatment response, we explored the gene expression profile of OPSCC in order to better understand the biology of these tumors and identify novel biomarkers. In this study, we investigated human genes associated with HPV transcription in 80 OPSCC samples from The Cancer Genome Atlas (TCGA). This exploratory analysis provided a list of 582 human genes associated with HPV biology. Hierarchical clustering analysis using the 582 human genes was used to separate HPV+ OPSCC in two groups with significantly distinct survival (log-rank test p &amp;lt; 0.001) and differential expression of HPV genes. A refinement of this analysis generated a prognostic gene expression signature for HPV+ OPSCC containing 41 human genes. These results were validated in two independent cohorts of HPV+ OPSCC (n=83 and n=47) and one independent cohort of cervical cancer (n=83). In all three validation cohorts our 41 gene expression signature was able to identify a group of HPV+ OPSCC patients with worse survival. Further refinement and validation of the signature is ongoing. In order to understand the biology related to poor outcome in HPV+ OPSCC, a whole transcriptome analysis between the two initial HPV+ OPSCC TCGA groups was performed. Pathway analysis identified cell metabolism, cell stress, and DNA damage related genes were highly associated with poor outcome. Similar patterns of gene expression were found in vitro in a panel of 10 HPV+ cell lines, and markers of the poor outcome were found to be associated with reduced radiation sensitivity in vitro. Our study has identified prognostic biomarkers in HPV+ OPSCC with potential clinical importance. These biomarkers may be useful for selection of low risk patients for treatment de-escalation or selection of high risk patients for novel therapeutic approaches. These biomarkers are also functionally linked to radiation sensitivity and may include new therapeutic targets. Citation Format: Frederico O. Gleber-Netto, Xiayu Rao, Kelly Erikson, Keiko Akagi, Faye M. Johnson, Jing Wang, Joseph Califano, Maura L. Gillison, Jeffrey N. Myers, Curtis R. Pickering. Risk stratification and biomarker discovery in HPV-positive oropharynx squamous cell carcinoma determined by HPV and human gene expression profile associations [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 4621.