tbuckley/cabot-search huggingface dataset:
Abstract 3157: p53 inactivation and STAT2 cooperate to enhance migration and metastasis of colon tumor cells
Authors: Ana M. Gamero, Kevin Kotredes, Aliza Abezis, Sruthi R. Gohimukkula, Alexandra Afanassiev, Tess Cremers, John J. Swain
Journal: Cancer Research (2018)

Abstract STAT2 is a pivotal signaling component in the antiviral and antiproliferative effects of type I and type III interferon (IFN), but its role in cancer remains understudied. To date, only IFNs are known to activate STAT2. Work by us and others has demonstrated that STAT2 deficiency impairs the antitumor effects of type I IFN, supporting its role in suppressing tumor growth. With the availability of Stat2-/- mice, we interrogated the tumor-suppressive role of STAT2 by employing the AOM/DSS model of colitis-associated cancer and the spontaneous ApcMin/+ model of colorectal cancer (CRC). In both cancer models, loss of STAT2 reduced the number of adenomas, showing that under specific conditions STAT2 can be tumorigenic. Next, immunohistochemical staining of human normal colon and CRC tumors revealed elevated STAT2 protein in both adenomas and adenocarcinomas, suggesting that STAT2 is implicated in human CRC. Conversion of adenomas to adenocarcinomas is linked to loss of p53 function, which occurs in &amp;gt;50% of colorectal cancers. Therefore, we evaluated whether STAT2 altered the aggressive phenotype of p53-deficient colon carcinoma cells. We silenced STAT2 in isogenic p53 null and p53 wild-type tumor cells. STAT2 knockdown in p53 null colon carcinoma cells reduced migration of 3D tumor spheroids and tumor colony formation while no effect was seen in p53 wild-type tumor cells. We also observed that STAT2 knockdown in p53 null tumor cells increased protein levels of the marker of epithelial-mesenchymal transition, E-cadherin. Conversely, overexpression of STAT2 in p53 null cells reduced E-cadherin protein. In vivo, STAT2 knockdown delayed subcutaneous tumor growth of p53 null tumor cells. Furthermore, using an experimental liver metastasis tumor model, STAT2 knockdown abrogated the formation of tumor nodules in the liver. RNA-seq profiling of subcutaneous p53 null tumors revealed a subset of genes that were differentially expressed in a STAT2-dependent manner. Clinically, analysis of the TCGA database showed a STAT2 transcriptional signature in colorectal tumors that we are presently correlating with p53 alterations. Overall, we conclude that STAT2 enhances tumor growth and can contribute to disease progression by promoting migration and invasion when normal p53 function is lost. Citation Format: Ana M. Gamero, Kevin Kotredes, Aliza Abezis, Sruthi R. Gohimukkula, Alexandra Afanassiev, Tess Cremers, John J. Swain. p53 inactivation and STAT2 cooperate to enhance migration and metastasis of colon tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3157.
Abstract 14929: Strokes Prevented: Biosurveillance of NVAF Patient Cohorts CHA2DS2-VASc and HAS-BLED Scores Using Natural Language Processing and SNOMED CT
Authors: Peter Elkin, Sarah Mullin, Chris Crowner, Sylvester Sakilay, Shyamashree Sinha, Gary Brady, Marcia Wright, Kim Nolen, JoAnn Trainer, Sashank Kaushik, Jane Zhou, Buer Song, Edwin Anand
Journal: Circulation (2017)

Introduction: Nonvalvular Atrial Fibrillation (NVAF), is estimated to affect 5.8 million people in the US. NVAF results in a five times greater stroke risk. This study compared the accuracy of stru...
Abstract 15787: Impact of Hypertension and Diabetes on Prevalence of Subclinical Arterial Damage in Subjects With Increased Body Mass Index (the FATCOR Project)
Authors: Mai T Lønnebakken, Ingeborg Eskerud, Helga Midtbø, Hilde Halland, Marina Kokorina, Eva Gerdts
Journal: Circulation (2017)

Introduction: Increased body mass index (BMI) is associated with a high prevalence of hypertension (HT) and diabetes (DM), and an increased risk of clinical cardiovascular (CV) disease. Whether inc...
Abstract 1888: The FAD-directed LSD1 specific inhibitor, INCB059872, is a promising epigenetic agent for AML therapy by inducing differentiation of leukemic stem/progenitor cells
Authors: Antony Chadderton, Min Ye, Melody Diamond, Valerie Roman, Michael Weber, Chunhong He, Liangxing Wu, Swamy Yeleswaram, Alan Roberts, Wenqing Yao, Gregory Hollis, Reid Huber, Peggy Scherle, Bruce Ruggeri, Sang Hyun Lee
Journal: Cancer Research (2018)

Abstract Numerous studies have elucidated that the most pivotal functions of lysine specific demethylase-1 (LSD1) are associated with regulating normal or malignant hematopoiesis by maintaining stem cell self-renewal and regulating myeloid differentiation. In preclinical models, studies with either pharmacological inhibition or genetic knockdown of LSD1 demonstrated that LSD1 is essential for differentiation of progenitor cells during normal hematopoiesis. In the clinic, AML manifests itself via clonal expansion of abnormal differentiation and proliferation of myeloid cells and, therefore, the inhibition of LSD1 activity with small molecule inhibitors could be a promising therapeutic approach for AML. Previously, we reported upon the identification of a flavin adenine dinucleotide (FAD) directed LSD1 specific inhibitor, INCB059872, which is efficacious in preclinical mouse models utilizing human AML cell lines and primary AML cells by inducing cell differentiation as indicated by the induction of CD11b and CD86 markers. Using a larger panel of myeloid and HSC flow cytometry markers, our currents efforts expanded upon these observations to ascertain whether INCB059872 enhanced lineage commitment at hematopoietic stem cell (HSC) and/ or promoted monocytic/granulocytic differentiation of human primary AML cells ex vivo and in human systemic AML PDX models. In both human AML PDX models and human primary AML samples, INCB059872 increased myeloid differentiation with increasing populations of monocytes (CD14+) and granulocytes (CD15+). Furthermore, INCB059872 induced the differentiation of early hematopoietic progenitors, CD34+/CD38- to more committed CD34+/CD38+ multipotent/oligopotent progenitors, which in turn gave rise to lineage specific progenitors in the human AML PDX models. These studies support further exploration of INCB059872 as a promising novel epigenetic agent for AML therapy whose mechanism of action lies in part through the induction of differentiation of leukemic stem/progenitor cells to more committed hematopoietic lineages. Citation Format: Antony Chadderton, Min Ye, Melody Diamond, Valerie Roman, Michael Weber, Chunhong He, Liangxing Wu, Swamy Yeleswaram, Alan Roberts, Wenqing Yao, Gregory Hollis, Reid Huber, Peggy Scherle, Bruce Ruggeri, Sang Hyun Lee. The FAD-directed LSD1 specific inhibitor, INCB059872, is a promising epigenetic agent for AML therapy by inducing differentiation of leukemic stem/progenitor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1888.
Abstract 1082: Loss of desmoglein 2 promotes tumor growth and progression through the activation of Src and facilitates the internalization of EGFR in biliary tract carcinoma cells
Authors: Sang-Hyun Lee, Jeong-Ki Min
Journal: Cancer Research (2018)

Abstract Understanding the molecular carcinogenesis pathways is critical to establish novel individualized molecular targeted therapies and finally to improve overall clinical outcomes of patients with a highly heterogeneous group of malignancies such as biliary tract cancers (BTCs). In this context, we investigated the patho-physiological roles of a desmosomal component, desmoglein 2 (Dsg2) and found that Dsg2 functions as a tumor suppressor protein in BTC, as Dsg2 loss induced a number of cellular biological activities including proliferation, motility, invasion, transendothelial migration in vitro and tumor growth and metastasis in vivo. Clinico-pathological analyses of BTC patients indicated that lower expression of Dsg2 is associated with a poor prognosis of patients as perineural and lymphatic invasion were highly increased in those patients. In addition, loss of Dsg2 showed a significant increase of EGFR clearance from the cell membrane in BTC cells and patients' tumor tissues. Those cells were significantly decreased in the EGF-driven activation of EGFR and highly resistant to the anti-EGFR antibody treatment. Src appears to be involved in the Dsg2-mediated clearance of EGFR, as this significantly blocked by the suppression of cSrc expression in Dsg2-depleted cells, possibly through the direct binding of Dsg2 preferentially with an inactive form of Src through its SH2 domain. Suppression of cSrc by Src inhibitors or siRNA dramatically reduced BTC tumor growth in vitro and in vivo. In comparison with the anti-EGFR antibody therapy, Src-targeted therapies produced consistent anti-tumor activities independent with the expression status of EGFR in the BTC tumors. In conclusion, targeting Src would be a promising therapeutic approach to patients with advanced BTC and potentially useful in overcoming resistance to current anti-EGFR therapies, although further clinical studies are essentially required to translate the current preclinical knowledge into clinical practice. Citation Format: Sang-Hyun Lee, Jeong-Ki Min. Loss of desmoglein 2 promotes tumor growth and progression through the activation of Src and facilitates the internalization of EGFR in biliary tract carcinoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1082.
Regulation of Vascular Calcification by Osteoclast Regulatory Factors RANKL and Osteoprotegerin
Authors: PatriciaCollin-Osdoby
Journal: Circulation Research (2004)

Vascular calcification often occurs with advancing age, atherosclerosis, various metabolic disorders such as diabetes mellitus and end-stage renal disease, or in rare genetic diseases, leading to serious clinical consequences. Such mineralization can occur at various sites (cardiac valves, arterial intima or media, capillaries), involve localized or diffuse widespread calcification, and result from numerous causes that provoke active inflammatory and osteogenic processes or disordered mineral homeostasis. Although valuable research has defined many key factors and cell types involved, surprising new insights continue to arise that deepen our understanding and suggest novel research directions or strategies for clinical intervention in calcific vasculopathies. One emerging area in vascular biology involves the RANKL/RANK/OPG system, molecules of the tumor necrosis factor-related family recently discovered to be critical regulators of immune and skeletal biology. Evidence is accumulating that such signals m...
Active-Shooter Response at a Health Care Facility
Authors: Kenji Inaba, Alexander L. Eastman, Lenworth M. Jacobs, Kenneth L. Mattox
Journal: New England Journal of Medicine (2018)

The "run, hide, fight" response to an active-shooter event may work in many places, but health care facilities should consider a different approach: "secure" the location, "preserve" the life of the patient and oneself, and "fight" only if necessary.
Abstract 1811: O-GlcNAc-dependent regulation of progesterone receptor function in breast cancer
Authors: Gloria M. Trinca, Merit L. Goodman, Evangelia K. Papachristou, Clive S. D'Santos, Prabhakar Chalise, Rashna Madan, Chad Slawson, Christy R. Hagan
Journal: Cancer Research (2018)

Abstract Emerging clinical trial data implicate progestins in the development of breast cancer. While the role for the progesterone receptor (PR) in this process remains controversial, it is clear that PR, a steroid-activated nuclear receptor, alters the transcriptional landscape of breast cancer. PR interacts with many different types of proteins, including transcriptional co-activators and co-repressors, transcription factors, nuclear receptors and proteins that post-translationally modify PR (i.e. kinases and phosphatases). Herein, we identify a novel interaction between PR and OGT, the enzyme that catalyzes the addition of a single N-acetylglucosamine sugar, referred to as O-GlcNAc, to acceptor serines and threonines in target proteins. This interaction between PR and OGT leads to the post-translational modification of PR by O-GlcNAc. Moreover, we show that O-GlcNAcylated PR is more transcriptionally active on PR-target genes, despite the observation that PR mRNA and protein levels are decreased when O-GlcNAc levels are high. O-GlcNAcylation in breast cancer is clinically relevant, as we show that O-GlcNAc levels are higher in breast cancer as compared to matched normal tissues, and PR-positive breast cancers have higher levels of OGT. These data predict that under conditions where O-GlcNAc levels are high (breast cancer), PR, through an interaction with the modifying enzyme OGT, will exhibit increased O-GlcNAcylation and potentiated transcriptional activity. Therapeutic strategies aimed at altering cellular O-GlcNAc levels may have profound effects on PR transcriptional activity in breast cancer. Citation Format: Gloria M. Trinca, Merit L. Goodman, Evangelia K. Papachristou, Clive S. D'Santos, Prabhakar Chalise, Rashna Madan, Chad Slawson, Christy R. Hagan. O-GlcNAc-dependent regulation of progesterone receptor function 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 1811.
Response rates of taxane rechallenge in metastatic breast cancer patients, previously treated with adjuvant taxanes.
Authors: Arzu Oguz, Taner Babacan, Omer Dizdar, Nadire Kucukoztas, Samed Rahatli, Gul Sema Yildiran Keskin, Ozden Altundag, Kadri Altundag
Journal: Journal of Clinical Oncology (2014)

1073 Background: This study was conducted to determine the efficacy of taxane-based regimens in metastatic breast cancer patients who have already taken taxanes in their adjuvant treatments and also to assess the response rates in each treatment line. Methods: The data of 938 metastatic breast cancer patients who had taken adjuvant taxane based chemotherapy, were reviewed retrospectively. Besides demographical variables, the treatments that were given when metastases occured, response rates (RR), clinical benefit rates (CBR: complete response (CR)+ partial response (PR) + stable disease (SD)) and progression free survival values were determined. For patient and tumor characteristics, descriptive statistical methods were used. Chi-Square test was used to compare differences between categorical variables. Kaplan-Meier curves were drawn to obtain survival probabilities and log rank test was used to compare these curves between groups. Results: Of 938 cases, metastases were detected in 189 (20.1%) during follow-up. The response rate in 45 patients receiving re-challenge with taxanes as first line treatment was 51.2% consisting of 4 (8.8%) complete and 19 (42.2%) partial remissions. The RR and CBR of taxane re-challenge in first line and later line therapies are summarized in the Table. When RR and progression free survivals were taken into account, there were no significant differences detected between patients receiving re-challenge with taxanes who had less than 2 years DFS until recurrence compared with those having DFS values more than 2 years (p values were 0.3 and 0.65 respectively). Conclusions: Re-challenge with taxanes both in the first line and later line trearments appear to be effecive and seems to be a reasonable option in taxane pre-treated patient group, due to the satisfactory response rates in all treatment lines. It was not possible to make a suggestion for those patients who had a DFS less than 1 year because of poor number of patients. Response rates of taxane rechallenge in treatment lines. First line Second line ≥ Third line Response rates 51% 40% 37% Clinical benefit rates 64% 51% 53%
Abstract 17799: Development and Validation of a Mechanical Surrogate to Assess the Ability of Chest Protectors to Prevent Commotio Cordis, Sudden Cardiac Death With Chest Wall Impact
Authors: ElizabethMcCalley, NathanDau, Kartik RKumar, Swati NMandleywala, CynthiaBir, DaveHalstead, Mark SLink
Journal: Circulation (2016)

Introduction: Commotio cordis is one of the leading causes of SCD on the playing field. Chest protection has not been demonstrated to prevent these SCDs. Hypothesis: A mechanical surrogate to assess for chest wall protection is feasible. Methods: An experimental commotio cordis model was utilized to assess mechanical variables that predicted for ventricular fibrillation (VF) with chest wall impact. Peak LV pressure, impact force, impulse, chest compression, compression rate, viscous criterion, momentum, energy, force*compression, and impact power were analyzed for the prediction of VF. Further data from post-mortem human specimens were incorporated into a mechanical surrogate, and this surrogate was utilized to assess and develop a standard for chest wall protectors. This mechanical surrogate was then independently validated with chest protector data from the original experimental model. Results: Of all variables assessed, force was the most robust at predicting for initiation of VF and force attenuation ...
Myocardial Hypertrophic Preconditioning Attenuates Cardiomyocyte Hypertrophy and Slows Progression to Heart Failure Through Upregulation of S100A8/A9
Authors: XuanWei, BingWu, JingZhao, ZhiZeng, WanlingXuan, ShipingCao, XiaoboHuang, MasanoriAsakura, DingliXu, JianpingBin, MasafumiKitakaze, YulinLiao
Journal: Circulation (2015)

Background—Transient preceding brief ischemia provides potent cardioprotection against subsequent long ischemia, termed ischemic preconditioning. Here, we hypothesized that transient short-term hypertrophic stimulation would induce the expression of hypertrophy regression genes and render the heart resistant to subsequent hypertrophic stress, and slow the progression to heart failure, as well. Methods and Results—Cardiomyocyte hypertrophy was induced in mice by either transverse aortic constriction or an infusion of phenylephrine, and in neonatal rat ventricular cardiomyocytes by norepinephrine exposures. In the preconditioning groups, hypertrophic stimulation was provided for 1 to 7 days and then withdrawn for several days by either aortic debanding or discontinuing phenylephrine or norepinephrine treatment, followed by subsequent reexposure to the hypertrophic stimulus for the same period as in the control group. One or 6 weeks after transverse aortic constriction, the heart weight/body weight ratio was...
Abstract 12388: Left Ventricular Layer Torsion in Hypertensive Patients using One-beat Real-time Three-dimensional Speckle Tracking Echocardiography With High Volume Rates
Authors: HirotakaMiwa, MasanoriKawasaki, RyuheiTanaka, MakiNagaya, ShingoMinatoguchi, TakahiroUeno, HidemaroSato, ShigekiSawada, RyotaWatanabe, TakashiKato, TakeshiHirose, MakotoIwama, MayumiKaneda, KojiOno, ToshiyukiNoda, SachiroWatanabe, ShinyaMinatoguchi
Journal: Circulation (2015)

Background: Left ventricle (LV) is composed of three myocardial layers and LV torsion caused by inner and outer oblique muscle contraction plays an important role in squeezing blood out of the heart. However, LV layer torsion has not been examined using echocardiography. We sought to examine LV layer torsion and the relation between layer torsion and systolic function in hypertension (HTN) by one-beat 3-dimensional speckle tracking echocardiography (3D-STE). Methods: We enrolled 31 controls (age 65±12), 47 HTN without hypertrophy (LVH) (age 67±12), 47 HTN with LVH (age 70±11) and 37 patients with hypertensive heart failure (HHF) (age 74±15) to characterize LV layer torsion {endocardium (end), midwall (mid) and epicardium (epi)} using 3D-STE with volume rate of 70-80vps. LV twist was defined as maximum difference in rotation angle between base and apex (°). LV torsion was defined as twist / long axis length (°/cm). Time to peak torsion was expressed as % systole by dividing the time by total systolic time....
Risk Factors Associated With Perioperative Complications and Prolonged Length of Stay After Laparoscopic Adrenalectomy
Authors: Yufei Chen, Anouk Scholten, Kathryn Chomsky-Higgins, Iheoma Nwaogu, Jessica E. Gosnell, Carolyn Seib, Wen T. Shen, Insoo Suh, Quan-Yang Duh
Journal: JAMA Surgery (2018)

Laparoscopic adrenalectomy is the gold standard for most adrenal disorders and its frequency in the United States is increasing. While national and administrative databases can adjust for patient factors, comorbidities, and institutional variations, granular disease-specific data that may significantly influence the incidence of perioperative complications and length of stay (LOS) are lacking.
Abstract 15149: Short-term Exposure to Fine Particulate Matter Air Pollution Preferentially Increases the Risk of ST-Elevation Acute Coronary Events
Authors: Kent G Meredith, C A Pope, Joseph B Muhlestein, Jeffrey L Anderson, John B Cannon, Nicholas M Hales, Viet T Le, Benjamin D Horne
Journal: Circulation (2015)

Introduction: Air pollution is associated with greater cardiovascular event risk, but which types of events and the specific at-risk individuals remain unknown. Hypothesis: Short-term exposure to fine particulate matter (PM 2.5 ) is associated with greater risk of acute coronary syndromes (ACS), including ST elevation myocardial infarction (STEMI), non-ST elevation myocardial infarction (NSTEMI), and unstable angina (USA). Methods: ACS events treated at Intermountain Healthcare hospitals in Utah’s urban Wasatch Front region between September 10, 1993 and May 15, 2014 were included if the patient resided in that area (N=16,314). A time-stratified case-crossover design was performed matching the PM 2.5 exposure at the time of event with periods when the event did not occur (referent), for STEMI, NSTEMI, and USA. Patients served as their own controls. Odds ratios (OR) were determined for exposure threshold versus linear, non-threshold models. Results: In STEMI, NSTEMI, and USA patients, age averaged 62, 64, and 63 years; males constituted 73%, 66%, and 68%; current or past smoking was prevalent in 33%, 25%, and 26%; and significant coronary artery disease (CAD) (defined as ≥1 coronary with ≥70% stenosis) was found among 95%, 75%, and 74%, respectively. Short-term PM 2.5 exposure was associated with ACS events (Table). Conclusions: Short-term exposure of PM 2.5 was strongly associated with greater risk of STEMI, especially in patients with angiographic CAD. No association with NSTEMI was found, and only a weak effect for USA. This study supports a PM 2.5 exposure threshold of 25 μg/m 3 , below which little exposure effect is seen, while the effect is linear above that level.
Fluid Shear Stress Activates Ca2+ Influx Into Human Endothelial Cells via P2X4 Purinoceptors
Authors: KimikoYamamoto, RisaKorenaga, AkiraKamiya, JojiAndo
Journal: Circulation Research (2000)

Abstract—Ca2+ signaling plays an important role in endothelial cell (EC) responses to shear stress generated by blood flow. Our previous studies demonstrated that bovine fetal aortic ECs showed a shear stress–dependent Ca2+ influx when exposed to flow in the presence of extracellular ATP. However, the molecular mechanisms of this process, including the ion channels responsible for the Ca2+ response, have not been clarified. Here, we demonstrate that P2X4 purinoceptors, a subtype of ATP-operated cation channels, are involved in the shear stress–mediated Ca2+ influx. Human umbilical vein ECs loaded with the Ca2+ indicator Indo-1/AM were exposed to laminar flow of Hanks’ balanced salt solution at various concentrations of ATP, and changes in [Ca2+]i were monitored with confocal laser scanning microscopy. A stepwise increase in shear stress elicited a corresponding stepwise increase in [Ca2+]i at 250 nmol/L ATP. The shear stress–dependent increase in [Ca2+]i was not affected by phospholipase C inhibitor (U-73...