tbuckley/cabot-search huggingface dataset:
Abstract A42: Prenatal role of medical radiation in children diagnosed with a blood cancer: Single-institution study, 2006-2016
Authors: Robin L. Rohrer
Journal: Clinical Cancer Research (2018)

Abstract Background: Prenatal exposure to medical radiation is an identified risk for childhood cancers, but is difficult to document. The author developed a family questionnaire and interview form to identify possible exposures in children diagnosed from 2006-2016 with a blood cancer at a single institution. The Children's Hospital of Pittsburgh historically in this ten-year period has seen 180-200 new cases of a pediatric cancer each year with approximately 35-40% of these cancers being a blood cancer, notably an acute leukemia, chronic leukemia, Hodgkins's lymphoma, or a non-Hodgkin's lymphoma. Method: Each converted family (approximately 30% of the cohort) has been interviewed at hospital, clinic, or through phone conversation who were diagnosed with a type of acute or chronic leukemia or lymphoma. All children were diagnosed/treated at the Children's Hospital of Pittsburgh (CHP). CHP is the tristate regional referral center which sees about 180-200 new cases of a pediatric cancer each year. Medical staff and psychosocial staff referred patient families for interview with the author. Results: Among the families interviewed, at least one medical radiation prenatally has been identified in over one-third of families. These exposures prominently included sinus, chest or abdominal x-rays, or CT in either patient. Conclusion: Exposures to medical radiation for a child later diagnosed with cancer may occur pre-conception, in utero, or in early childhood. These exposures may be part of the “perfect storm” which eventually results in a blood or other cancer in children. Documenting these exposures may possibly in future lead to more preventive measures pre-conception similar to the “image gently” initiative to limit the number of diagnostic procedures and radiation doses in CT imaging of children today. Citation Format: Robin L. Rohrer. Prenatal role of medical radiation in children diagnosed with a blood cancer: Single-institution study, 2006-2016 [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr A42.
Abstract 3312: Identification of tissue-of-origin in cancer of unknown primary site (CUPS) using methylation-specific targeted resequencing: A pilot study
Authors: Jeong Mo Bae, Kwangsoo Kim, Hee Jun Chae, Xianyu Wen, Kang Yeol Kim, Hwang Kwan Gwon, Nam-Yun Cho, Gyeong Hoon Kang
Journal: Cancer Research (2018)

Abstract Purpose: Cancer of unknown primary site (CUPS) is a group of cancers for which the anatomic site of origin remains occult after detailed investigation. Until now, immunohistochemistry and tissue-specific RNA expression pattern have been used to predict tissue-of-origin in CUPS. However, these techniques do not fulfill the sensitivity and specificity for clinical practice. Recently, several studies found the tissue-specific methylation patterns in the genome. In this context, we tried to discover the tissue-specific methylation markers by analyzing genome-wide methylation data in The Cancer Genome Atlas (TCGA). Then, we aimed to develop the methylation-specific next-generation sequencing panel that predicts the tissue-of-origin in CUPS by validating panels in clinical samples. Experimental Design: We selected every 17 mostly hypermethylated CpG sites in 31 cancer types by analyzing 8,350 cases of Infinium 450K methylation data in TCGA. With the selected 527 CpG sites as input variables, we constructed 465 decision tree models for all pairwise classification of 31 cancer types by using C50 package in R. Based on the two class classification models, we implemented an ensemble voting classifier for tissue-of-origin prediction test in fresh frozen tissue of 50 primary cancers of 8 tissue types using methylation-specific next-generation sequencing, which targeted 527 tissue-specific CpG sites by post-bisulfite method. Results: In in silico analysis, we randomly selected 80% of the TCGA data for training decision tree models and used the remaining 20% of the data for testing those models. The sensitivity and specificity for the tissue-of-origin in 31 cancer types of testing data were 0.91 and 0.99 in decision tree models, respectively. In methylation-specific next-generation sequencing, our model predicted 40 cases (80%) of total 50 clinical samples, successfully. Conclusions: Prediction of tissue-of-origin using methylation-specific next-generation sequencing might be promising. For clinical application, further study using more comprehensive targeted resequencing panel using formalin-fixed, paraffin-embedded tissues will be followed. Citation Format: Jeong Mo Bae, Kwangsoo Kim, Hee Jun Chae, Xianyu Wen, Kang Yeol Kim, Hwang Kwan Gwon, Nam-Yun Cho, Gyeong Hoon Kang. Identification of tissue-of-origin in cancer of unknown primary site (CUPS) using methylation-specific targeted resequencing: A pilot study [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 3312.
Abstract 3447: IL-6 promotes tumor metastasis by promoting anoikis resistance and stemness phenotype in cancer cells via the activation of FAK and nanog stabilization
Authors: Arti Yadav, Bhavna Kumar, Pawan Kumar
Journal: Cancer Research (2018)

Abstract The process of tumor metastasis is highly complex and involves dissemination of tumor cells from the primary tumor through the vascular system. However, most of the cancer cells, particularly epithelial cancer cells, have very low survival rates in circulation and undergo rapid anoikis. Tumor cells that acquire malignant potential have developed mechanisms to resist anoikis and thereby survive while travelling though the lymphatic or circulatory systems. Recently, we have shown that IL-6 promotes epithelial-mesenchymal transition (EMT) and tumor metastasis. A number of studies have shown that FAK signaling pathways play an important role in inducing anoikis resistance in tumor cells. In this study, we examined if IL-6 promoted tumor metastasis by enhancing stemness and anoikis resistance in cancer cells via the activation of FAK signaling. Our results demonstrate that IL-6 significantly enhanced stemness phenotype in cancer cells as measured by tumorsphere formation and ALDH positive cells by upregulating nanog protein levels. Nanog knockdown significantly reversed IL-6-mediated cancer stem cell (CSC) phenotype. IL-6 treatment of cancer cells induced FAK phosphorylation in a time dependent manner. Interestingly, FAK knockdown did not significantly decrease nanog mRNA levels but markedly decreased nanog protein levels. FAK depletion completely blocked IL-6-mediated nanog phosphorylation and enhanced nanog protein ubiquitination and degradation. These results suggest that FAK may be modulating nanog protein levels by stabilization nanog protein through phosphorylation. Furthermore, FAK knockdown significantly decreased IL-6-mediated tumorsphere formation, anoikis resistance and tumor metastasis. Taken together, our results show that IL-6 promotes tumor metastasis by enhancing stem cell phenotype and anoikis resistance in head and neck cancer cells via FAK activation and nanog protein stabilization. Citation Format: Arti Yadav, Bhavna Kumar, Pawan Kumar. IL-6 promotes tumor metastasis by promoting anoikis resistance and stemness phenotype in cancer cells via the activation of FAK and nanog stabilization [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 3447.
Abstract 3834: Antibodies targeting Resokine, a soluble immune modulator, inhibit tumor growth in syngeneic mouse models
Authors: Kathy Ogilvie, Cherie Ng, Leslie Nangle, Jeanette Ampudia, Joon Chang, Andrea Cubitt, David J. King, John Mendlein
Journal: Cancer Research (2018)

Abstract A number of non-canonical functions have been established for proteins generated from the tRNA synthetase gene family. One of these, termed Resokine, is derived from histidyl tRNA synthetase and plays an important role in controlling immune cell activation. Circulating levels are sufficient to down-regulate the extent of T cell activation that can be achieved in vitro. A panel of specific monoclonal antibodies have been generated and tested for their anti-tumor activity in mouse syngeneic tumor models. Antibodies to Resokine demonstrated anti-tumor activity across three different tumor models. Treatment of subcutaneous CT26 tumors resulted in improved efficacy compared to treatment with antibodies that block the PD-1/PD-L1 interaction. Significant efficacy was also observed in the difficult to treat subcutaneous B16F10 melanoma and 4T1 breast tumor models. In addition anti-Resokine demonstrated significant activity in a tumor seeding model using B16F10 melanoma which resulted in inhibition of tumor nodules in the lung, and was more efficacious than a combination of antibodies to PD-L1 and CTLA-4. Combinations of anti-Resokine antibody with either anti-PD-1 or anti-PD-L1 demonstrated at least additive, and potentially synergistic activity in these models. Animals with long-term tumor regressions were re-implanted with viable tumor cells, and demonstrated long-term immune memory with rejection of the newly implanted tumors. To understand the mechanism of anti-Resokine antibody therapy, cell depletion studies were carried out in the B16F10 tumor model. In these experiments activity of anti-Resokine antibodies was demonstrated to be dependent upon the presence of CD8 T cells and also NK cells, but independent of CD4 T cells. The immune based mechanism of antibodies to Resokine was further demonstrated by re-challenge of mice that had regressed tumors upon treatment. Tumor re-growth was not observed even in the absence of further treatment whereas control mice grew tumors at the normal rate, suggesting that immune memory had been induced. Antibodies to Resokine offer an exciting new potential option for immunotherapy of cancer, which has significant activity as monotherapy and is compatible with more established modalities. Anti-Resokine antibodies are currently being developed to initiate clinical evaluation. Citation Format: Kathy Ogilvie, Cherie Ng, Leslie Nangle, Jeanette Ampudia, Joon Chang, Andrea Cubitt, David J. King, John Mendlein. Antibodies targeting Resokine, a soluble immune modulator, inhibit tumor growth in syngeneic mouse models [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 3834.
Nitric Oxide–Induced Motility in Aortic Smooth Muscle Cells
Authors: YingziChang, BogdanCeacareanu, MadhulikaDixit, NairSreejayan, AvivHassid
Journal: Circulation Research (2002)

We have previously reported that SHP-2 upregulation is necessary for NO-stimulated motility in differentiated rat aortic smooth muscle cells. We now test the hypothesis that upregulation of SHP-2 is necessary and sufficient to stimulate cell motility. Overexpression of SHP-2 via recombinant adenoviral vector stimulated motility to the same extent as NO, whereas the expression of C463S-SHP-2, the dominant-negative SHP-2 allele, blocked the motogenic effect of NO. On the basis of previous studies, we next tested the hypothesis that NO decreases RhoA activity and that this event is necessary and sufficient to explain NO-induced motogenesis. We found that NO decreased RhoA activity in a concentration-dependent manner. Moreover, a dominant-negative SHP-2 allele, DSH2, blocked the NO-induced inhibition of RhoA activity, indicating that upregulation of SHP-2 is necessary for this event. Expression of G14V-RhoA, the constitutively active RhoA allele, decreased cell motility and blocked the motogenic effect of NO,...
Abstract 9406: ST-Segment Elevation in Lead AVR Strongly Predicts Long-Term Adverse Outcomes in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome
Authors: MasamiKosuge, ToshiakiEbina, KiyoshiHibi, KengoTsukahara, NoriakiIwahashi, NobuhikoMaejima, EiichiAkiyama, SatoshiUmemura, KazuoKimura
Journal: Circulation (2014)

Introduction: In non-ST-segment elevation acute coronary syndrome (NSTE-ACS), ST-elevation in lead aVR (ST↑aVR) on admission ECG has been shown to be associated with severe coronary artery disease, but its impact on long-term clinical outcomes is unclear. Methods: We studied 454 patients with NSTE-ACS who underwent coronary angiography during initial hospitalization. Patients were divided into the 3 groups according to the degree of ST↑aVR on admission ECG: no ST↑aVR (n=301, G-A); ST↑aVR <1.0 mm (n=82, G-B); and ST↑aVR ≥1.0 mm (n=71, G-C). Troponin T (TnT), hemoglobin (Hb), estimated glomerular filtration rate (eGFR), brain natriuretic peptide (BNP), high-sensitivity C-reactive protein (hsCRP), TIMI risk score, and summed ST-segment depression in other leads were also measured on admission. Results: There were no differences in sex or coronary risk factors except for diabetes mellitus in the 3 groups. In G-A, G-B, and G-C, age was 66±11, 68±11, and 70±11 years; the rates of diabetes mellitus were 30%, 48%...
Stabilization of Atherosclerotic Plaques by Blockade of Macrophage Migration Inhibitory Factor After Vascular Injury in Apolipoprotein E–Deficient Mice
Authors: AndreasSchober, JürgenBernhagen, MichaelThiele, UteZeiffer, SandraKnarren, MarionRoller, RichardBucala, ChristianWeber
Journal: Circulation (2004)

Background— Macrophage migration inhibitory factor (MIF), a cytokine that controls cell-mediated inflammatory responses, is upregulated in atherogenesis; however, its functional contribution to lesion development has not been evaluated. Methods and Results— We studied the role of MIF on neointima lesion formation after wire-induced injury of carotid arteries in apolipoprotein E–deficient (apoE−/−) mice. Immunohistochemistry revealed that MIF expression was detectable in endothelial cells before injury and upregulated in smooth muscle cells (SMCs) 24 hours after endothelial denudation. Three weeks after injury, MIF was predominantly found in endothelial cells and macrophage-derived foam cells. Neutralizing MIF with a monoclonal antibody resulted in a marked reduction of neointimal macrophages and inhibited transformation of macrophages into foam cells. Conversely, the content of SMCs and of collagen in the neointima were increased, amounting to a slight but not significant reduction in neointima and media ...
Myocardial Contraction Frequency and Onset of Cardiac Glycoside Action
Authors: Jankoch-Weser
Journal: Circulation Research (1971)

Left atrial strips and right ventricular papillary muscles of kittens and left atrial strips of guinea pigs, rabbits, dogs, and chickens were exposed to ouabain, acetylstrophanthidin, or digoxin at 37°C during rest or while contracting at frequencies from 0.06 to 60/min. Both the positive inotropic effect and increases in resting tension developed fully in all preparations exposed to the three drugs during complete quiescence. Contraction frequency had some influence on the rate of development of these effects, but this influence was not the result of the number of beats during exposure. In ventricular myocardium, exposure times required for the attainment of the maximum positive inotropic effect and for the induction of contracture at different contraction frequencies were proportional to the increase in tension development. It is concluded that the development of the myocardial effects of digitalis-like compounds does not require cardiac activity. The limited influence of contraction frequency on the ra...
Efficacy of the Flexible Lifestyles Empowering Change intervention on metabolic and psychosocial outcomes in adolescents with type 1 diabetes (FLEX): a randomised controlled trial
Authors: Elizabeth J Mayer-Davis, David M Maahs, Michael Seid, Jamie Crandell, Franziska K Bishop, Kimberly A Driscoll, Christine M Hunter, Jessica C Kichler, Debra Standiford, Joan M Thomas, Franziska Bishop, Alexis Bouffard, Michelle Clay, Jamie Crandell, Larry Dolan, Kimberly Driscoll, Daniel Grossoehme, Michelle Hull, Christine Hunter, Tonya Jenkins, Anna Kahkoska, Jessica Kichler, Georgeanna Klingensmith, David Maahs, Elizabeth Mayer-Davis, Nancy Morwessel, Jessica Ruiz, Michael Seid, Emily Simmons, Thomas Songer, Katie Souris, Debbie Standiford, Joan Thomas, Mariana Villarreal, Timothy Wysocki, Michael Zickler
Journal: The Lancet Child & Adolescent Health (2018)
The Expanding Spectrum of Primary Aldosteronism: Implications for Diagnosis, Pathogenesis, and Treatment
Authors: Anand Vaidya, Paolo Mulatero, Rene Baudrand, Gail K Adler
Journal: Endocrine Reviews (2018)

Primary aldosteronism is characterized by aldosterone secretion that is independent of renin and angiotensin II and sodium status. The deleterious effects of primary aldosteronism are mediated by excessive activation of the mineralocorticoid receptor that results in the well-known consequences of volume expansion, hypertension, hypokalemia, and metabolic alkalosis, but it also increases the risk for cardiovascular and kidney disease, as well as death. For decades, the approaches to defining, diagnosing, and treating primary aldosteronism have been relatively constant and generally focused on detecting and treating the more severe presentations of the disease. However, emerging evidence suggests that the prevalence of primary aldosteronism is much greater than previously recognized, and that milder and nonclassical forms of renin-independent aldosterone secretion that impart heightened cardiovascular risk may be common. Public health efforts to prevent aldosterone-mediated end-organ disease will require improved capabilities to diagnose all forms of primary aldosteronism while optimizing the treatment approaches such that the excess risk for cardiovascular and kidney disease is adequately mitigated. In this review, we present a physiologic approach to considering the diagnosis, pathogenesis, and treatment of primary aldosteronism. We review evidence suggesting that primary aldosteronism manifests across a wide spectrum of severity, ranging from mild to overt, that correlates with cardiovascular risk. Furthermore, we review emerging evidence from genetic studies that begin to provide a theoretical explanation for the pathogenesis of primary aldosteronism and a link to its phenotypic severity spectrum and prevalence. Finally, we review human studies that provide insights into the optimal approach toward the treatment of primary aldosteronism.
Improvement of Subendocardial Myocardial Perfusion After Percutaneous Transluminal Coronary Angioplasty
Authors: HervéPerchet, PatrickDupouy, Anne-MarieDuval-Moulin, LucHittinger, GabrielPelle, PhilippeBrun, AlainCastaigne, HerbertGeschwind, Jean-LucDubois-Randé
Journal: Circulation (1995)

Background After angioplasty coronary reserve improves but does not normalize in most patients. The purpose of this study was to examine before and after angioplasty coronary reserve and transmural myocardial blood flow distribution using myocardial contrast echocardiography. Methods and Results Twelve patients with left anterior descending coronary artery stenosis were investigated before and immediately after angioplasty. A Doppler catheter was placed in the proximal segment. Myocardial contrast echocardiography was performed by imaging the septum in M mode in a parasternal view using a 3.0-mL bolus of sonicated amidotrizoate sodium meglumine through the guiding catheter. The gray level before injection was subtracted from the gray level after injection to maximize contrast time-intensity curves. The area under the curve was used as an indicator of myocardial blood flow, and subendocardial/subepicardial ratios were measured. After baseline measurements were obtained, Doppler and echographic data were re...
Experimental Autoimmune Myocarditis Produced by Adoptive Transfer of Splenocytes After Myocardial Infarction
Authors: AlanMaisel, DavidCesario, StephenBaird, JaleesRehman, ParvizHaghighi, SteveCarter
Journal: Circulation Research (1998)

Abstract—One possible mechanism for neurohumoral activation after myocardial infarction may be the generation of an immune response against cardiac self-antigens. We hypothesize that if there is a T cell–mediated reaction to self-antigens, the transfer of splenic lymphocytes from postinfarct rats into syngeneic rats with normal hearts should result in a T cell–mediated autoimmune myocarditis in the healthy syngeneic rats. Rats were killed 6 weeks after coronary ligation. Splenocytes from animals with large and small infarcts were purified from spleens, activated with concanavalin A, and injected in varying doses into normal syngeneic rats. These recipient rats were killed 6 weeks later, and histopathological studies were performed. Our results demonstrate in vivo evidence of lymphocyte-mediated myocardial injury by adoptive transfer of sensitized lymphocytes from rats who developed congestive heart failure after acute myocardial infarction. The amount of infiltrate and necrosis in the recipient rats appea...
Abstract B13: COP1-ETS axis regulates ERK transcriptional output and modulates sensitivity to MAPK inhibitors
Authors: Yuanyuan Xie, Zhen Cao, Wai Pung Wong, Youxin Guan, Jenny Zhang, Edward Walczak, Devan Murphy, Leili Ran, Inna Sirota, Shangqian Wang, Shipra Shukla, Dong Gao, John Wongvipat, Simon Knott, Kenneth Chang, Cristina Antonescu, Gregory Hannon, Ping Chi, Yu Chen
Journal: Clinical Cancer Research (2018)

Abstract Aberrant activation of the mitogen activate kinase (MAPK) pathway is highly prevalent in cancer and therapies targeting the pathway are approved or under active investigation in multiple malignancies. MAPK signaling leads to activation of a transcriptional program that includes general growth promoting genes, negative feedback regulators of the MAPK pathway, and lineage-specific genes. While the mechanisms of upstream signal transduction that leads to MAPK activation have been studied in detail, how MAPK activation is dynamically coupled with downstream nuclear transcriptional response is not fully understood. In gastrointestinal stomal tumor (GIST) and melanoma, two malignancies with aberrant MAPK activation, we find that Pea3 family ETS transcription factors ETV1, ETV4, and ETV5 are critical nuclear effectors of MAPK signaling. We find that the primary mechanism linking MAPK and Pea3 activity is through protein stability via the COP1 E3 ligase. The loss of COP1 leads to decoupling between upstream MAPK signaling and downstream transcription with constitutively stabilized Pea3 protein levels, constitutively high MAPK transcriptome, yet decreased upstream signaling due to Pea3-mediated transcription of negative feedback regulators. This leads to decreased therapeutic sensitivity to MAPK pathway inhibition in vitro and in vivo. These observations indicate that MAPK signaling-dependent regulation of Pea3 ETS protein stability is a crucial pathway that couples downstream transcriptional response to MAPK signaling and can shape the therapeutic sensitivity to MAPK pathway inhibition in cancer. Citation Format: Yuanyuan Xie, Zhen Cao, Wai Pung Wong, Youxin Guan, Jenny Zhang, Edward Walczak, Devan Murphy, Leili Ran, Inna Sirota, Shangqian Wang, Shipra Shukla, Dong Gao, John Wongvipat, Simon Knott, Kenneth Chang, Cristina Antonescu, Gregory Hannon, Ping Chi, Yu Chen. COP1-ETS axis regulates ERK transcriptional output and modulates sensitivity to MAPK inhibitors [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr B13.