tbuckley/cabot-search huggingface dataset:
Abstract 486: BET protein inhibition by JQ1 blocks EWS-FLI1 activity in Ewing sarcoma
Authors: Krista L. Bledsoe, Aaron Stonestrom, Stephan Kadauke, Laura Quick, Robert Young, Gerd A. Blobel, Margaret M. Chou
Journal: Cancer Research (2015)

Abstract Ewing sarcoma is the second most common bone cancer in children, with an estimated 5-year survival rate of 20% for metastatic cases. These tumors harbor the characteristic chromosomal translocation t(11;22)(q24;q12), which leads to expression of the oncogenic chimeric transcription factor, EWS-FLI1. EWS-FLI1 drives Ewing sarcoma tumorigenesis, and is an attractive therapeutic target because it is expressed exclusively in tumor cells. However, directly targeting EWS-FLI1 has proved difficult. Thus, despite advances in our understanding of EWS-FLI1 function, treatment options remain limited, and to date, no targeted therapeutics have been developed. In this study, we investigated the effects of the epigenetic modifier drug, JQ1, on Ewing sarcoma pathogenesis. JQ1 is a small molecule inhibitor of the BET family of bromodomain proteins, which bind to acetylated histones and transcription factors to regulate gene expression. JQ1 selectively inhibits these acetylation-dependent BET protein interactions. Recent studies reveal that JQ1 has potent anti-neoplastic activity against multiple cancers, with c-MYC downregulation being a key mechanism by which it induces cell death in several tumor types. Because Ewing sarcoma cells express high levels of c-MYC, we predicted that they would be sensitive to the cytotoxic effects of JQ1. Our results demonstrate that JQ1 indeed inhibits growth of Ewing sarcoma cells, but unexpectedly, it does not function through inhibition of c-MYC. Using multiple patient-derived Ewing sarcoma cell lines, we find that JQ1 induces apoptosis as measured by PARP cleavage. Preliminary data further indicate that JQ1 suppresses growth of Ewing sarcoma xenografts in vivo. Mechanistic studies and microarray analysis reveal that JQ1 inhibits EWS-FLI1 activity, with multiple targets of the oncogene being rapidly downregulated upon JQ1 treatment. Studies are currently underway to identify the specific BET family members required for EWS-FLI1 function, and to determine the mechanism by which they regulate EWS-FLI1 activity. Given the emergence of numerous JQ1-derivative compounds targeting specific BET proteins, it is hopeful that this class of compounds may ultimately be used as targeted therapies for the treatment of Ewing sarcoma. Citation Format: Krista L. Bledsoe, Aaron Stonestrom, Stephan Kadauke, Laura Quick, Robert Young, Gerd A. Blobel, Margaret M. Chou. BET protein inhibition by JQ1 blocks EWS-FLI1 activity in Ewing sarcoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 486. doi:10.1158/1538-7445.AM2015-486
New Directions in Environmentally Related Cardiovascular Disease
Journal: Environmental Health Perspectives (2002)

A 417Cardiovascular disease (CVD) is the primary cause of death in the industrialized world.CVD can be caused by many factors, including diet, genetics, and lifestyle.In addition, research over the last several years has made it clear that environmental factors are also associated with CVD.Epidemiology studies, as well as animal and controlled human studies, have consistently shown an association between exposure to ambient particulate matter and CVD.Likewise, research has shown that environmental contaminants such as polyaromatic hydrocarbons can lead to changes in the vascular wall, consistent with early atherosclerotic changes that may lead to CVD.Yet despite the large amount of research on the contribution of environmental agents to CVD, many questions still remain as to which environmental agents play a role and the nature of their pathophysiological mechanisms.Recent advances in the fields of signal transduction, genetics, molecular biology, and epidemiology make expansion of research efforts in this area very timely.To help identify new directions for research related to this important public health issue, the NIEHS, the U.S. EPA, the American Heart Association, and the National Heart, Lung, and Blood Institute are cosponsoring a workshop titled "The Role of Environmental Agents in Cardiovascular Disease," to be held 6-7 August 2002 in Durham, North Carolina.The workshop will focus on mechanisms of environmentally related CVD and on identifying potential environmental cardiovascular toxicants.The workshop is also designed to promote collaborations among researchers in environmental health science, CVD, and epidemiology to develop novel ways to address the problem.
Occurrence of Tumors, Particularly Mammary Tumors, in Agent-Free Strain C3HeB Mice2
Authors: Margaret K. Deringer
Journal: JNCI Journal of the National Cancer Institute (1959)

Journal Article Occurrence of Tumors, Particularly Mammary Tumors, in Agent-Free Strain C3HeB Mice Get access Margaret K. Deringer Margaret K. Deringer Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 22, Issue 5, May 1959, Pages 995–1002, https://doi.org/10.1093/jnci/22.5.995 Published: 01 May 1959 Article history Received: 02 December 1958 Published: 01 May 1959
Efficient Gene Delivery to Quiescent Interleukin-2 (IL-2)-Dependent Cells by Murine Leukemia Virus-Derived Vectors Harboring IL-2 Chimeric Envelopes Glycoproteins
Authors: Marielle Maurice, Stéphane Mazur, Frances J. Bullough, Anna Salvetti, Mary K.L. Collins, Stephen J. Russell, François Loïc Cosset
Journal: Blood (1999)
Abstract 15759: B-type And C-type Natriuretic Peptides Regulate Heart Rate And Sinoatrial Node Function By Activating Multiple Natriuretic Peptide Receptor Subtypes
Authors: John Azer, Courtney Robbins, Jeremy Springer, Andrew Adamczyk, Rui Hua, Robert A Rose
Journal: Circulation (2011)

The natriuretic peptides (NPs) BNP and CNP elicit their effects by binding to specific receptors denoted NPR-A, NPR-B and NPR-C. NPR-A and NPR-B stimulate guanylyl cyclase (GC) and cGMP signaling, ...
Abstract 2965: Identification of SMARCA4/BRG1 mutation types in NSCLC cell lines and tumors
Authors: Wei Zhang, Yibing Yao, Yunyun Zhou, Xiaotu Ma, Jingsheng Yan, Tao Wang, Luc Girard, John Minna, Guanghua Xiao, Yang Xie, Adi Gazdar
Journal: Cancer Research (2015)

Abstract Purpose: Identification of SMARCA4/BRG1 mutation types in NSCLC cell lines and tumors. Background: The SMARCA4 gene encodes the major catalytic subunit of the SWI/SNF chromatin remodeling complex and is necessary for the transcriptional regulation of multiple cellular pathways. SMARCA4 is frequently mutated in lung cancer cell lines and in lung cancers. Methods: Sixty four NSCLC cell lines were analyzed. The Cancer Genome Atlas (TCGA) data were examined. SMARCA4 mutations were identified by NextGen and/or Sanger sequencing using genomic DNA or cDNA. Gene expression profiles and global methylation was determined by Illumina BeadChips. BRG1 protein was detected by immunoblotting. Results: SMARCA4 abnormalities were divided into Type1 (loss of full length protein, usually due to deletions, non-sense mutations or splicing site mutations) and Type 2 (homozygous or heterozygous missense mutations with protein present). Sequencing often failed to detect large deletions. Loss of SMARCA4/BRG1 resulted in profound downstream effects on the transcriptome and methylome, while existence of BRG1 with mutations has much less effects. Analysis using most significantly regulated transcripts can distinguish SMARCA4 type 1 abnormality from WT group, and indicate that type 2 abnormality effects were heterogeneous. SMARCA4 regulated transcripts are involved in many important cellular functions such as cell movement, death and proliferation and participate in many cytokines and hormone/nuclear receptors-mediated pathways. The expressions of transcription factors FOXA2 and NKX2-1 were decreased, while two groups of cancer testis antigens (CTAs), PRAME and MAGEA family were elevated in NSCLC cell lines and tumors with SMARCA4 mutations/low expression. Furthermore, FOXA2 and NKX2-1 were downregulated in an inducible SMARCA4 knock- down immortalized human lung epithelial cell line. Conclusions: SMARCA4 mutations can be divided into two types having varying downstream effects. Citation Format: Wei Zhang, Yibing Yao, Yunyun Zhou, Xiaotu Ma, Jingsheng Yan, Tao Wang, Luc Girard, John Minna, Guanghua Xiao, Yang Xie, Adi Gazdar. Identification of SMARCA4/BRG1 mutation types in NSCLC cell lines and tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2965. doi:10.1158/1538-7445.AM2015-2965
Measuring quality of life is important
Authors: K. Rose, A. Tullo
Journal: BMJ (1996)

EDITOR,—John Cairns raises important issues relating to the use of quality of life measures in decision making in health care.1 He seems to imply that allocation of resources is the principal purpose for developing such measures and that they should therefore be designed with this as their main function.

The primary concern of clinicians, however, is not, or …
Uric Acid
Authors: David S. Campion, Rodney Bluestone, James R. Klinenberg
Journal: Journal of Clinical Investigation (1973)

Binding of sodium urate to human serum albumin (HSA) was measured by continuous ultrafiltration at pH 7.4 and ionic strength 0.16 over the concentration range 1-13 mg/100 ml. The percent sodium urate bound to 5 g/100 ml HSA was constant over this concentration range: 30.3 (SE+/-0.6)% being bound at 4 degrees C, 22.6+/-0.3% at 22.5 degrees C, and 19.6+/-0.3% at 37 degrees C. Derived association constants, assuming one binding site were 6.0 x 10(2) M(-1) (4 degrees C), 4.47 x 10(2) M(-1) (22.5 degrees C), and 3.88 x 10(2) M(-1) (37 degrees C).
Abstract 16022: Reactive Oxygen Species in Rostral Ventrolateral Medulla Contribute to Neural Mechanisms of Hypertension by Modulating Paraventricular Nucleus of Hypothalamus
Authors: Masaaki Nishihara, Yoshitaka Hirooka, Ryuichi Matsukawa, Koji Ito, Takuya Kishi, Kenji Sunagawa
Journal: Circulation (2010)

Background: Increased reactive oxygen species (ROS) in the rostral ventrolateral medulla (RVLM) of the brainstem play a pivotal role in the neural mechanism of hypertension. The paraventricular nuc...
In situ Activation of Dendritic Cells (DC) with Imiquimod for Cancer Immunotherapy
Authors: Hubert R. Kuebler, Philipp Dahm, Timothy T. Tseng, Aijing Zhang, Doris Coleman, Johannes Vieweg, Jens Dannull
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

3997 

The concept that active immunotherapy with antigen-loaded dendritic cells (DC) may have therapeutic promise in oncology is well established. Induction of potent immune response in cancer patients requires an activation step - termed maturation - that turns DC into potent antigen presenting cells. However, the appropriate conditions for ex-vivo maturation remain largely unknown. The objective of this study was to develop a more effective vaccination platform for human immunotherapy trials by maturing DC in vivo through injection of DC into dermal sites conditioned with the immunomodulator Imiquimod (Aldara®). In order to assess the biological response to Imiquimod treatment, skin biopsies from prostate cancer patients were analyzed for secretion of cytokines, including RANTES, MIG, MCP-1, MIP-1α, MIP-1β, IL-1β, IL-8, IL-6, TNF-α, IL-10, IL-12, IFN-α, and PGE-2. Furthermore, immunohistochemistry was performed on Imiquimod-treated skin using mAbs against CD3, CD4, CD11b, CD11c, CD14, CD15, CD56, CD68, and CD123. TLR expression by DC was assessed by RT-PCR and Imiquimod-mediated activation of DC was determined by assessing upregulation of maturation markers (CD80, CD83, CD25, and CCR-7) and by functional assays, including primary allogeneic mixed lymphocyte reactions (MLR) and DC migration assays. Topical application of Imiquimod led to increases in levels of the chemokines RANTES and MCP-1 in human skin biopsies with peak levels after the second administration, while expression of other cytokines known to facilitate DC maturation (TNF- α, MIP-1α, IL-1β, IL-6, IFN- α and PGE2) was not altered. Immunohistochemical analyses revealed activation of skin residing Langerhans cells after Imiquimod treatment. Activation was mediated by TLR-8 and not TLR-7. Imiquimod had no direct effects on maturation of monocyte-derived DC, however, incubation of DC with supernatant derived from Imiquimod-treated Langerhans cells greatly enhanced expression of maturation markers CD80 and CD83 as well as the immunostimulatory properties of monocyte-derived DC, as evidenced by allogeneic MLRs. Furthermore, DC acquired migratory properties as shown by in vitro migration towards MIP-3β gradients and imaging of DC migration in prostate cancer patients. In summery, injection of immature DC into Imiquimod-conditioned skin may represent a superior method of maturing monocyte-derived DC for immunotherapy. Based on these results, a phase I/II clinical trial is ongoing at our institution to assess the immunological and clinical efficacy of in situ-activated DC in patients with metastatic prostate cancer. Results of this ongoing clinical trial will be presented.
Association of the Trp719Arg Polymorphism in Kinesin-Like Protein 6 With Myocardial Infarction and Coronary Heart Disease in 2 Prospective Trials
Authors: Olga A. Iakoubova, Carmen H. Tong, Charles M. Rowland, Todd G. Kirchgessner, Bradford A. Young, Andre R. Arellano, Dov Shiffman, Marc S. Sabatine, Hannia Campos, Christopher J. Packard, Marc A. Pfeffer, Thomas J. White, Eugene Braunwald, James Shepherd, James J. Devlin, Frank M. Sacks
Journal: Journal of the American College of Cardiology (2008)
HER-2 status of the primary breast cancer in patients with relapse at least five years after the initial diagnose
Authors: Z. I. Tomasevic, D. Jovanovic, L. Radosevic-Jelic, Z. Tomasevic, S. Vasovic, L. Stamatovic, S. Jelic, J. Spasic
Journal: Journal of Clinical Oncology (2006)

10631 Background: HER-2 status of the primary breast carcinoma in the subgroup of patients who relapsed after many years is not well known. The aim of this paper is to determine the HER-2 status of the primary breast cancer in patients with late relapse, defined as local recurrence, distant metastases or carcinoma in the contralateral breast, at least five years after the initial diagnosis Methods: During six month period (June-November 2005) 1256 patients were diagnosed with primary or relapsed breast cancer at the IORS. HER-2 (HercepTest, DAKO) status was determined on the archived pathological specimens of patients with late relapse. Results: One hundred eleven patients (111/1256; 8,8%) were diagnosed with late relapse. At the time of the initial diagnose, majority of patients have been treated for early breast carcinoma. Median age at the initial diagnose was 50 years (33–74). Initial tumor characteristic were: ductal carcinoma 49%; lobular carcinoma 41%;cancer mastitis 6,5%;not reported 3,5%; T1 34%; T2 52%; T3 4,5%; T4 6%;unknown 3,5%; Nodal status: positive 73,5%; negative 23%;not reported 3,5% Steroid receptor status: ER and/or PR positive 59%; both negative 14%; unknown 27%. Median time to relapse is 7 years, (range 5–29), the most frequent first relapse sites were: local recurrence (22%); carcinoma of the contralateral breast (18%); bone metastases (18%). Archived pathological specimens are identified for 63/111 (56,7%) patients and HER-2 status of the those primary breast carcinoma is: 0+ 36,5%; 1+ 34,9%; 2+ 9,5%; 3+ 14,2%; Thirty four patients (30,6%) had disease free interval 10 or more years, and HER-2 3+ in this subgroup is 17,6% (6/34). Conclusions: Long disease free interval in breast cancer patients is usually explained by initial more favorable cancer characteristics. Still, a significant percentage (14,2%) of our patients with median time to relapse of 7 years, initially had breast cancers with HER-2 3+. No significant financial relationships to disclose.
Chemotherapy in non-small cell lung cancer
Authors: R J Stephens, M K B Parmar, R L Souhami, S Spiro
Journal: BMJ (1996)

istration is focusing on this in its "health in the next millennium" work programme, as is the Medical Research Council in its Gambia project, and the Liverpool School of Tropical Medicine now incorporates non-communicable diseases into its diploma courses.We suggest that the specialty of tropical medicine should shift towards a broader specialty of "health in developing countries," with the multidisciplinary inputs that the authors recommend, rather than be subsumed into infectious diseases.
Abstract 17143: Obstructive and Central Sleep Apnea and Risk of Incident Atrial Fibrillation
Authors: Patricia Tung, Yamini S Levitzky, Rui Wang, Stuart F Quan, Daniel J Gottlieb, Michael Reuschman, Naresh M Punjabi, Suzie Bertisch, Emelia J Benjamin, Susan Redline
Journal: Circulation (2014)

INTRODUCTION: Prior studies have documented a higher prevalence of atrial fibrillation (AF) in those with obstructive sleep apnea (OSA). OSA has been associated with AF recurrence following cardioversion and ablation, and with prevalent and incident AF in cross-sectional and retrospective studies. Central sleep apnea (CSA) also has been associated with AF in patients with heart failure. However, data from prospective cohorts are sparse and few studies have evaluated the association of CSA with AF in population studies. METHODS: We assessed the association of OSA and CSA with incident AF among 3,420 subjects without a history of AF in the Sleep Heart Health Study (SHHS), a prospective, community-based study designed to evaluate the cardiovascular consequences of sleep disordered breathing. Subjects underwent overnight polysomnography at baseline and were followed over time for the development of incident AF, documented at any time after baseline polysomnogram until the end of follow-up. OSA was defined as an obstructive apnea-hypopnea index ≥ 5 and CSA was defined as a central apnea index ≥ 5. RESULTS: At baseline, the sample include 1499 men (44.4%) with a mean age of 62.4 (±10.9); 1569 (45.9%) subjects met criteria for mild to severe OSA and 54 (1.6%) for CSA. Over a mean follow-up of 8.2 years, 382 cases of incident AF were identified. The prevalence of both OSA and CSA was higher among those who developed AF compared to those who did not (OSA 49% vs 44%, p=0.001 and CSA 5% vs 1.2%, p=0.001). After adjustment for multiple AF risk factors, CSA was associated with an approximately 2-fold increased odds of incident AF (RR=2.38, 95% CI, 1.15-4.94; p = 0.02). The association persisted after exclusion of 258 subjects with a history of heart failure (RR=2.78, 95% CI, 1.28-6.04; p = 0.01). We did not find a significant association of OSA with incident AF (Table). CONCLUSION: In our prospective, community-based cohort baseline CSA was associated with incident AF.
Relation of C reactive protein to cardiovascular risk factors
Authors: W A C Sewell, S E Marshall, A G Bird, H M Chapel
Journal: BMJ (1996)

least, more than one symptom could be scored and perhaps more attention could be paid to the patients' experience of their illness,' including how they explain their illness and its course, what effect it has, how they feel about it, and what they expect of treatment (this is relatively easily done in an n of 1 trial).The n of 1 trial could indeed be used more in everyday clinical practice with good instruments, generic diaries, and a patient centred approach.
RNA interference-directed knockdown of urokinase plasminogen activator receptor inhibits MMPs expression via dephosphorylation of Erk1/2 and Stat3 in AML
Authors: Kwang-Sung Ahn, Yong-Ju Kim, Ju_won Park, Seonyang Park, Byoung-Kook Kim, Sung-Soo Yoon, Yong-Yeol Lee, Eunkyung Bae
Journal: Cancer Research (2006)

4355  Plasminogen activation is implicated in solid tumor growth, invasion and metatastic spread. extracellular proteolytic enzymes of the urokinase-type plasminogen activator (uPA) and metalloproteinase (MMP) family play a crucial role in the matrix degradation and tissue remodeling process characteristic of malignant disorders. The receptor for urokinase plasminogen activator (uPAR) serves to localize and intensify the action of uPA and is expressed on the surface of malignant cells. However, little is known about its role in leukemia. Since uPA and uPAR expression correlates with the progression of leukemia, therapies designed to inhibit uPA and uPAR expression would be beneficial. In this study, we utilized small hairpin RNAs (shRNAs), also referred to as small interfering RNAs, to target human uPAR. These small interfering RNA constructs significantly inhibited uPAR expression at both the mRNA and protein levels in myeloid leukemia cell line, HEL. uPAR knockdown in HEL cells resulted in a dramatic reduction of MMPs expression (MMP- 2,–9, MT-MMP-1) and tumor cell invasion as indicated by a Matrigel invasion assay. Furthermore, RNA interference for uPAR abrogated uPA-uPAR signaling to downstream target molecules such as JAK2, JNK, ERK1/2 and Stat-3. These findings uncovered evidence of a complex signaling network operating downstream of uPA-uPAR that actively contributes to leukemia progression. Thus, RNA interference-directed targeting of uPAR is a convenient and novel tool for studying the biological role of the uPAR system and suggests the potential of its application for leukemia therapy.
Activating Mutation in the Catalytic Domain of c-kit Elicits Hematopoietic Transformation by Receptor Self-Association Not at the Ligand-Induced Dimerization Site
Authors: Tohru Tsujimura, Koji Hashimoto, Hitoshi Kitayama, Hirokazu Ikeda, Hiroyuki Sugahara, Itaru Matsumura, Tsuneyasu Kaisho, Nobuyuki Terada, Yukihiko Kitamura, Yuzuru Kanakura
Journal: Blood (1999)