tbuckley/cabot-search huggingface dataset:
Abstract LB-92: RVX-2135 is a novel, orally bioavailable epigenetic BET inhibitor that synergizes with cytarabine and idarubicin to inhibit proliferation of acute myeloid leukemia cells.
Authors: Eric Campeau, Ravi Jahagirdar, Jin Wu, Emily M. Gesner, Olesya Kharenko, Raymond Yu, Sarah Attwell, Henrik C. Hansen, Gregory S. Wagner, Kevin G. McLure, Peter R. Young
Journal: Cancer Research (2013)

Abstract Current treatment of acute myeloid leukemia (AML) often includes a combination of intravenous cytarabine (Ara-C) and an anthracycline such as idarubicin. Bromodomain and extra-terminal domain (BET) proteins contain two bromodomains that bind to acetylated lysines in histones and regulate gene transcription by an epigenetic mechanism. Here we describe a novel small molecule BET inhibitor, RVX-2135, which selectively binds recombinant BET bromodomains of BRD2, BRD3, and BRD4 but not non-BET bromodomains. RVX-2135 inhibited BRD2, BRD3, and BRD4 dual bromodomains binding to acetylated histones in vitro with sub to low micromolar IC50 values. In the human AML cell line MV4-11, RVX-2135 displaced BET proteins from chromatin and significantly reduced expression of c-MYC and BCL-2 mRNAs, with IC50s of 4 and 5 μM, respectively. RVX-2135 inhibited proliferation of cultured MV4-11 cells with an IC50 value of 6 μM, and induced cell cycle arrest and apoptosis. In vivo, nude mice bearing MV4-11 xenografts were treated orally with RVX-2135 at doses of 75 and 120 mg/kg b.i.d, and showed tumor growth inhibition of 77 and 92% respectively. There was a corresponding inhibition of c-MYC and BCL-2 mRNA expression in the xenograft tumors. In combination therapy in vitro, RVX-2135 synergized with idarubicin and cytarabine, with Chou-Talalay's combination indices of 0.17 and 0.18, respectively. The synergistic effect also translated into increased apoptosis when cytarabine was combined with RVX-2135. Similar data were seen with BET inhibitors from different chemical scaffolds, suggesting that this may represent a promising new class of drugs for AML. Citation Format: Eric Campeau, Ravi Jahagirdar, Jin Wu, Emily M. Gesner, Olesya Kharenko, Raymond Yu, Sarah Attwell, Henrik C. Hansen, Gregory S. Wagner, Kevin G. McLure, Peter R. Young. RVX-2135 is a novel, orally bioavailable epigenetic BET inhibitor that synergizes with cytarabine and idarubicin to inhibit proliferation of acute myeloid leukemia cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-92. doi:10.1158/1538-7445.AM2013-LB-92
SAT0570 Cardiovascular Risk and Statin Therapy in Rheumatoid Arthritis and Spondyloarthritis
Authors: T. Eidner, G. Wolf, P. Oelzner
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Individual cardiovascular risk (CVR) in patients with inflammatory-rheumatic diseases can be estimated according to the SCORE-algorithm [1] and the EULAR recommendations for cardiovascular risk management [2]. <h3>Objectives</h3> To evaluate CVR in patients with rheumatoid arthritis (RA) or spondyloarthritis (SpA) in daily practice and to relate this risk to the frequency of statin therapy. <h3>Methods</h3> We studied 366 consecutive patients with RA and 101 patients with SpA from our university rheumatological outpatient department. The following data were collected: age (&gt;40 years), gender, duration of disease, RF/CCP-antibody-status, lipid-status, blood pressure/use of antihypertensive drugs, comorbidities (diabetes mellitus, cardiovascular diseases), smoking, use of statins. The 10-year-CVR was estimated according to the SCORE-algorithm [1] and the EULAR-recommendations [2]. For patients with diabetes mellitus or established cardiovascular disease (coronary heart disease, peripheral or cerebrovascular arterial occlusive disease) an indication for statin use was postulated. In patient without these comorbidities, an indication for statin use was supposed in case of a 10-year-risk for cardiovascular events of at least 10 %. <h3>Results</h3> Diabetes mellitus and/or a cardiovascular disease were comorbidities in 92 of 366 RA patients (25,1 %) and in 23 of 101 SpA-patients (22,8 %). From these patients 58 with RA (63 %) and 10 with SpA (43 %) were treated with statins. In 274 RA- and 78 SpA-pts. without these comorbidities the assumed 10-year-risk for severe cardiovascular events according to the SCORE-algorithm accounted for: - at least 10 % in 37 RA-pts. (13,5 %) and 9 SpA-pts. (11,5 %) - between 5 and 10 % in 68 RA-pts. (24,8 %) and 13 SpA-pts. (16,7 %) - under 5 % in 169 RA-pts. (61,7 %) and 56 SpA-pts. (71,8 %) From 46 pts. with CVR of at least 10 % only 8 pts. (17,4 %) were treated with statins. <h3>Conclusions</h3> In both RA- and SpA-patients diabetes mellitus or established cardiovascular diseases are common comorbidities, in these pts. statins are a common comedication. In contrast, in patients without these comorbidities but with high cardiovascular risk statins are only rarely used. Therefore, particularly patients over 60 years should be examined for the individual cardiovascular risk including reassessing the indication for statin use at least yearly. This requires a tight cooperation between rheumatologist and general practitioner. <h3>Acknowledgements</h3> Conroy et al.; Eur Heart J 2003;24:987–1003. Peters et al.; Ann Rheum Dis 2010 69: 325-331. <h3>Disclosure of Interest</h3> None Declared
PTH-083 Methylation Signatures of Non-Expressed Genes Reveal Insights into the Effects of Inflammation on Stem Cell Dynamics and Crypt Fission in Inflammatory Bowel Disease
Authors: N Jawad, T Graham, M Novelli, M Rodriguez-Justo, N Wright, S McDonald
Journal: Gut (2013)

<h3>Introduction</h3> Inflammatory bowel disease (IBD) confers a high risk of development of colitis-associated colorectal cancer (CACRC) in patients with extensive colitis. Crypt fission (a crypt bifurcating into two) has been shown to be a mechanism of clonal expansion in the intestinal epithelium. Although fission is rare in normal colon, many crypts in patients with colitis appear to be in the process of fission. A recent study from the host laboratory demonstrated that protumourigenic mutations can spread through the entire inflamed colon suggesting that this occurs at a considerable rate indicating stem cell dynamics are altered in IBD<sup>1</sup>. <h3>Methods</h3> Somatic mitochondrial DNA (mtDNA) mutations are a reliable marker of clonal expansion in human colon. Combining mtDNA mutations with additional markers of clonal expansion that change over time, such as methylation patterns of non-expressed genes, reveals whether populations of cells show a recent ancestry. This is measured by evaluating methylation pattern diversity between samples. Methylation patterns of <i>CSX</i> and<i> MYOD1</i> genes were examined in clonally related and unrelated crypts from multiple areas in IBD patients by laser capture microdissection bisulphite sequencing. Clonality was demonstrated by cytochrome <i>c</i> oxidase deficient (CCO-) cells sharing an identical somatic mtDNA mutation. <h3>Results</h3> In active inflammation, both adjacent clonally related CCO- crypts and adjacent unrelated crypts had similar methylation patterns, indicating recent crypt fission. In contrast, adjacent unrelated crypts in quiescent disease had dissimilar methylation patterns, indicating that crypt fission rates are slow and resemble that of normal colon. The number of unique methylation patterns in crypts from active IBD were significantly less than those obtained from normal patients suggesting that niche succession (a stem cell populating the niche) is elevated in IBD. <h3>Conclusion</h3> Elevated crypt fission in active IBD may explain the extensive dispersion of protumourigenic clones previously observed in IBD. Subsequent cycles of crypt atrophy and mucosal healing by crypt fission, may provide a key growth stimulus in the inflamed colon. Furthermore, there appears to be an increased rate at which a single stem cell populates the niche within IBD crypts. Such expansion facilitates the establishment of protumourgenic mutations within crypts. <h3>Disclosure of Interest</h3> None Declared. <h3>Reference</h3> Galandiuk S, Rodriguez-Justo M, Jeffery R, Nicholson AM, Cheng Y, Oukrif D, Elia G, Leedham SJ, McDonald SA, Wright NA<i> et al.</i> 2012. Field cancerization in the intestinal epithelium of patients with Crohn’s ileocolitis.<i> Gastroenterolog</i>y<b> 14</b>2: 855–864 e858
Abstract SY28-04: Targeting the tumor extracellular matrix with armed antibodies
Authors: Dario Neri
Journal: Cancer Research (2012)

Abstract Antibodies can be used to deliver bioactive molecules (drugs, cytokines, photosensitizers, radionuclides, etc.) to the tumor environment, thus sparing normal tissues. The targeting of modified sub-endothelial extracellular matrix components using armed antibodies is particularly attractive, because of: (i) the abundance and stability of some of these antigens (e.g., splice isoforms of fibronectin and tenascin-C); (ii) the dependence of cancer on new blood vessels (iii) accessibility of these structures from the blood-stream (iv) the fact that some of these antigens are very aboundant in many different cancer types, while being virtually undetectable in most normal adult tissues. Advanced preclinical and clinical data on armed antibodies will be presented in this lecture. References: Neri &amp; Bicknell (2005) Nature Rev. Cancer, 5: 436-446 Neri &amp; Supuran (2011) Nature Rev. Drug Discov.: 10: 767-777 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY28-04. doi:1538-7445.AM2012-SY28-04
The Essentials of Materia Medica and Therapeutics for Nurses.
Journal: JAMA (1918)

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 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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
The phase I clinical compound SNS-595 acts during S-phase and causes a sustained G2 arrest
Authors: Jennifer Hyde, Jasmin Wright, Neil Osheroff, Jeffery A. Silverman, Duncan H. Walker, Michelle R. Arkin
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

2293 

Although recent research has identified cancer therapies with non-cytotoxic mechanisms, there is still a need to discover and develop the next generation of cytotoxics with strong activities, manageable toxicities, and novel mechanisms of action. SNS-595 is a first-in-class naphthyridine compound that demonstrates potent cytotoxic activity as well as robust antineoplastic activity in several syngeneic and human xenograft tumor models, and is currently in phase I clinical trials for solid tumors. In vitro, SNS-595 has been observed to induce G2 cell cycle arrest and subsequent apoptosis in various cancer cells, including many multi-drug resistant lines. The effect of SNS-595 on cell cycle progression and checkpoint stimulation has been characterized and compared to the effects of a number of therapeutically relevant cell cycle modulators (cisplatin, docetaxol, gemcitabine, etoposide, doxorubicin, irinotecan, bleomycin, and mitomycin C). Cell cycle progression was analyzed using both DNA content and the cell cycle markers cyclins A, B, and E. In asynchronous populations, SNS-595 treatment causeed a full G2 arrest in all cell lines tested. This arrest was accompanied by rapid apoptosis as determined by DNA fragmentation. In synchronized cell populations treated with SNS-595, cells cycled normally until they reached S phase, which was 30% longer than in untreated cells. Checkpoint markers (chk kinases, cdc25 phosphatases, cdc2, and p21) appeared rapidly upon entering S phase, and the cells eventually reached a sustained and irreversible arrest with 4N DNA content. SNS-595 is shown to be distinct from the other G2 arrestors tested in that it causes p21 expression early in S phase and a significant S-phase lag. SNS-595 is also differentiable from other S-phase active compounds in showing a definitive arrest at G2 as opposed to a varied G1/S/G2 arrest profile. Further research into the stimulation of checkpoint and apoptotic pathways by SNS-595 will lead to a more detailed understanding of this compound’s potent anticancer activity.
Abstract 4183: Modeling soft tissue sarcomas by conditional inactivation of p53 and Rb tumor suppressor genes
Authors: Jinhyang Choi, David M. Roy, Stephen J. Curtis, Andrea Flesken-Nikitin, Chang-il Hwang, Wei Wang, Alexander Yu. Nikitin
Journal: Cancer Research (2010)

Abstract Soft tissue sarcomas, particularly its most common type, undifferentiated pleomorphic sarcomas (also known as malignant fibrous histiocytomas), frequently carry mutations in p53 and Rb tumor suppressor genes. We have established the sarcoma mouse model using conditional inactivation of p53 and Rb by a single subcutaneous injection of adenovirus carrying Cre-recombinase into transgenic mice with floxed copies of p53 and Rb genes. The majority of sarcomas in this model are malignant fibrous histiocytomas, which is a neoplasm consisting of intermixed fibroblast- and histiocyte-like cells. By using irradiation chimeras that have been generated by transplanting bone marrow cells from mice carrying the Rosa26StopLacZ or the Z/EG reporter, as well as floxed p53 and Rb genes, to irradiated p53loxP/loxPRbloxP/loxP mice, we have determined that sarcomas in this model do not originate from hematopoietic cells but arise from the local resident cells. Although the majority of dermal cells infected with AdCMVCre-eGFP have shown expression of fibroblast marker procollagen type I or macrophage marker F4/80, we have observed that cells expressing stem cell markers Sca-1 and nestin also have been targeted by adenovirus. Notably, isolated mesenchymal multipotent cells characterized by strict plastic adherence and low levels of Sca-1 expression have shown enhanced potential for malignant transformation according to proliferation, invasion, and soft agar assays, following conditional inactivation of p53 and Rb. Additionally, we have determined that sarcomas have increased expression of CXCR4, while its ligand SDF-1 is expressed by infiltrating macrophages. Treatment of sarcoma cells with SDF-1 leads to their increased invasion in Boyden chamber assay while CXCR4 knockdown with siRNA abrogates this effect. Taken together, our results indicate that local Sca-1low multipotent dermal stem/progenitor cells may be a preferential target for malignant transformation associated with p53 and Rb deficiency. Furthermore, accumulation of SDF-1 producing macrophages may stimulate sarcomagenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4183.
PERCUTANEOUS LIGATION OF THE LEFT ATRIAL APPENDAGE RESULTS IN ATRIAL ELECTRICAL SUBSTRATE MODIFICATION
Authors: Faisal F. Syed, Samuel Asirvatham, Venu Rangu, Susan Mikell, Dorothy Ladewig, Andrew Danielsen, Susan Johnson, Douglas Packer, Charles Bruce, Paul Friedman
Journal: Journal of the American College of Cardiology (2013)
Assessing Tumor Hypoxia in Head and Neck Cancer by PET With 62Cu-Diacetyl-Bis(N4-Methylthiosemicarbazone)
Authors: Yoshitaka Sato, Tetsuya Tsujikawa, Myungmi Oh, Tetsuya Mori, Yasushi Kiyono, Shigeharu Fujieda, Hirohiko Kimura, Hidehiko Okazawa
Journal: Clinical Nuclear Medicine (2014)

The aim of this study was to investigate the potential of PET imaging with a hypoxia-selective tracer ⁶²Cu-diacetyl-bis(N⁴-methylthiosemicarbazone) (⁶²Cu-ATSM) for evaluating the prognosis of patients with head and neck cancer (HNC).Twenty-five patients with HNC including stage II to IV underwent both ⁶²Cu-ATSM and ¹⁸F-FDG PET before the initiation of treatment. Volumes of interest were placed on the tumor and sternocleidomastoid muscles to obtain SUVmax and to calculate the tumor-to-muscle activity ratio (TMR). The PET results were correlated with clinical follow-up, and the receiver operating characteristic analysis was used to determine the optimal cutoff values. Progression-free survival (PFS) and cause-specific survival (CSS) were statistically analyzed.Patients were followed up for periods ranging from 4 to 32 months. Twelve patients died from local recurrence or metastasis of a primary cancer, and 2 had recurrence of the 13 remaining patients. Mean (SD) periods of PFS and CSS were 15.5 (12.5) and 18.6 (11.0) months, respectively. Optimal cutoff values for each PET index were as follows: SUVs of ⁶²Cu-ATSM (SUVATSM) and FDG were 3.6 and 7.9; TMRs of ATSM (TMRATSM) and FDG were 3.2 and 5.6. When the cutoff for TMRATSM was set at 3.2, patients with a greater TMRATSM had significantly worse PFS (P = 0.014) and CSS (P = 0.031). Two-year PFS and CSS rates were 73% and 80% for patients with a lower TMRATSM (≤3.2); however, they were 20% and 33% for those with hypoxic tumors (TMRATSM, >3.2), respectively. F-FDG-related indices did not show any significant difference in either PFS or CSS.Pretreatment ⁶²Cu-ATSM PET is useful for predicting the prognosis of patients with HNC.
Sudden Death for a Challenge to Federal Funding of Stem-Cell Research
Authors: George J. Annas
Journal: New England Journal of Medicine (2011)

The National Institutes of Health (NIH) and researchers using human embryonic stem cells (ESCs) have been operating under some uncertainty since the August 2010 ruling by federal districtcourt judge Royce Lamberth that the Dickey–Wicker Amendment (which Congress has attached to all appropriations bills for the Department of Health and Human Services [DHHS] since 1996) prohibits the NIH from funding human ESC research.1 Two scientists had challenged the NIH's 2009 guidelines that permitted the agency to fund research using human ESCs that had been derived without the use of federal funds. Judge Lamberth found the funding prohibition in Dickey–Wicker unambiguous and . . .
Case 44-1990
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, Deeb N. Salem, James F. Southern
Journal: New England Journal of Medicine (1990)

Presentation of CaseA 71-year-old woman was admitted to the hospital with biventricular congestive heart failure and a pericardial effusion.The patient was well and active until four months earlier, when she began to have epigastric "pressure" on exertion, sometimes accompanied by dyspnea and relieved by one minute of rest. About the same time she also noticed the onset of an intermittent petechial rash that tended to occur at points of contact or friction with her clothing.Two months before entry a prolonged episode of epigastric pressure and dyspnea occurred, and she was admitted to another hospital. An electrocardiogram showed . . .
Abstract PD06-01: Automated computational Ki67 scoring in the GeparTrio breast cancer study cohort
Authors: F Klauschen, S Wienert, J-U Blohmer, BM Mueller, W Eiermann, B Gerber, H Tesch, J Hilfrich, J Huober, T Fehm, J Barinoff, C Jackisch, E Erbstoesser, S Loibl, C Denkert, G von Minckwitz
Journal: Cancer Research (2012)

Abstract Background: Scoring proliferation through Ki67-immunohistochemistry is an important component in predicting therapy response to chemotherapy in breast cancer patients. Therefore, an accurate and standardized Ki67-scoring is pivotal both in routine diagnostics and larger multi-center studies aiming at improving present or establishing new cut-off values for existing or novel therapy regimens. However, recent studies have cast some doubt on the reliability of “visual” Ki67 scoring by pathologists, especially within the lower - yet clinically important - proliferation range. Here, we present and apply a novel automated image analysis approach for Ki67-quantification in breast cancer tissue. Methods: We perform automated Ki67-scoring in 1219 breast cancer patients from the GeparTrio study cohort using a novel image analysis approach that avoids detection biases due to morphological variability by using a generic minimum-model approach. The method is capable of tumor-stroma-separation and may be used to process large data sets fully unsupervised in batch mode while allowing for efficient visual checks of the results. We compare these results with a different in-house-developed subtiling-based automated quantification method and moreover, gauge our approach with manual scoring performed by pathologists. Results: The results show deviations of 10% (automated method 1 vs. manual), 9% (automated method 2 vs. manual) and 3% (automated method 1 vs. automated method 2) on average. The Ki67 scores show Pearson correlations between automated and manual scoring of r&amp;gt;0.8 (p &amp;lt; 0.001) for both automated methods and r&amp;gt;0.95 (p &amp;lt; 0.001) between the two tested automated methods. Conclusion: Because of the methodological differences of the presented techniques our results suggest a high robustness of the automated methods that at the same time show a good agreement with manual Ki67 scoring. Our approach therefore offers an automated and standardized means of Ki67 quantification applicable in routine diagnostics as well as larger clinical study settings, such as in the GeparTrio cohort shown here. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD06-01.
The American Health Care System
Authors: John K. Iglehart
Journal: New England Journal of Medicine (1992)

America's private and public third-party payers, squeezed by health care costs that continue to soar at rates well above inflation, are persuaded that "managed care" plans will produce demonstrable savings as compared with the current cost trends of traditional fee-for-service medicine. They are accelerating their efforts to promote plans that integrate the delivery and financing of care and that apply new constraints on encounters between physicians and patients. The key constraint for doctors is the limitation placed on the autonomy of their clinical decisions. The constraint for patients is the requirement that they see only physicians who are members of . . .