tbuckley/cabot-search huggingface dataset:
Abstract 873: Combined targeting of Akt and MEK with the Akt inhibitor GDC-0068 and MEK inhibitor GDC-0973 demonstrates synergistic anti-tumor effects
Authors: Michelle A. Nannini, Rebecca Hong, Brian B. Lee, Alfonso Arrazate, Robert Kassees, Jie Lin, Michael Degtyarev, Deepak Sampath, Kui Lin
Journal: Cancer Research (2012)

Abstract Background: Akt, a serine/threonine protein kinase, and MEK, a dual specificity kinase, are key signaling nodes in the PI3K/Akt/mTOR and the Ras/Raf/MAPK pathway, respectively. Both Akt and MEK play key roles in regulating numerous cellular processes such as cell proliferation, growth, survival, protein synthesis and oncogenic transformation. Many cancer types have alterations in both of these pathways and inhibiting only one of these pathways can result in up-regulation of the other pathway. We previously reported on a potent highly selective ATP-competitive pan-Akt inhibitor, GDC-0068 as well as a potent selective inhibitor of MEK, GDC-0973 that are currently in Phase 1 clinical trials. We hypothesized that dual inhibition of both MEK and Akt pathways with the combination of these two agents would induce synergistic antitumor activity. Methods: In these studies, we evaluated the efficacy of GDC-0068 and GDC-0973 both individually and in combination on a panel of cancer cell lines. Cells were treated with either GDC-0068 or GDC-0973 or in combination at increasing concentrations and assayed after 4 days for viability. For in vivo studies, tumor cells were subcutaneously implanted in the flank of female NCR.nude mice. Once tumors reached sufficient size, mice were dosed orally for 21 days with GDC-0068, GDC-0973 or the combination of both compounds. Results: In vitro, the combination of GDC-0068 and GDC-0973 results in enhanced inhibition of cell viability compared to either single agent alone. Synergistic effects are observed in multiple cell lines; especially in cell lines that have activation of the Ras/Raf/MAPK pathway or both pathways (e.g. via the combination of PTEN loss or PI3K mutations and Ras or BRaf mutations). Combined knockdown of downstream targets of both Akt and MEK is observed at concentrations where a synergistic effect is observed, with enhanced knockdown of several converged targets. Increased cell death is also observed. These results were recapitulated in vivo in xenograft models, where the combination of GDC-0068 and GDC-0973 resulted in increased tumor growth inhibition or regression compared to either single agent alone. All combinations tested were well tolerated as assessed by animal body weights and mortalities. Conclusions: Our studies demonstrate significant combination benefit between GDC-0068 and GDC-0973 on cell viability in vitro and tumor growth in vivo. These data support the clinical development of the combination of these two compounds. 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 873. doi:1538-7445.AM2012-873
The effects of hormonal replacement therapy (HRT) on mammographic breast density and abnormal mammograms prompting further investigation.
Authors: Liran Barda, Avinoam Nevler, Esther L Shabtai, Mordechai Gutman, Moshe Shabtai
Journal: Journal of Clinical Oncology (2014)

8 Background: Mammographic density has been associated with higher risk of breast cancer and lower sensitivity. HRT has been implicated with increased density and is also a risk factor. The relationship between HRT, breast density, and mammographic findings requiring investigation has not been fully investigated. We aimed at analyzing this correlation. Methods: 2,758 consecutive, single-center screening mammograms performed during 1 year were analyzed. Mammograms were supplemented by ultrasound. Density was measured by a semiquantitative, 5-grade scale, and grouped into low (1-3) (LDM) and high density (4-5) (HDM). Demographic and obstetric data, personal and family history of breast cancer, and the use of HRT were entered into database. These parameters were correlated with breast density and any abnormality detected. Univariate and multivariate analysis as well as multivariate logistic regression were performed on SAS 9.2. Results: Mean overall age was 48 (SD = 10.8, range 27-78), mean ages of LDM and HDM groups were 59 ± 10.5 and 50.9 ± 9.3 respectively (p = 0.001). Of 2,758 tests, 2,094 (76%) were LDM and 664 (24%) were HDM. 1,962 women (71%) were postmenopausal and 592 (30%) were on HRT. A difference in density between pre- and postmenopausal women was observed (p = 0.0001). HRT was not associated with higher rate of HDM (18%, n = 105/582) vs.15% n = 211/1370 (p = n.s) without HRT. Abnormality was more likely in postmenopausal HRT-less (52% n = 711/1370) vs. (30% n = 226/582) HRT (p = 0.0001) including solid lump (p = 0.0001), tissue irregularity (p = 0.016) and calcifications (p = 0.0005). Menopause was associated with 48% of any finding vs. 41.4% in pre-menopause women (p = 0.0017). 104 malignant lesions were found in 267 with mammographic findings prompting histological assessment. HRT was associated with lower incidence (28%) of malignancy compared to 50% without HRT. Conclusions: HRT was not associated with increased density nor with higher risk of malignancy; moreover, a lower rate of mammographic abnormality was noted. Albeit further studies are required, the results of this study do not support the notion that HRT increases the likelihood of malignancy or affects breast density.
The Role of Cholesterol in Cancer
Authors: Omer F. Kuzu, Mohammad A. Noory, Gavin P. Robertson
Journal: Cancer Research (2016)

The roles played by cholesterol in cancer development and the potential of therapeutically targeting cholesterol homeostasis is a controversial area in the cancer community. Several epidemiologic studies report an association between cancer and serum cholesterol levels or statin use, while others suggest that there is not one. Furthermore, the Cancer Genome Atlas (TCGA) project using next-generation sequencing has profiled the mutational status and expression levels of all the genes in diverse cancers, including those involved in cholesterol metabolism, providing correlative support for a role of the cholesterol pathway in cancer development. Finally, preclinical studies tend to more consistently support the role of cholesterol in cancer, with several demonstrating that cholesterol homeostasis genes can modulate development. Because of space limitations, this review provides selected examples of the epidemiologic, TCGA, and preclinical data, focusing on alterations in cholesterol homeostasis and its consequent effect on patient survival. In melanoma, this focused analysis demonstrated that enhanced expression of cholesterol synthesis genes was associated with decreased patient survival. Collectively, the studies in melanoma and other cancer types suggested a potential role of disrupted cholesterol homeostasis in cancer development but additional studies are needed to link population-based epidemiological data, the TCGA database results, and preclinical mechanistic evidence to concretely resolve this controversy. Cancer Res; 76(8); 2063-70. ©2016 AACR.
The Prevalence of Drug-Resistant<i>Streptococcus pneumoniae</i>In Atlanta
Authors: Jo Hofmann, Martin S. Cetron, Monica M. Farley, Wendy S. Baughman, Richard R. Facklam, John A. Elliott, Katherine A. Deaver, Robert F. Breiman
Journal: New England Journal of Medicine (1995)

Streptococcus pneumoniae is a major cause of illness, and the emergence of drug-resistant strains threatens to complicate the management of pneumococcal infections. We conducted a laboratory-based surveillance for drug-resistant S. pneumoniae among patients with invasive pneumococcal infections in Atlanta.
THU0484 Impact of TNF Antagonists on the Joint Manifestations of Sarcoidosis
Authors: C. Banse, A. Bisson-Vaivre, M. Kozyreff-Meurice, S. Dominique, O. Vittecoq, V. Goeb
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> Use of anti-TNF agents to treat joint manifestations of sarcoidosis has not been described. We evaluated the efficacy and safety of 3 such biologics in patients with these symptoms refractory to conventional therapy (NSAIDs, corticosteroids and/or DMARDs). <h3>Methods</h3> This retrospective study, covering January 2001 to September 2011, examined the following clinical–biological parameters collected before anti-TNF treatment (age, sex, duration of disease evolution, drugs taken), and at introduction and under anti-TNF therapy (number of painful and swollen joints, visual analogue-scale score of global disease activity, Disease Activity Score-28 with ESR or CRP, TNF-antagonist duration). At 3, 6 and 12 months, anti-TNF impact on joints and the therapeutic response according to EULAR criteria used for rheumatoid arthritis were assessed. <h3>Results</h3> Ten patients data were evaluated; some of them had received several anti-TNF agents (median (range) duration on each biotherapy was 10 (4–30) months), which enabled analysis of 19 prescriptions. The total duration of anti-TNF exposure was 17.6 patient-years, that was started a median of 3 (0.33–17) years after sarcoidosis diagnosis. The median numbers of painful and swollen joints were, respectively, 1 (0–28) and 0 (0–9). Despite rapid efficacy, after 1 year of treatment, clinical (especially joint) and biological parameters were comparable to pretreatment and only the corticosteroid dose was significantly lower (<i>P =</i> 0.03). One case of mild skin toxicity was noted. <h3>Conclusions</h3> TNF antagonists allowed significant steroid-sparing and were well-tolerated but do not seem to be effective against sarcoidosis joint involvement. <h3>Disclosure of Interest</h3> None Declared
COST IMPLICATIONS OF PROCEDURAL THROMBOTIC COMPLICATIONS IN PATIENTS UNDERGOING PERCUTANEOUS CORONARY INTERVENTION: RESULTS FROM THE CHAMPION PHOENIX ECONOMICS STUDY
Authors: Hector Tamez, Philippe Genereux, Weihong Fan, Ajay Kirtane, Stephanie Plent, Efthymios Deliargyris, Jayne Prats, Gregg Stone, C. Michael Gibson, Robert Harrington, Deepak Bhatt, Duane Pinto
Journal: Journal of the American College of Cardiology (2016)
SP0144 The Role of Omega-3 Derived Resolvins in Arthritis
Authors: M. Perretti
Journal: Annals of the Rheumatic Diseases (2013)

<h3></h3> Omega-3 polyunsaturated fatty acids (PUFAs) are beneficial as coadjuvant therapy in Rheumatoid arthritis patients, with indication for efficacy in reducing joint pain, morning stiffness and NSAID usage. It is likely that they exert beneficial effects through specific molecular mechanisms, which have been poorly investigated. Recent work has identified that omega-3 PUFA; eicosapentaenoic acid and docosahexaenoic acid can be enzymatically converted <i>in vivo</i> to novel bioactive lipid mediators, which promote the resolution of inflammation and are log-orders more potent than their precursors, termed resolvins. Delivery of resolvins, such as Resolvin D1 or D2, affords potent tissue protection in a variety of disease models, from lung inflammation to sepsis, from ocular to periodontal disease. I will discuss how resolvins exert inhibitory effects on acute inflammation and how these findings may be translated to relevant models of inflammatory arthritis. Definition of the mode of action of omega-3 PUFA can lead to the development of novel therapeutics, active at lower dosages, able to activate tissue-specific reparative circuit with beneficial effects in arthritis. I acknowledge the contribution of my colleague, Dr Lucy Norling. Our work on omega-3-derived resolvins is supported by Arthritis Research UK <h3>Disclosure of Interest</h3> None Declared
SAT0479 Bloodstream Infections (BSI) in Finnish Children with Juvenile Idiopathic Arthritis in 2004-2011
Authors: P. H. Salonen, M. Leirisalo-Repo, H. Repo, H. Säilä, J. H. Salonen, M. Kauppi, M. Vuorela, O. Lyytikäinen, H. Kautiainen
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> The treatment of JIA has become more effective by means of biological disease modifying antirheumatic drugs (DMARDs). Biological DMARDs, however, increase the risk of infections. <h3>Objectives</h3> The aim of the study is to find out the incidence and the individual risk factors for bloodstream infections in JIA. <h3>Methods</h3> The Social Insurance Institution (SII) register of reimbursement of medicines and National Infectious Disease Register (National Institute of Health and Welfare) were used to identify JIA patients aged 2-18 years hospitalized for BSI during the years 2004-2011. Antirheumatic treatment of JIA was searched by using SII nationwide register. We also analysed the incidence of BSI in JIA patients with new diagnosis during the study period, and compared it with BSI in Finnish population of same age and study period. <h3>Results</h3> By means of combination of the register data we found a total of 10 patients (11 episodes) with BSI during the study period. The median age of children was 14 years. One patient had two distinct episodes of BSI. Pneumonia was the most common focus of infection. The following bacteria were detected: <i>Staphylococcus aureus</i> (4 cases), <i>Streptococcus pneumoniae</i> (3 cases), <i>Staphylococcus epidermidis, Escherichia coli, Fusobacterium necroforum</i> and <i>Pseudomonas aeruginosa</i> in one patient, respectively. Six patients were on biological DMARD and four on glucocorticoid treatment. We identified 1604 patients with JIA diagnosed in 2004-2011 with 6630 patient years of follow-up. Five JIA patients (7.5 infections/10 000 patient years, 95% CI 2.4 – 17.6) and 2184 control population subjects (2.8 infections/ 10 000 patient years, 95% CI 2.7 – 2.9) had BSI. <h3>Conclusions</h3> Bloodstream infections seem to be rare in patients with JIA. Interestingly, half of the patients with BSI were on biological DMARDs. Compared with control population, the standardized incidence ratio for BSI in JIA patients was 3.0 (95% CI 1.25 – 7.20). <h3>References</h3> Hashkes PJ, Uziel Y, Laxer RM. The safety profile of biologic therapies for juvenile idiopathic arthritis. Nat Rev Rheumatol 2010;6:561-571. Beukelman T, Xie F, Chen L et al. Rates of hospitalized bacterial infection associated with juvenile idiopathic arthritis and its treatment. Arthritis Rheum 2012;64:2773-2780. <h3>Disclosure of Interest</h3> None Declared
Aortic Coarctation and Bicuspid Aortic Valve
Authors: C J Bruce, J F Breen
Journal: New England Journal of Medicine (2000)

Figure 1. A 30-year-old farmer was referred for evaluation of a bicuspid aortic valve. He had no history of hypertension. He had no symptoms other than mild dyspnea and aching calves on walking briskly. On examination he had a regular pulse (78 beats per minute) with a pronounced radiofemoral delay. The blood pressure was 148/92 mm Hg in the right arm and 148/76 mm Hg in the left arm while he was sitting upright. A grade 3/6 mid-to-late systolic murmur was present at the apex. Electrocardiography revealed normal sinus rhythm without features of left ventricular hypertrophy. The chest roentgenogram revealed . . .
Abstract 3640: Age-related DNA methylation in normal breast tissues.
Authors: Kevin C. Johnson, Amanda K. Jensen, Megan A. Murphy, Devin C. Koestler, Brock C. Christensen
Journal: Cancer Research (2013)

Abstract Age-related DNA methylation in normal breast tissues It is well established that age is a key risk factor for breast cancer, with increasing incidence associated with older age. Epigenetic mechanisms, such as DNA methylation alterations, may contribute to age-related increases in breast cancer risk. Altered patterns of DNA methylation can modify the regulation of gene expression or expression potential, and DNA methylation alterations are frequently observed in the early stages of breast tumorigenesis. However, genome-wide interindividual variation in normal breast DNA methylation has not been well characterized for its relation with age and other key breast cancer risk factors. To investigate the relationship between age and DNA methylation in normal breast tissues, we first performed a meta-analysis using two independent data sets GSE32393 (n=23) and GSE31979 (n=15), from the Gene Expression Omnibus (GEO) database. For each of the considered datasets, genome-wide DNA methylation was assessed using the Illumina Infinium HumanMethylation27 Beadchip, which profiles the methylation status of ∼27,000 CpG loci, associated with &amp;gt;14,000 genes. Associations between DNA methylation and age were examined by fitting a series of linear regression models to arcsine square root transformed average beta values for all CpG loci in both data sets. Between these data sets, 204 CpG loci were significantly and consistently associated (P &amp;lt; 0.05) with subject age. Relative to the distribution of CpG loci on the array, we observed a significant enrichment of age-related DNA methylation patterns at CpG loci residing in CpG islands (P = 8.7e-6). Further, compared to non-island CpGs, loci in CpG islands were significantly more likely to exhibit increased age-related methylation (P = 0.008). To validate observed age-related DNA methylation, we performed bisulfite pyrosequencing of selected CpGs in an independent set of normal breast tissues (n=20) obtained through the National Disease Research Interchange. Our findings demonstrate consistent age-related methylation changes in normal breast tissue that may represent early events contributing to breast carcinogenesis and additional investigation for enrichment of local sequence and bioinformatic features near CpGs with age-related methylation is ongoing. This work contributes to the understanding of epigenetic mechanisms by which age serves as a major risk factor in the development of breast cancer. Citation Format: Kevin C. Johnson, Amanda K. Jensen, Megan A. Murphy, Devin C. Koestler, Brock C. Christensen. Age-related DNA methylation in normal breast tissues. [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 3640. doi:10.1158/1538-7445.AM2013-3640
The Value of Immunotherapy with Venom in Children with Allergy to Insect Stings
Authors: Martin D. Valentine, Kenneth C. Schuberth, Anne Kagey-Sobotka, David F. Graft, Kathy A. Kwiterovich, Moyses Szklo, Lawrence M. Lichtenstein
Journal: New England Journal of Medicine (1990)

The treatment of patients allergic to insect stings with insect-venom injections has been shown to be 97 percent effective in reducing the risk of sting-induced anaphylaxis. However, the frequency of systemic reactions to subsequent stings in unimmunized adults with previous reactions is approximately 60 percent. To determine which factors, in addition to a history of reaction and evidence of venom-specific IgE antibody, predispose patients to future insect-sting reactions, we studied a venom-sensitive group of children who were deemed to be at relatively low risk for severe reactions; 28 percent of them received venom therapy.
P59 * DIAGNOSTIC APPLICATION OF VIBRATIONAL SPECTROSCOPY FOR THE SEGREGATION OF BRAIN TUMOUR CELL LINES COUPLED WITH MULTIVARIATE STATISTICS
Authors: T. Mudariki, R. W. Lea, G. Clemens, M. J. Baker
Journal: Neuro-Oncology (2014)

INTRODUCTION: Brain tumours are caused by the proliferation and multiplication of single cells which go through molecular mutations. These neoplasms are identified histologically through an increased cellular grouping and disorder in tissue giving it a unique morphological appearance. Histopathology has been shown to be highly subjective and pathological discrepancies have been shown to occur in 1-43% of specimen. Raman and Infrared spectroscopy are types of vibrational spectroscopy which have a potential to be used as diagnostic tools in neuropathology. They provide an intrinsic molecular fingerprint of the sample based on the interaction of light and the sample. Our study investigates the potential application of vibrational spectroscopy in the segregation of different types of brain tumours using two tumour cell lines and a control. METHOD: U87MG (WHO grade IV), 1321N1 (WHO grade III) and SVGP12 (Control) cells were cultured based on the manufacturers protocols and fixed on CaF2 slides using 10% formalin and left to dry at room temperature. Spectra were collected using ATR-FTIR and Raman spectroscopy from three biological replicates of each cell line, n = 30. RESULTS: PCA, DFA and SVM models were able to separate the three cell lines based on their chemical information with very high sensitivities, 1321N1 = 100%, SVGP12 = 100%, U87MG =90% and specificities 1321N1 = 100, SVGP12 = 100% and U87MG =94.7%. Separation based on the loading was mostly due to C-C/C-O phospholipids, CH3 CH2 wagging mode of collagen, nucleic acids, proteins and lipids. CONCLUSION: Both Infrared and Raman spectroscopy can be used as diagnostic tools to purge chemical information on biological samples with good reproducibility.
Commentary: Science and Politics: The Possible Regulation of Cancer Promoters
Authors: Jerry R. Williams, William L. Clark
Journal: Environmental Health Perspectives (1983)

To address the problems associated with the regulation of tumor promoters, one must recognize that a regulatory agency's actions in the formulation of policy redound from a matrix of political, social and scientific pressures; each affecting the other, and all influencing the final policy outcome. Scientific understanding of the mechanism(s) of tumor promotion plays a determinant role in such interaction, for the selection of particular biological tests as surrogates for human response to chemical exposure provides the radical upon which such interaction occurs, industry responding to the legal, regulatory instrument that relies in turn on scientific confidence in required tests. These parties operate within the penumbra cast by political expedients, environmental action groups, and special interest lobbies whose concerns involve the cost of testing, the availability of resources, the consideration of particular chemicals of economic or symbolic value, and other such aspects of regulatory policy or its consequence. In examining the complex development of policy for future regulation of tumor promoters, we must attend first to the legal instrument framing such regulations, assessing probable impact on these various scientific, economic, social and political factors. Potential regulation of most tumor promoters would fall within the regulatory ambit of the U.S. Environmental Protection Agency, specifically the Toxic Substances Control Act of 1976 (TSCA). As with other regulatory acts, the making of public policy, in this case concerning the manufacture and use of chemicals, derives from two major concerns: the attempt to achieve technical analyses of risks and benefits as one base for regulation, and a gener-