tbuckley/cabot-search huggingface dataset:
DOES BASELINE GLOBAL LONGITUDINAL STRAIN PREDICT MORTALITY IN HIGH RISK PATIENTS WITH AORTIC STENOSIS AND LEFT VENTRICULAR DYSFUNCTION?
Authors: Amit Vora, Fawaz Alenezi, Allison Dunning, Phillip Schulte, Svati Shah, Joseph Kisslo, John Harrison, Eric Velazquez, Zainab Samad
Journal: Journal of the American College of Cardiology (2015)
Abstract 3163: ZMAT3, a signature gene for sporadic osteosarcoma.
Authors: Cristina Baciu, Rinnat Porat, Margaret Pienkowska, Noa Alon, Jonathan Wasserman, David Malkin
Journal: Cancer Research (2013)

Abstract Osteosarcoma (OS) is a primary bone malignancy with high incidence in children and young adults. It frequently occurs in patients with strong cancer history (Li-Fraumeni syndrome, retinoblastoma), but the etiology of sporadic OS is still uncertain. The present study is an intensive investigation on susceptibility to sporadic osteosarcoma by genome wide copy number analysis. We evaluated the hypothesis that germline copy number variants (CNVs) could act as a source of genetic susceptibility that may contribute to the development of sporadic osteosarcoma. We analyzed 78 sporadic pediatric OS cases and 2375 controls using Affymetrix SNP 6.0 Array. Two independent methods, Genotyping Console™ (Affymetrix) and Birdsuite (Broad Institute) were employed to call for CNVs. Outliers with large genomic alterations and TP53 mutations were flagged and filtered out. Both bioinformatics methods show similar distribution of CNVs per chromosome, with slightly higher range depicted by Genotyping Console™, with an enriched set of CNVs in the diseased data. Bioinformatics analysis predicts overlap of copy number variable regions with several candidate genes (PIK3CA, STK11, AKT3, ZMAT3, BAI1), for selected samples. We validated these findings by performing real time quantitative PCR experiments that not only verified most of the computational results, but also identified more amplifications, in an extended selection of samples and regions. The most affected candidate gene, showing gain in 66% of osteosarcoma samples tested, is ZMAT3 (Chr. 3q26.32). A very recent method, digital droplet PCR (BioRAD), with very high sensitivity, also confirms qPCR results, although for a smaller number of samples. In addition to calling for CNVs, pathways analyses have been also pursued, to address the hypothesis that disruption of multiple genes from the same pathway in the germline of a particular individual may cause susceptibility for developing osteosarcoma. DAVID software predicted several pathways that are enriched, p53 being one of them. Further investigations by KEGG suggest that several genes, including ZMAT3, are disrupted in the p53 signaling pathway. In order to validate these findings, functional assays on osteosarcoma derived lymphoblastoid cell lines are designed and currently in progress. In all, the current study suggests that ZMAT3 could represent a good candidate signature gene for susceptibility to sporadic osteosarcoma. Citation Format: Cristina Baciu, Rinnat Porat, Margaret Pienkowska, Noa Alon, Jonathan Wasserman, David Malkin. ZMAT3, a signature gene for sporadic osteosarcoma. [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 3163. doi:10.1158/1538-7445.AM2013-3163
AB0256 Risk factors associated with generalized bone loss in patients with rheumatoid arthritis: retrospective longitudinal study.
Authors: S. Mizuki, T. Murakami, K. Oryoji, K. Kamada, E. Yokota
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Vertebral fractures are major cause of disability and impaired quality of life in elderly people. Low bone mineral density has been reported a major risk factor for vertebral fracture. In patients with rheumatoid arthritis, it have been suggested that an appropriate management of the disease and the quality of bone prevent vertebral fractures. However, there are limited data concerning risk factors for bone mineral density loss in patients with rheumatoid arthritis. <h3>Objectives</h3> To evaluate the risk factors for generalized bone mineral density loss in patients with rheumatoid arthritis. <h3>Methods</h3> In a longitudinal study, lumbar spine bone mineral density (BMD) was measured at baseline and after average 1.2 years. Data of RA disease activity, treatment agents towards RA and osteoporosis, dietary and physical status were collected. With univariate logistic regression analyses we tested baseline variables for association with BMD loss. Variables showing an association (p&lt;0.10) with BMD loss were entered as possible predictors in a multivariate logistic analysis. <b>Results: 218 patients were examined at baseline and follow-up time. Patients included in this study were on average 61 years old and the average disease duration were 12 years at baseline.</b> In the univariate regression analysis, age, smoking status, Steinbrokcer's stage, usage of drugs for osteoporosis and pre-existing of vertebral fracture at baseline were associated (p&lt;0.10) with lumbar BMD loss. Subsequently in multivariate logistic regression analysis, only usage of drugs for osteoporosis was associated with decreased risk for lumbar spine bone mineral density loss (OR 2.57, 95% CI: 1.18-5.66, p= 0.017). In addition, smoking and shortage of calcium intake were associated with BMD loss among current users of drugs for osteoporosis, while among patients without drugs for osteoporosis, low body mass index was associated with BMD loss. <h3>Conclusions</h3> Results of this longitudinal study suggest that management of osteoporosis, including drugs and patient education towards life style, is important in patients with rheumatoid arthritis. <h3>Disclosure of Interest</h3> None Declared
1140 HEPATITIS C VIRUS AND LIPID DROPLETS: ROLE OF ADIPOSE DIFFERENTIATION-RELATED PROTEIN IN LIPID DROPLET MORPHOLOGY AND VIRAL LIFE CYCLE
Authors: E. Branche, S. Clement, P. Levy, C. Parisot, S. Conzelmann, V. Kaddai, F. Negro
Journal: Journal of Hepatology (2013)
Acute heart failure with cardiomyocyte atrophy induced in adult mice by ablation of cardiac myosin light chain kinase
Authors: Michael T. Massengill, Hassan M. Ashraf, Rajib R. Chowdhury, Stephen M. Chrzanowski, Jeena Kar, Sonisha A. Warren, Glenn A. Walter, Huadong Zeng, Byung-Ho Kang, Robert H. Anderson, Richard L. Moss, Hideko Kasahara
Journal: Cardiovascular Research (2016)

Under pressure overload, initial adaptive hypertrophy of the heart is followed by cardiomyocyte elongation, reduced contractile force, and failure. The mechanisms governing the transition to failure are not fully understood. Pressure overload reduced cardiac myosin light chain kinase (cMLCK) by ∼80% within 1 week and persists. Knockdown of cMLCK in cardiomyocytes resulted in reduced cardiac contractility and sarcomere disorganization. Thus, we hypothesized that acute reduction of cMLCK may be causative for reduced contractility and cardiomyocyte remodelling during the transition from compensated to decompensated cardiac hypertrophy. To mimic acute cMLCK reduction in adult hearts, the floxed-Mylk3 gene that encodes cMLCK was inducibly ablated in Mylk3flox/flox/merCremer mice (Mylk3-KO), and compared with two control mice (Mylk3flox/flox and Mylk3+/+/merCremer) following tamoxifen injection (50 mg/kg/day, 2 consecutive days). In Mylk3-KO mice, reduction of cMLCK protein was evident by 4 days, with a decline to below the level of detection by 6 days. By 7 days, these mice exhibited heart failure, with reduction of fractional shortening compared with those in two control groups (19.8 vs. 28.0% and 27.7%). Severely convoluted cardiomyocytes with sarcomeric disorganization, wavy fibres, and cell death were demonstrated in Mylk3-KO mice. The cardiomyocytes were also unable to thicken adaptively to pressure overload. Our results, using a new mouse model mimicking an acute reduction of cMLCK, suggest that cMLCK plays a pivotal role in the transition from compensated to decompensated hypertrophy via sarcomeric disorganization.
Abstract 1960: Nanosponges as suitable platforms for targeted chemotherapy
Authors: Eva M. Harth, Ghazal Hariri, David M. Stevens, Benjamin R. Spears
Journal: Cancer Research (2012)

Abstract We will report on the treatment efficacy of a degradable nanosponge drug delivery system. Degradable targeted nanosponges have been developed that are tailored in size and cross-linking density as supramolecular 3-D nano-networks. The organic polyester backbone can be functionalized in convenient ‘click’ chemistries with targeting peptides, dyes and cell penetrating units with particles that are fully soluble in organic solvents but retain their cross-linked architecture like a macromolecule. Furthermore, we found that the tailoring of the cross-linking density of the particles are correlated to the degradation and release properties of the particles to govern a fast, medium and slow linear release of the encapsulated drugs. Drugs can be encapsulated after the nanoparticle is formed and specifically hydrophobic drugs, for example chemotherapeutics, can be encapsulated with high efficiencies. The encapsulation into particle was found to be advantageous towards the solubility of the drug itself and resulted in vivo studies that showed a 3-5 time higher efficacy of the drug in targeted tumor regression studies. Similar efficacies are observed in glioma and lung cancer. We will report on novel combination therapies and efforts towards the delivery of a broad range of therapeutics in non-small lung cancer. 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 1960. doi:1538-7445.AM2012-1960
Abstract 3450: ABT-348 in combination with inhibition of CDK4/6 highlights a strategy to target RB mutant cells while sparing RB wild-type cells.
Authors: Jun Guo, Michael L. Curtin, Zehan Chen, Daniel H. Albert, Paul Tapang, Yujia Dai, Mia-Ha Bui, Peter Kovar, Michael R. Michaelides, Keith B. Glaser, Chris Tse, O. Jameel Shah
Journal: Cancer Research (2013)

Abstract ABT-348 is a novel, potent and orally bioavailable inhibitor of the Aurora kinases as well as the VEGF and PDGF families of receptor tyrosine kinases. ABT-348 is broadly efficacious preclinically as a single agent against a wide range of tumor types and is currently in Phase I/II clinical trials. Several published studies have supported the potential utility of combining targeted anti-proliferative agents with cytotoxic chemotherapies. Herein, the efficacy of combining the neocytotoxic agent, ABT-348, with CDK4/6 inhibition in the treatment of solid tumor cells has been evaluated. Inhibition of CDK4/6 via siRNA elicits a potent cytostatic response in cells that harbor a wild-type, functional RB. We demonstrate that features of cellular senescence are induced in human tumor cells with siRNAs targeting both CDK4 and CDK6. Dual inhibition of CDK4 and CDK6 is required for antiproliferative activity in most cancer cell lines and this is not accompanied by induction of apoptosis. In RB wild-type cells, CDK4/6 inhibition antagonizes the activity of ABT-348 by inducing G0/G1 arrest. Conversely, CDK4/6 inhibition does not alter the therapeutic response of RB-deficient cells to ABT-348, indicating that the effects of ABT-348 are dependent on cells progressing into mitosis. A preponderance of evidence from previous publications and our studies indicate that CDK4/6 inhibition attenuates the cellular response to cytotoxic chemotherapies in RB wild-type cells providing a potential to expand the therapeutic window for ABT-348. Thus combination with ABT-348 and a CDK4/6 inhibitor may provide an opportunity to selectively target RB mutant cells. Citation Format: Jun Guo, Michael L. Curtin, Zehan Chen, Daniel H. Albert, Paul Tapang, Yujia Dai, Mia-Ha Bui, Peter Kovar, Michael R. Michaelides, Keith B. Glaser, Chris Tse, O. Jameel Shah. ABT-348 in combination with inhibition of CDK4/6 highlights a strategy to target RB mutant cells while sparing RB wild-type 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 3450. doi:10.1158/1538-7445.AM2013-3450
The p53-Independent Tumoricidal Activity of an Adenoviral Vector Encoding a p27–p16 Fusion Tumor Suppressor Gene
Authors: Salil D. Patel, Annie C. Tran, Ying Ge, Marina Moskalenko, Lisa Tsui, Gautam Banik, Warren Tom, Michael Scott, Lili Chen, Melinda Van Roey, Marianne Rivkin, Michael Mendez, Jeno Gyuris, James G. McArthur
Journal: Molecular Therapy (2000)

<h2>Abstract</h2> We describe here that DE1-adenovirus vectors (AV) expressing a p27–p16 fusion molecule, termed W9, induce tumor cell apoptosis when overexpressed in a wide range of tumor cell types. However, in primary human cells derived from a variety of normal tissues, AV–W9 induced minimal apoptosis. In tumor cells AV–W9 demonstrated 5- to 50-fold greater tumoricidal activity than either of the parental molecules p16 and p27. In these studies, AV–W9 elicited apoptosis independent of the p53 and Rb status of the tumor cells. In several murine tumor models AV–W9 demonstrated p53-independent antitumor activity. It completely prevented tumor formation in two <i>ex vivo</i> models, whereas the parental molecules resulted in partial protection. Furthermore, AV–W9 induced tumor regression or suppressed tumor growth when introduced intratumorally into preestablished tumors in mice. This effect may be mediated through tumor cell apoptosis or antiangiogenic activity of AV–W9. Thus, this novel chimeric molecule is more potent and capable of killing a broader spectrum of tumors than the parental p16 and p27 molecules independent of the tumor cell p53 and phenotype and represents a powerful new therapeutic agent for cancer gene therapy.
Case 20-2006
Authors: Mark D. Denton, Subba R. Digumarthy, Sarah Chua, Robert B. Colvin
Journal: New England Journal of Medicine (2006)

An 84-year-old man with a pacemaker was hospitalized for staphylococcal bacteremia and renal failure. Fever and respiratory symptoms had developed two weeks earlier; blood cultures were positive for methicillin-sensitive Staphylococcus aureus. Fever and bacteremia persisted despite antibiotic therapy, and slowly progressive renal failure developed. A diagnostic procedure was performed.
A2.22 Influence of TNF on the proteome of rheumatoid arthritis synovial fibroblasts
Authors: E Ossipova, H Wähämaa, L Klareskog, AI Catrina, PJ Jakobsson
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background and objectives</h3> Rheumatoid arthritis (RA) is a chronic autoimmune systemic disorder that affects primarily the joints and leads to their destruction. Rheumatoid arthritis synovial fibroblasts (RASFs) localised in the RA synovium play a crucial role in the destructions of joints by production of pro-inflammatory cytokines, matrix-degrading enzymes or via production of matrix metalloproteinases (MMPs). Activated leukocytes or adipocytes secrete Tumour Necrosis Factor (TNF), which in turn stimulates RASFs resulting in production of MMPs, maintenance of inflammation, and induction of osteoclastogenesis. For better understanding on how TNF contributes to RASFs stimulation and to reveal pathways activated by TNF in RASFs, we investigate the effect of TNF-alpha on the proteome of human RASFs obtained from synovial tissues of patients with RA. <h3>Materials and Methods</h3> Expanded in cell culture, RASFs (passages 5 and 7) obtained from two CCP- donors, were stimulated with TNF (10 ng/ml, 24 h). Cells were harvested and lysed in buffer containing SDS. Quantitative proteome analysis utilising iTRAQ (Isobaric Tagging for Relative and Absolute Quantification) - labelling was employed to the TNF treated and untreated cells in order to detect gene expression at the protein level. Pathway analysis was performed by using Ingenuity Systems Pathway Analysis (IPA) program. <h3>Results</h3> Out of 1028 profiled proteins, 14 proteins exhibited elevated expression and 28 proteins showed reduced expression upon stimulation with TNF-alpha. The following canonical pathways (top 5) were activated: EIF2 Signalling, Regulation of eIF4 and p70S6K Signalling, mTOR Signalling, Remodelling of Epithelial Adherens Junctions and Protein Ubiquitination Pathway. IPA analysis showed that TNF-alpha increased cell-to-cell signalling and interaction and tissue development by increasing attachment of cells, promotion of cell death of connective tissue cells, induction of reactive oxygen species, increased apoptosis and decreased degradation of oxygen peroxide. <h3>Conclusions</h3> Quantitative proteomic analysis of RASFs stimulated with TNF-alpha revealed upregulation of several genes involved in inflammatory processes in RA and bone destruction as well as activation of several pathways, which play an important role in protein folding and osteoclastgenesis.
Abstract 4807: Identification of pre-invasive pancreatic cancer serum biomarkers using genetically engineered mouse models and mass spectrometry techniques
Authors: Michael R. Ludwig, Kyoko Kojima, William Grizzle, James A. Mobley, Christopher A. Klug
Journal: Cancer Research (2012)

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the United States. Surgery is the only curative treatment approach if the tumor is diagnosed early at an organ confined stage. Therefore, serum biomarkers specific for early stage pancreatic neoplasia would be of tremendous value in the treatment of this disease. Genetically engineered mouse models (GEM) of pancreatic neoplasia have been generated that closely recapitulate the molecular and biological properties of human PDAC. Here we take advantage of these GEMs and a high-throughput proteomics approaches to “dig deep” into the serum proteome of these mice to identify representative biomarkers of early stage pancreatic neoplasia. Methods: Serum was collected from 9 Pdx1-Cre (control) and 9 Pdx1-Cre;LSL-RasG12D (pre-invasive PDAC model) mice at 4 months of age. Serum was then pooled into 3 sets of 3 samples for each arm. The top 7 most abundant proteins were depleted from each pooled sample prior to labeling with a tandem mass tag (TMT) sixplex isobaric labeling system and long-column MudPIT analysis. Data were searched in SEQUEST, and quantified in ProteoIQ. Candidate proteins were accepted only with 97-99% confidence, and at least 2 unique TMT tagged peptides. Only biomarkers with &amp;gt;2 fold change and passing 2 non-parametric statistical tests were further evaluated. The same samples were also analyzed with a 1D MALDI-TOF MSMS approach to survey the low-mass serum proteome. In addition, a multi-dimensional MALDI-TOF approach was carried out on whole protein serum samples using spectral counting to quantify proteins instead of TMT labeling. Results/Discussion: Long-column MudPIT analysis resulted in identification of 3001 proteins with high confidence. Seventy of these proteins passed fold change and statistical filters, with 25 of these having known biological connections to pancreatic disease or function. A number of these proteins are currently being validated by immune assays. Multi-dimensional MALDI-TOF analysis resulted in identification of 8 differentially abundant proteins. Two of these proteins have been validated by Western blot. Taken together, these mass spectrometry techniques allow for a relatively in-depth survey of the serum proteome with accurate quantitation of potentially novel early stage pancreatic neoplasia biomarkers. Ultimately, the biomarkers identified in this study will be validated in human studies with the expectation that high risk patients will benefit from the application of these biomarkers for early diagnosis and improved treatment of disease. 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 4807. doi:1538-7445.AM2012-4807
PTH-065 Diagnostic and Therapeutic Utility of Spyglass single Operator Peroral Cholangioscopy for Indeterminate Biliary Lesions: A Single Centre Experience in Scotland
Authors: U Basavaraju, A Fraser, J Leeds
Journal: Gut (2013)

<h3>Introduction</h3> The SpyGlass single-operator peroral cholangioscopy is a promising technique designed to overcome some of the limitations of conventional peroral cholangioscopy. We aimed to evaluate the diagnostic utility of the SpyGlass system in a cohort of patients with indeterminate biliary strictures and lesions. <h3>Methods</h3> All patients who were listed for SpyGlass cholangioscopy for for further evaluation or treatment of indeterminate strictures or filling defects previously identified at ERCP or other imaging modality were included in this study. After SpyGlass direct visual evaluation, targeted biopsies were taken with the SpyBite forceps and histopathological assessment was made by experienced gastrointestinal pathologists. <h3>Results</h3> Between April 2009 and January 2013, 21 subjects (mean age 60, 12 males) underwent SpyGlass cholangioscopy for indeterminate biliary strictures (n = 12) or filling defects (n = 9). SpyGlass cannulation was not possible in 1 subject. In those with previously identified strictures, 8/12 had a stricture identified during SpyGlass, 2 as probable malignant and 6 as benign strictures using endoscopic criteria. In those with filling defect, choledocholithiasis was identified in 7 subjects and 1 subject was found to have a villous adenoma. The cholangioscopy was reported normal in 4 subjects (19%). SpyBite biopsies were taken in 10 subjects with histology showing inflammation (n = 5), atypia (n = 2), adenoma (n = 2) and normal (n = 1) giving a biopsy adequacy of 100%. Overall, the SpyGlass evaluation agreed with the histopathologic evaluation of SpyBite-targeted biopsies in 8/10 (80%) cases and therefore a definitive diagnosis was made in 18/21 (86%) patients. There were no serious complications with only 1 case of mild pancreatitis, 1 case of liver abscess (after 2 weeks) and 6/15 patients received prophylactic anti-biotic. Two subjects have had successful surgery for cholangiocarcinoma and all but 1 subjects are alive at the mean follow-up period of 19 months. <h3>Conclusion</h3> Using the SpyGlass cholangioscope, a definitive diagnosis can be made with a high accuracy in 86% of patients with indeterminate biliary lesions. This is primarily due to direct visualisation and targeted biopsy sampling. Therefore, the SpyGlass system should be considered in all patients with indeterminate biliary lesions. <h3>Disclosure of Interest</h3> None Declared.