tbuckley/cabot-search huggingface dataset:
Abstract 5087: Mirk/Dyrk1B kinase mediates survival of quiescent tumor cells and is downstream of the cellular energy sensor AMPK
Authors: Xiaobing Deng, Eileen Friedman
Journal: Cancer Research (2010)

Abstract The Mirk kinase gene has been localized to the 19q13 amplicon and is amplified in a subset of pancreatic cancers and ovarian cancers, and less frequently in colon cancers. Mirk mediates survival of these cancers at least in part by reducing reactive oxygen species (ROS). Mirk is expressed at very low levels in most normal tissues. However, Mirk is highly expressed in normal skeletal muscles and in C2C12 myoblasts where it mediates differentiation and survival. Using immunofluorescence techniques we now show that Mirk is localized in fast twitch skeletal muscles. Such muscle endogenously produces ROS in response to repeated contractions. Depletion of Mirk from C2C12 myoblasts led to an increase in ROS, consistent with ROS control being a major role of Mirk in muscle development and function. This protective ROS-decreasing role is likely to have provided a selective pressure to upregulate Mirk expression in tumor cells. Mirk is a co-activator for several transcription factors and increases expression of a series of antioxidant proteins in cancer cells including superoxide dismutase 2 (SOD2), the ferroxidase ceruloplasmin, glutathione peroxidase 2, sulfiredoxin, peroxiredoxin 2, COX2 and archidonate 12-lipoxygenase (12-LOX), as assayed by either Northern blotting or quantitative RT-PCR or both measurements. Mirk is most abundant and active as a kinase when cells are in a quiescent G0 state. Low intracellular energy levels due to nutrient deprivation lead to transient cellular arrest in G0 through the function of AMPK (AMP-activated protein kinase). Mirk expression is controlled through AMPK which serves as a metabolic checkpoint kinase, arresting cell growth in response to low nutrient levels which depress intracellular ATP levels. Thus the serine/threonine kinase Mirk mediates tumor cell survival through maintenance of its original function in skeletal muscle cells, depletion of ROS, when cells are in a transient quiescent state, with both Mirk expression and cell arrest controlled by AMPK. 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 5087.
Using a gastroscope to accomplish ERCP: a forward-viewing endoscope for cannulation of the intradiverticular papilla
Authors: Yun Qian, Jin Huang, Yin Zhang, Li Ma, Zhi Fan
Journal: Endoscopy (2014)

A 68-year-old man was admitted to our hospital with right upper quadrant pain and jaundice. Laboratory studies revealed leukocytosis, elevated liver enzymes, and hyperbilirubinemia. Magnetic resonance cholangiopancreatography examination revealed distal bile duct stenosis. On duodenoscopy, the papilla was hidden within a diverticulum. We tried using two devices simultaneously to perform endoclip-assisted biliary cannulation but without success ([Fig. 1 a]). Thus, the duodenoscope was withdrawn and a gastroscope (GIF Q260; Olympus, Tokyo, Japan) was inserted. Cannulation of the pancreatic duct was achieved but deep access of the common bile duct remained impossible ([Fig. 1 b]). A pancreatic duct plastic stent was then inserted to facilitate biliary cannulation [1]. Endoscopic retrograde cholangiopancreatography (ERCP) confirmed the distal biliary stricture ([Fig. 1 c]). The patient was treated with balloon dilation ([Fig. 1 d]). The patient was discharged 3 days after the procedure without any complications.
Abstract 3329: A let-7 signaling pathway targets metastatic genes enriched in tumor initiating cells
Authors: Casey A. Frankenberger, Jieun Yun, Eva M. Eves, Max Diehn, Andy J. Minn, Marsha R. Rosner
Journal: Cancer Research (2012)

Abstract Stem-like “Tumor Initiating Cells” (TICs) have been isolated from a number of tumors including breast, and they are likely involved in all aspects of tumor biology including metastasis. Recent studies have established a link between epithelial stem-like properties and the epithelial-mesenchymal transition (EMT), a step that leads to invasion and metastasis. Identifying key signaling pathways that regulate both tumor initiating and metastatic events could enable more accurate prognosis and reveal important mediators of the process that could serve as novel therapeutic targets. Previous studies from our laboratory and others have shown that let-7 inhibits breast tumor initiation and metastasis. Previously, we have shown that BACH1, a transcription factor that is a direct target of let-7, promotes metastasis. Using gene expression arrays to quantify transcription in BACH1 depleted cells, we show that BACH1 regulates a number of downstream targets including Bone Metastasis Signature (BMS) genes. Utilizing an approach based on experimental and clinical validation, we identify genes implicated in both tumor initiation and metastasis. Gene set analysis confirmed that the BACH1 target genes significantly correlate to the metastatic pathway including BACH1, let-7 and BMS gene expression across a set of more than 1200 primary human tumors, and, in tumors selected for a basal phenotype, the expression levels of individual BACH1 target genes can significantly stratify metastasis free survival in patients. Using FACS to sort metastatic breast cancer cell lines, we see a significant increase in the transcription levels of BACH1 regulated genes when comparing TICs to non-tumor initiating cells. Additionally, in metastatic cell lines known to be enriched in TICs, BACH1 depletion reduces the population of cells expressing cell surface markers (CD44+CD24-/lowESA+) specific to a tumor initiating phenotype. And finally, gene set enrichment analysis indicates that BACH1 and the BACH1 target genes are enriched in human and mouse primary breast TICs relative to non-initiating tumor cells. Taken together, these results suggest that let-7 regulates a signaling cascade involving BACH1 and BACH1 target genes that promotes both tumor initiation and metastasis. 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 3329. doi:1538-7445.AM2012-3329
THU0078 Polymorphisms of the genes encoding CD40 and growth differentiation factor 15 and in the 9P21.3 region in patients with rheumatoid arthritis and cardiovascular disease
Authors: S. Rantapää Dahlqvist, L. Ärlestig
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> An increased morbidity and mortality due to cardiovascular disease in patients with rheumatoid arthritis has been identified. <h3>Objectives</h3> Genes related to coronary artery disease in the general population, CD40, growth differentiation factor 15 (GDF15) and the 9p21.3 locus were analyzed in patients with rheumatoid arthritis (RA) with respect to atherothrombotic (AT) comorbidity <h3>Methods</h3> A cross-sectional study of 681 individuals (498 females; 183 males) with RA (ACR criteria), having a mean age of 60.6±13.2 years and mean disease duration of 15.5±12.6 years, were consecutively recruited and followed up for 6 years. The prevalence of AT manifestations (ATM), [acute myocardial infarction (AMI), angina pectoris with intervention, deep vein thromboses/pulmonary embolism (DVT/PE) and/or stroke/TIA] and hypertension (HT) was registered. Polymorphisms in the gene coding for GDF15, rs1058587 and in CD40 gene, rs1535045 and rs3765459, and the 9p21.3 locus (rs 1333049) were analyzed. Polymorphisms were genotyped using a TaqMan 9700HT and the 5'nuclease allelic discrimination assay. Controls (n=687) were randomly selected and matched for age and gender from the Medical Biobank of Northern Sweden. <h3>Results</h3> The distribution of the genotype of GDF15 differed significantly between patients with RA and controls (p=0.034, odds ratio (X2=6.40, 2df, p&lt;0.05). During the follow up were 149 new AT events were registered. Overall ATM was predicted by carriage of the GG genotype of GDF15 and also by the rare genotype of 9p21.3, Odds ratio (OR)=2.21 (95%CI 1.17-4.18, adjusted) and 1.92 (95%CI 1.15-3.19, adjusted), respectively. 9p21.3 genotype predicted also a new AT event during the follow up (OR=2.46, 95%CI 1.29-4.7). The minor allele and genotype GG of GDF15 were related to stroke/TIA in female patients (OR=3.75, 95%CI 1.06-13.33, adjusted). Male patients homozygous for major allele of CD40, CC in rs1535045 (OR=6.48, 95%CI 1.31-32.00, adjusted) and GG in rs3765459 (OR=3.45 95%CI 1.21-9.85, unadjusted, OR=2.78, 95%CI 0.78- 9.91, adjusted) were more often affected by stroke. The adjustments were HLA-shared epitope, disease activity, anti-citrullinated antibodies/rheumatoid factor, HT, diabetes and treatments, smoking and age. <h3>Conclusions</h3> The gene polymorphisms analysed were associated with different manifestations of AT events in RA. The GDF15 gene polymorphism was also associated with RA per se suggesting a common aetiology for RA and ATM. <h3>Disclosure of Interest</h3> None Declared
Reduced Expression of Endothelial Nitric Oxide Synthase in the Lungs of Patients with Pulmonary Hypertension
Authors: Adel Giaid, Dina Saleh
Journal: New England Journal of Medicine (1995)

Pulmonary hypertension is characterized by abnormal thickening of the pulmonary arteries and increased pulmonary vascular resistance. Nitric oxide is a potent endothelium-derived vasorelaxant substance and an inhibitor of smooth-muscle-cell growth. Nitric oxide is produced in various cell types by the action of an enzyme, nitric oxide synthase. We compared the expression of endothelial nitric oxide synthase in the lungs of control subjects with that in the lungs of patients with pulmonary hypertension.
TRANSCRIPTIONAL PROFILING OF GBM INVASIVE GENES IDENTIFIES EFFECTIVE INHIBITORS OF THE LIM KINASE-COFILIN PATHWAY
Authors: J. Rutka, J.-B. Park, S. Agnihotri, B. Golbourn, K. Bertrand, A. Luck, N. Sabha, S. Croul, C. A. Smith
Journal: Neuro-Oncology (2014)

BACKGROUND: The malignant astrocytoma is a highly proliferative and invasive neoplasm that infiltrates diffusely into regions of normal brain rendering total surgical resection impossible and effective local radiation therapy difficult. For truly significant advances to be made in the treatment of patients with malignant astrocytoma, we must develop a greater understanding of the molecular machinery driving invasion and identify novel treatment targets. METHODS: We recently compared gene-expression data of 400 invasion/migration genes by performing microarray analysis comparing 10 normal brain samples versus 51 mesenchymal GBM, which are highly invasive, and of poor prognosis. RESULTS: We identified over 141 significant genes with a 1.5 fold change (p-value <0.05, and a false discovery rate (q < 0.05) compared to normal brain. Of the 141 genes, the cofilin pathway, which disassembles actin filaments (namely LIMK1, LIMK2, CFL, CAP1) was highly up-regulated compared to normal brain. Furthermore we identified up-regulation of LIM domain kinase 1 and 2 (LIMK1/2) that phosphorylates and inactivates cofilin (CFL) in an additional data set comparing normal brain to GBM. Using a well-characterized tissue microarray of 20 GBM patients for which a central and a matched periphery sample was available we undertook immunohistochemical (IHC) analysis of LIMK1 and pCFL. We observed significant expression of LIMK1 in the periphery of the GBM compared to the center (11/20 in the periphery versus 2/20 in the center). Previously, we established that pCFL plays an integral role in GBM invasion. Consequently we explored how to target this pathway using small molecule inhibitors. We tested the LIMK1 and LIMK2 inhibitors BMS-5 and Cucurbitacin I. Both BMS-5 and Cucurbitacin I inhibited p-CFL at the protein level at 10uM and 100nM respectively in U87 cells. Using the MTT cell viability assay, we observed significant decrease in cell viability in U87 and T98G cells using doses of 10-20uM BMS-5 and 100nM-10uM Cucurbitacin I while no cytotoxic effect was seen in normal human astrocytes that lack LIMK expression. Both BMS-5 (10uM) and Cucurbitacin I (100nM) promoted increased adhesion in U87 and T98G cells. Interestingly, BMS-5 and Cucurbitacin I reduced migration and invasion of both U87 and T98G cells. CONCLUSIONS: Taken together, the use of LIMK inhibitors to target the invasive machinery in GBM are attractive candidates to move forward with in preclinical trials. SECONDARY CATEGORY: Tumor Biology.
Markers of Myocardial Damage and Inflammation in Relation to Long-Term Mortality in Unstable Coronary Artery Disease
Authors: Bertil Lindahl, Henrik Toss, Agneta Siegbahn, Per Venge, Lars Wallentin
Journal: New England Journal of Medicine (2000)

In patients with unstable coronary artery disease, there is a relation between the short-term risk of death and blood levels of troponin T (a marker of myocardial damage) and C-reactive protein and fibrinogen (markers of inflammation). Using information obtained during an extension of the follow-up period in the Fragmin during Instability in Coronary Artery Disease trial, we evaluated the usefulness of troponin T, C-reactive protein, and fibrinogen levels and other indicators of risk as predictors of the long-term risk of death from cardiac causes.
Abstract 4268: Interleukin-27 inhibits angiogenesis in non-small cell lung cancer
Authors: Puja Kachroo, Ling Zhang, Tonya C. Walser, Xiaoyan Cui, Saswati Hazra, Qiang Ying Lin, John D. Minna, Steven M. Dubinett, Jay M. Lee
Journal: Cancer Research (2011)

Abstract Interleukin-27 (IL-27), the newest member of the IL-6/IL-12 family, is secreted by antigen presenting cells and has anti-tumor activity through its activation of the JAK-STAT pathway. Transcriptional factors STAT1 and STAT3 have been implicated in the balance of tumor suppressor and oncogenic functions. Angiogenesis is a critical process during carcinogenesis. We investigated the role of IL-27 in tumor angiogenesis in lung cancer. Human bronchial epithelial cells (HBECs), genetically modified HBEC to over express Snail and K-ras (HBEC-Snail, HBEC-K-ras), and human non-small cell lung cancer (NSCLC) lines (A549, H2122) were treated with IL-27 at multiple time points. Phosphorylation of STAT1 and STAT3 measured by Western Blot after IL-27 exposure demonstrated activation of both pathways in these cell lines. Protein production of an important pro-angiogenic factor, vascular endothelial growth factor (VEGF), was measured by ELISA and Western analysis. After exposure to IL-27, there was a 60-80% decrease in VEGF protein expression of VEGF by ELISA (confirmed by Western analysis in the NSCLC lines but not in the HBECs or their genetically modified derivatives). The IL-27 down regulation of VEGF was not increased by the addition of a STAT3 inhibitor. In summary, IL-27 inhibits VEGF production in NSCLC through a mechanism independent of STAT3, suggesting that STAT1 may play a dominant role in IL-27 mediated angiogenesis suppression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4268. doi:10.1158/1538-7445.AM2011-4268
Nutrition Support in Critical Illness — Bridging the Evidence Gap
Authors: Thomas R. Ziegler
Journal: New England Journal of Medicine (2011)

The modern field of specialized nutrition support began with seminal studies showing that parenteral nutrition could stimulate growth and development in infants, as well as wound healing and convalescence in adults with the severe short bowel syndrome, who until that time had been unable to survive with enteral nutrition alone.1,2 Later, technical developments and recognition that malnutrition among hospitalized patients was common3 led to growth in nutrition support services. By the 1980s, the use of specialized regimens of enteral and parenteral nutrition were routine in intensive care units (ICUs) worldwide, despite little evidence from rigorous, controlled clinical trials supporting . . .
NI-25 * PHYSIOLOGIC IMAGING IN PATIENTS WITH BRAIN METASTASES; HETEROGENEITY BASED UPON PRIMARY TUMOR SUBTYPE
Authors: S. Fouke, P. LaMontagne, E. Fontana, D. Marcus, T. Benzinger, K. Rich, C. Abraham, M. Milchenko, C. Robinson
Journal: Neuro-Oncology (2014)

BACKGROUND: Structural and biologic tissue characteristics prior to and following radiosurgery (SRS) can be quantified by analyzing physiologic imaging sequences including diffusion and perfusion weighted imaging (DWI, PWI) and considering their derived parameters including apparent diffusion coefficient (ADC) and relative cerebral blood volume (rCBV). Increasingly in neuro-oncology, these types of imaging sequences are being considered as prognostic and diagnostic markers. Patients' primary tumor type may impact these imaging values, and an understanding of how baseline DWI and PWI measures depend upon primary tumor type is necessary in order to consider how these markers may impact therapeutic response or when considering diagnostic possibilities such as radiation necrosis. METHODS: 78 patients with 187 brain metastases were identified retrospectively from a cohort of patients who underwent SRS between August, 2011 and March 2014 at two institutions. Included subjects had undergone MRI with physiologic (DWI and PWI) imaging prior to SRS. The physiologic sequences were processed and co-registered to anatomic sequences acquired on the day of treatment. Lesions were segmented and ROIs were generated for image analysis using the T1 + Gd sequence. Quantitative measures included rCBV, rCBF, ADC and tumor volume for each lesion. Tumor subtypes included breast, lung, colon, melanoma, renal cell, ovarian, and “other”. RESULTS AND CONCLUSIONS: There was no significant difference in tumor volume based upon tumor type, although there was a trend toward larger tumors at diagnosis for colon and ovarian primaries. There was no significant difference in ADC between tumor type; a significant elevation in rCBV was seen for renal cell and ovarian primary tumors (2.51 and 2.46) when compared with breast, colon, melanoma and lung primary tumors (1.18, 1.24, 1.38, 1.27, respectively). When considering questions of diagnostic specificity, it is important to recognize the relatively low rCBV in many active brain metastases, particularly as compared with primary brain tumors.
AB0889 Tnfα Blockade is Perspective in Systemic JIA after Partial Effect of Rituximab or TOCILIZUMAB Treatment
Authors: E. Alexeeva, S. Valieva, R. Denisova, T. Bzarova, K. Isayeva, E. Chistyakova, A. Chomahidze, T. Sleptsova, E. Mitenko, A. Fetisova, O. Lomakina
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Patients with systemic juvenile idiopathic arthritis (sJIA) may not respond sufficiently to tocilizumab and rituximab therapy. Some patients reached remission of systemic features but had persistent arthritis. In these cases switching to TNFα ingibitor might be beneficial. <h3>Objectives</h3> To evaluate efficacy and safety of TNF blockers in the treatment of sJIA refractory to DMARDS, rituximab or tocilizumab. <h3>Methods</h3> Patients fulfilling the ILAR classification criteria for sJIA (n=14, boys 5) who were switched from rituximab (n=9) or tocilizumab (n=5) to TNF blockers (adalimumab n=10, etanercept n=4) were enrolled in a prospective observational study conducted in one Russian pediatric center. Patients received concominant therapy: methotrexate (n=2), methotrexate and cyclosporine (n=12), prednisolone (n=1). The mean age was 9,1 (8; 14,9) (here and after Me (25;75)), the mean age at disease onset - 2,1 (1;4,5) years, mean disease duration - 7 (4; 10)years, the remission of systemic features - 2,2 (range from 1 to 5 years). Because of persistent arthritis without systemic manifestations antiTNF therapy were initiated after 2,4 years rituximab and 1,4 years tocilizumab treatment. The efficacy was evaluated according to the ACR30/50/70/90 paediatric criteria and criteria of remission. The duration of TNFblockers therapy and observation was 2 months (n=14), 6 m (n=11), 12 m (n=7) and 24 m (n=5). <h3>Results</h3> The ACR30/50/70/90 improvements were reached by 95/64/50/28% of patients at month 2, by 100/82/73/73% of patients at month 6, by 100/100/86/86% of patients at month 12. The inactive disease was registrated at 54% (6/11) patients in 6 months, inactive disease and remission was registrated at 86% (6/7) patients in 12 months, at 100% (5/5) patients in 24 months. Nobody had flare of systemic manifestations. The number of AE decreased from 4,6 to 2,6 per 100 patients year (p,0.05) versus rituximab or tocilizumab treatment and antiTNF therapy. <h3>Conclusions</h3> AntiTNF therapy may be perspective in patients with sJIA with remission of systemic features and active arthritis. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.1934