tbuckley/cabot-search huggingface dataset:
NI-73 * MONITORING OF BIOLOGICAL RESPONSE TO BEVACIZUMAB IN MALIGNANT GLIOMA PATIENTS BASED ON L-[methyl-11C] METHIONINE-POSITRON EMISSION TOMOGRAPHY
Authors: K. Tamura, M. Inaji, T. Nariai, M. Tamaki, S. Hirai, K. Saigusa, Y. Tanaka, T. Maehara
Journal: Neuro-Oncology (2014)

BACKGROUND: Although anti-angiogenic therapy using bevacizumab (BEV) can induce normalization of the blood brain barrier, its effect on tumor biological activity is not well understood. We used L-[methyl-11C] methionine-positron emission tomography (met-PET), to monitor the biological response to BEV in malignant glioma patients. METHODS: 5 malignant glioma patients (anaplastic oligodendroglioma 1, glioblastoma 3, gliosarcoma 1) were treated with BEV (Avastin) at the time of recurrence after surgery, radiation therapy and Temozolomide treatment. After initiation of BEV, they were monitored with magnetic resonance imaging (MRI) and met-PET. RESULT: MRI reveled that the size of contrast-enhanced tumor was reduced and peritumoral edema was diminished after the initiation of BEV in all 5 cases. In these contrast-enhanced tumor lesion, methionine uptake on PET was decreased after initiation of BEV. In the non-enhancing lesion, methionine uptake was not changed before and after initiation of BEV. CONCLUSION: Our results indicate that initiation of BEV is related not only to the effect on vascular permeability reduction by repairing the blood-brain barrier, but also to the effect on suppression of biological activity of the tumor for the contrast-enhanced lesion. On the contrary, tumor biological activity was not changed in the non-enhancing lesion. Met-PET could give us important information to understand the therapeutic mechanisms of BEV.
P239Human resistance artery relaxing responses to an angiotensin AT2 receptor agonist depend on the type of contractile stimulus
Authors: M H Fredgart, T M Leurgans, L M Rasmussen, A Irmukhamedov, U M Steckelings, J G R De Mey
Journal: Cardiovascular Research (2014)

Aim: Test whether stimulation of angiotensin type 2 receptors (AT2R) reduces effects of various vasoconstrictor stimuli in resistance-sized arteries of cardiovascular disease patients. Methods: From biopsies of the parietal pericardium, obtained during open cardio-thoracic surgeries and stored overnight in physiological salt solution (PSS), 4 arterial segments were micro dissected, mounted in wire myographs, and studied at a diameter (202 ± 6 μm) corresponding to a distending pressure of 100 mmHg. Relaxing responses were recorded during submaximal contractions and compared to appropriate "time controls". Results: 10 μM acetylcholine reduced contractile responses to 32 mM K+, suggesting presence of functional endothelium. Angiotensin II (0.1 – 100 nM) caused transient contractions that could be prevented by 3 nM valsartan (AT1R antagonist) and that tended to be reduced by 10 μM PD123319 (AT2R antagonist). 24 mM K+, 0.1 μM U46619 (thromboxane A2 analogue) and 2 nM endothelin-1 (ET-1) caused submaximal contractions of comparable amplitude. Increasing concentrations of the AT2R agonist Compound 21 (C21, 0.1 – 100 nM) did not modify these contractile responses to K+ (n = 14) or ET-1 (n = 7). However, 100 nM C21 significantly reduced the contraction induced by U46619 by 53± 11 % (n = 9) and this relaxation was not influenced by valsartan. Conclusion: A non-peptidergic AT2R agonist can relax intact pericardial resistance arteries of patients with ischemic heart disease and/or cardiac valve problems. This effect is either selective for mechanisms stimulated by thromboxane or inhibited by depolarization and ET-1, a potent stimulus of oxidative stress.
Inflammatory signaling in human tuberculosis granulomas is spatially organized
Authors: Mohlopheni J Marakalala, Ravikiran M Raju, Kirti Sharma, Yanjia J Zhang, Eliseo A Eugenin, Brendan Prideaux, Isaac B Daudelin, Pei-Yu Chen, Matthew G Booty, Jin Hee Kim, Seok Yong Eum, Laura E Via, Samuel M Behar, Clifton E Barry, Matthias Mann, Véronique Dartois, Eric J Rubin
Journal: Nature Medicine (2016)
PWE-017 Short Term Outcomes Following The Use Of Self Expanding Metallic Stents In Acute Malignant Colonic Obstruction
Authors: S Sahebally, A Sarwar, F Cooke
Journal: Gut (2014)

<h3>Introduction</h3> Colonic self-expanding metallic stents (SEMS) may provide prompt relief of acute malignant colorectal obstruction (AMCO) and are increasingly used either palliatively or as a bridge to surgery (BTS) in patients in whom a definitive surgical approach is unsuitable. We evaluated short-term outcomes of malignant colorectal obstructive patients treated with SEMS in our institution over a 3-year period. <h3>Methods</h3> A prospectively maintained database was reviewed to identify all patients who presented to our institution with AMCO between August 2010 and 2013 and who were treated with a SEMS either temporarily or permanently. Additional data was retrieved from chart and pathology reviews. A single colorectal surgeon inserted all stents under both endoscopic and fluoroscopic guidance. Data was analysed using SPSSv21 (SPSS Inc., Chicago, IL, USA) and presented as median (interquartile range). Continuous variables were assessed using analysis of variance. A p value &lt;0.05 was considered statistically significant. <h3>Results</h3> Sixteen patients each had a single stent inserted during the study period, either palliatively (n = 11) or as a BTS (n = 5). Their median (IQR) age was 75 (21) years and 12 (75%) patients were males. Most tumours were located in the sigmoid colon (6/16, 37%). The technical and clinical success rates were both 87.5% (14/16) and there were no SEMS-related perforations. The two unsuccessful stenting cases both had metastatic disease and required emergency surgery while five patients with potentially curable disease proceeded to elective resections. There was no procedure-related mortality. There was no difference in the median length of stay (LOS) post SEMS insertion in the palliative group compared to the BTS group [4 (4) vs. 5 (3), p = 0.2]. However, the median (IQR) LOS post acute surgery was longer than elective surgery [45 (30) vs. 14 (8) days, p = 0.018]. All patients in the BTS group were stoma-free post-operatively, while both patients who had emergency surgery ended up with permanent stomas. Finally, the stent complication rate was 6.2% (1/16), secondary to migration in a patient who was stented palliatively. The latter patient did not undergo further attempted stenting as his obstructive symptoms had been alleviated. <h3>Conclusion</h3> AMCO poses significant challenges in management due to the frailty of the presenting patients and the high morbidity/mortality rates associated with emergency surgery. Although limited by a small sample size, our study shows that SEMS are a favourable alternative to emergency surgery for the management of AMCO. Further larger scale studies looking at long-term survival and oncological outcomes are awaited. <h3>Disclosure of Interest</h3> None Declared.
Abstract 4768: Receptor interacting protein (RIP) and Sirtuin-3 (SIRT3) on opposite sides of anoikis resistance and promotes tumorigenesis
Authors: Pachiyappan Kamarajan, Turki Alhazzazi, Nisha D'Silva, Eric Verdin, Yvonne Kapila
Journal: Cancer Research (2011)

Abstract Anoikis-apoptotic cell death triggered by loss of extracellular matrix (ECM) contacts is disregulated in many chronic debilitating and fatal diseases. Regulating crosstalk between anoikis and survival signaling pathways is crucial to regulating tissue processes and mitigating diseases like autoimmune diseases and cancer. Previously, we showed that anoikis activates a CD95/Fas-mediated signaling pathway regulated by receptor-interacting protein (RIP), a kinase that shuttles between Fas-mediated cell death and integrin/FAK-mediated survival pathways in a variety of cell systems. Since sirtuin 3 (SIRT3), an NAD-dependent deacetylase, is known to regulate longevity, cell survival, metabolism, and tumorigenesis, we hypothesized that SIRT3, might engage in crosstalk with Fas/RIP/integrin/FAK survival-death pathways. Specifically, we examined the roles of RIP and SIRT3 in oral squamous cell carcinoma (OSCC) anoikis resistance and tumorigenesis. Using immunohistochemical staining, immunoblotting, human tissue micro arrays, and overexpression and suppression approaches we examined the roles of RIP and SIRT3 in this context. RIP and SIRT3 have an opposite expression profile in OSCC cells and tissues. Stable suppression of RIP by RIP-targeted shRNA enhances SIRT3 levels, whereas, stable suppression of SIRT3 by SIRT3-targeted shRNA does not impact RIP levels in OSCC cells. Forced expression of RIP in RIP null cells downregulates SIRT3. As OSCC cells become anoikis-resitant they form multicellular aggregates in suspension conditions and their expression of SIRT3 increases as their expression of RIP decreases. Anoikis-resistant cells with high SIRT3 and low RIP levels induce an increased tumor burden and incidence in mice unlike their adherent OSCC cell counterparts, which express low SIRT3 and high RIP levels. OSCC cells with SIRT3 suppression fails to form multicellular aggregates in suspension conditions. Taken together, these data demonstrate that RIP is an upstream negative regulator of SIRT3 in anoikis resistance and anoikis resistance contributes to a more aggressive phenotype in OSCC development and progression (Supported by NIH grant R01DE014429 and NIH grant 2R56DE014429 to YLK). 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 4768. doi:10.1158/1538-7445.AM2011-4768
CBIO-04DAXX INHIBITION SUPPRESSES TUMOR GROWTH IN PTEN-DEFICIENT HUMAN GLIOBLASTOMAS
Authors: Jorge Benitez, Antonia Boyer, Fernanda Camargo, Ciro Zanca, Jianhui Ma, Nathan Jameson, Webster Cavenee, Frank Furnari
Journal: Neuro-Oncology (2015)

Glioblastoma (GBM) is the most lethal type of brain cancer, where deletions and/or mutations in the tumor suppressor gene PTEN (phosphatase and tensin homolog) are associated to responsiveness of cancer to radiotherapy and chemotherapy. Herein, we show that a PTEN-DAXX-H3.3 chromatin complex negatively regulates proliferation and tumor growth. PTEN directly regulates oncogene expression by coordinating DAXX and histone H3.3 deposition on chromatin and in turn, DAXX protects PTEN from acetylation and ubiquitination. Furthermore, DAXX disruption in PTEN-deficient glioblastoma patient derived xenograft models suppresses tumor growth and promotes therapy sensitivity. Since PTEN loss is a common alteration in cancer, DAXX inhibition presents an approach to ablate the growth of such cancers.
SAT0201 Relationship of Matrix Metalloproteinase-3 With Pulmonary and Joint Involvement in Scl-70 Positive Systemic Sclerosis Patients
Authors: M. Zlatanovic, M. Sefik-Bukilica, P. Ostojic, S. Prodanovic, S. Seric, G. Radunovic, M. Radak-Perovic, N. Damjanov
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Extracellular matrix degradation is regulated mainly by matrixmetalloproteinases (MMPs). MMP-3 can degrade many components of the extracellular matrix and an increase in serum MMP-3 concentration has been proposed as a synovial derived marker of inflammation. <h3>Objectives</h3> To determine matrix metalloproteinase-3 (MMP-3) serum levels in anti Scl 70 positive patients with systemic sclerosis (SSc) and to study clinical significance and the relationship between MMP-3 and pulmonary and joint involvement <h3>Methods</h3> Forty-seven anti-Scl 70 antibodies positive patients with systemic sclerosis (43 female, 4 male) and 50 healthy controls were included in the study. All SSc patients underwent standard assessment, including laboratory tests, physical examination with joint assessment, chest X-ray and pulmonary functional tests, including diffusion capacity for carbon monoxide (DLco) and forced vital capacity (FVC). Levels of MMP-3 were measured with specific ELISA kit (Aeskulisa DF) with normal range between 18-60 ng/ml for female and 24-120ng/ml for male. <h3>Results</h3> SSc patients had significantly higher MMP-3 concentration compared to healthy donors 122.64±188.40 vs. 57.4±46.79, p&lt;0.001. Twenty-two (46.8%) SSs pts had increased MMP-3 levels above normal range and those had more frequently pulmonary fibrosis (p&lt;0.001) and arthritis (p&lt;0.001). Patients with increased levels of MMP-3 had significantly more frequently reduction in DLco &lt;75% predicted (p&lt;0.001). <h3>Conclusions</h3> In 47 patient with systemic sclerosis and anti-Scl 70 positive antibodies, high levels of MMP-3 significantly positively correlate with pulmonary fibrosis, DLCo &lt; 75% predicted and joint involvement (arthritis). <h3>Disclosure of Interest</h3> None Declared
S89 Identification Of Potentially Pathogenic Microorganisms By Selected Ion Flow Tube -mass Spectrometry (sift-ms)
Authors: J. Jackson, V. Kim, A. Tuck, S. Wootton, T. Wilkinson
Journal: Thorax (2014)

<h3>Introduction</h3> Improved targeted therapy and reduced clinical burden from respiratory bacterial infection could result from early identification of specific Potential Pathogenic Microorganisms (PPM). Sputum culture for identification usually requires several days. SIFT-MS has the potential to reduce the required incubation time by sampling the culture headspace to generate an ionic spectrum from volatile organic compounds that may be characteristic of the PPM. Additionally, these signatures may be detectable in breath taken directly from patients. This pilot study investigates the potential of SIFT-MS to identify 5PPMs, incubated separately for 24 hr. <h3>Methods</h3> Training set<i>: Haemophilus influenzae</i> (HI), <i>Moraxella catarrhalis</i> (MC), <i>Streptococcus pneumoniae</i> (SP), <i>Staphylococcus aureus</i> (SA) and <i>Pseudomonas aeruginosa</i> (PA) cultures and a negative control incubated at 37<sup>0</sup>C on chocolate agar plates in sealed bags for 24 hr, 48 hr and 72 hr. Plates were opened for 10 min at room temperature before ionic spectra of the gas above the culture dishes in the range 15 to 200 mass units were recorded using SIFT-MS and standardised to operating conditions. Test set: the same five PPMs and a negative control were incubated in triplicate for 24 hr only and analysed as above. <h3>Results</h3> Using the spectra generated with H3O+ ionisation, 6 ion sets were identified. The sum of ions within each set, expressed as a percentage of the total ion sum of masses 15 to 200 (excluding reagent ions) fell into ranges that, in combination, differentiated between the PPMs. This set of conditions was incorporated into an algorithm that was then applied to the test set of triplicate plates. The algorithm correctly differentiated all 24 hr plates with MC, SP, SA and PA from each other and from the negative control and HI plates with 100% accuracy. Negative control and HI could not be differentiated. <h3>Conclusion</h3> This pilot study illustrates the potential for SIFT-MS to identify monocultures of 4 common PPMs within a short incubation time and encourages further study with a wider range of pathogens alone and in combination. Early identification of PPMs in culture, and translation to potentially detect carriage or infection with specific pathogens in breath may improve management of respiratory infections.
The Effect of Lithium on Murine Hematopoiesis in a Liquid Culture System
Authors: Lee J. Levitt, Peter J. Quesenberry
Journal: New England Journal of Medicine (1980)

Lithium carbonate has been shown to increase granulocyte production. We studied the effect of lithium on murine hematopoiesis in a liquid culture system providing for the prolonged growth of stem cells and their progeny. After one week of incubation, lithium, at a supernatant concentration of 1 mmol per liter, increased murine pluripotent stem cells (CFU-S, or colony-forming units in spleen) to 232 per cent of control values (P<0.001), granulocyte-monocyte progenitor cells (CFU-C, or colony-forming units in culture) to 218 per cent of control values (P<0.0001), granulocytes to 125 per cent of control values (P<0.01), and megakaryocytes to 246 per cent of control values (P<0.001). These increases were associated with transient elevations in colony-stimulatory activity. Prolonged exposure to lithium (three to 12 weeks) was associated with a dose-dependent progressive depletion of stem cells and their progeny. Lithium enhancement of granulopoiesis may be explained by primary stimulation of the pluripotent stem cell. Prolonged proliferative stress induced by lithium when the stem-cell reserve is limited may be associated with diminished replicative potential of the stem cells and rapid depletion of cells. (N Engl J Med. 1980; 302:713–9.)
AB0831 Management of Primary Hyperparathyroidism with Cinacalcet
Authors: I. Kostoglou-Athanassiou, P. Athanassiou, E. Xanthakou, A. Gkountouvas, P. Kaldrymides
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Primary hyperparathyroidism is currently recognized with increasing frequency by routine calcium measurement in biochemical examinations. Primary hyperparathyroidism may be due to a parathyroid adenoma, parathyroid hyperplasia and, rarely, parathyroid carcinoma. Cinacalcet is used in the medical management of primary hyperparathyroidism. <h3>Objectives</h3> The aim was to assess the role of cinacalcet in the treatment of primary hyperparathyroidism. <h3>Methods</h3> Patients with primary hyperparathyroidism (n=20) (aged 56-85 years) were studied. Amongst them 4 patients had parathyroid hyperplasia and 16 had a parathyroid adenoma. Calcium and PTH levels were increased in all patients. All patients had ultrasonography and a <sup>99m</sup>Tc-Sestamibi scan. In 16 patients a parathyroid adenoma was observed either on ultrasound or on scanning or in both. In 4 of the patients a parathyroid adenoma was not localized by imaging. <h3>Results</h3> Cinacalcet was used in all 16 parathyroid adenoma patients to normalize serum calcium levels prior to surgery. In 10 of the parathyroid adenoma patients the adenoma was surgically excised, in a female aged 56, hyperparathyroidism recurring a year after surgery. Sequentially, cinacalcet was administered at a dose of 30 mg twice daily and serum calcium levels normalized. Within the group of patients with a parathyroid adenoma 6 were elderly, aged &gt;75 years, with comorbidity and cinacalcet was administered at a dose of 30 mg twice daily in 3 and 60 mg twice daily in 1 to avoid surgery. In the group of patients with parathyroid hyperplasia cinacalcet was used for the treatment of hypercalcemia. Within the whole group, 2 patients experienced mild gastrointestinal symptoms, but discontinuation of the drug could be avoided. <h3>Conclusions</h3> Cinacalcet may be used for the treatment of primary hyperparathyroidism. It can be used for the normalization of serum calcium prior to surgery, if surgery is not an option, in the event of recurrence after surgery and in parathyroid hyperplasia. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.4848
PP-011 Collagen proportionate area: a continuous quantitative of histological collagen has the best correlation with transient elastography
Authors: G Isgro, T Luong, L Andreana, M Garcovich, S Maimone, P Manousou, V Calvaruso, E Tsochatzis, D Patch, D Thornburn, A Dhillon, A Burroughs
Journal: Gut (2010)

<h3>Introduction</h3> Liver stiffness (LS) measured by transient elastography (TE) is related to liver fibrosis, which histologically is categorised into stages which do not have quantitatively relationships. Collagen proportionate area (CPA) measured by computer-assisted digital image analysis (DIA) on biopsies stained with Sirius red is an histological method for quantifying collagen in liver biopsies. The aim of this study is to correlate LS to Ishak score and CPA in patients with chronic viral hepatitis. <h3>Methods</h3> LS was measured by TE in 100 patients with chronic viral hepatitis (HCV, HBV). <h3>Results</h3> We evaluated 100 patients: 58 male, mean age 46.4 (±11.5). HCV (n=51), mean age 48.8, 28 males, mean CPA (6.4±6.6), mean LS 12.6 (±15.1). Univariately CPA (r<sup>2</sup> 0.57 p&lt;0.0001), METAVIR (r<sup>2</sup> 0.37 p&lt; 0.0001) and Ishak (r<sup>2</sup> 0.37 p&lt; 0.0001), were correlated with LS but multivariately only CPA was independently associated (p&lt;0.0001, 95% CI 1.139 to 2.789). Ishak and METAVIR were both correlated with CPA univariately, but multivariately only Ishak (p&lt;0.0001, 95% CI 1.544 to 4.135). HBV (n=49), mean age 43.9, 29 males, mean CPA 4.09 (±4.5), mean LS (8.1 ±6.5). Univariately, LS correlated with CPA (r<sup>2</sup> 0.59, p&lt;0.000), Ishak (r<sup>2</sup> 0.49, p&lt;0.0001) and METAVIR (r<sup>2</sup> 0.55, p&lt; 0.000), mutivariately with CPA (p=0.002, 95% CI 0.305 to 1.286) and METAVIR (p=0.03, 95% CI 0.441 to 9.446). METAVIR (r<sup>2</sup>0.69, p&lt; 0.0001) and Ishak (r<sup>2</sup>0.70, p&lt;0.0001) correlated with CPA univariately, but not multivariately. In HCV patients with Ishak stage &gt;4 the AUROC for CPA was 0.96 (95% CI 0.90 to 1.03) and the best cut off was 11.7 (90%sensitivity, 100%specificity). For METAVIR F4 AUROC was 0.98 (95% CI 0.96 to 1.01) and the best cut off for CPA was 12.4 (87%sensitivity, 99%specificity). In HBV patients, the AUROC for CPA was absolute (ie, 1, 95% CI 1.00 to 1.00) in both patients with Ishak &gt;4 and patients with METAVIR F4. In the first case the best cut off was 8.9 (100%sensitivity, 100%specificity), in the latter the best cut off for CPA was 10.3 (100%sensitivity, 100%specificity). <h3>Conclusion</h3> In chronic viral hepatitis, the measurement of CPA which is a continuous quantitative measurement of liver collagen was correlated well with current stage systems. CPA had a much better correlation with TE than METAVIR or Ishak stages. CPA should replace traditional histological staging systems for quantifying fibrosis in comparison with TE.
Ligand-Dependent Regulation of Vascular Endothelial Growth Factor and Erythropoietin Expression by a Plasmid-Based Autoinducible GeneSwitch System
Authors: Ronald V. Abruzzese, Debra Godin, Vidya Mehta, Jerry L. Perrard, Martha French, Wendy Nelson, Gaylen Howell, Michael Coleman, Bert W. O'Malley, Jeffrey L. Nordstrom
Journal: Molecular Therapy (2000)

We investigated the ability of an improved mifepristone-dependent GeneSwitch system to regulate the expression of genes for two therapeutic proteins: vascular endothelial growth factor (VEGF) and erythropoietin. The GeneSwitch system consisted of two plasmids, one encoding the chimeric GeneSwitch protein, the other an inducible transgene. When the constitutive CMV promoter of the GeneSwitch plasmid was replaced by an autoinducible promoter consisting of four copies of GAL4 DNA binding sites linked to a minimal thymidine kinase promoter, the tightness of transgene regulation was improved by an order of magnitude. Quantitative RT-PCR analysis of GeneSwitch mRNA confirmed that the autoinducible promoter was responsive to mifepristone. We demonstrated the ability of the improved GeneSwitch system to regulate the expression of VEGF or erythropoietin in a biologically relevant manner after delivery of plasmids to the hind-limb muscle of adult mice. This ability of the autoinducible GeneSwitch system to regulate the expression of therapeutic proteins in mice indicates its potential for use in human gene therapy applications.
355TiP Phase III clinical trials of atezolizumab compared with standard chemotherapy in PD-L1–selected chemotherapy-naïve patients with advanced NSCLC
Authors: R.S. Herbst, F. de Marinis, J. Jassem, D.R. Spigel, G. Shankar, S. Mocci, A. Sandler, A. Lopez-Chavez, S. Li, G. Giaccone
Journal: Annals of Oncology (2015)