tbuckley/cabot-search huggingface dataset:
Abstract 633: Tumor cell resistance mechanisms to aurora kinase inhibitors
Authors: Madhusudhan Kollareddy, Daniella Zheleva, Petr Dzubak, Marian Hajduch
Journal: Cancer Research (2010)

Abstract Aurora kinase inhibitors are being developed as anti-cancer drugs and more than 10 small molecules are currently undergoing clinical trials. CYC116, an Aurora kinase inhibitor, discovered and developed by Cyclacel Ltd. is currently in phase I clinical trial in patients with advanced solid tumors. CYC116 showed significant anti-proliferative activity in preclinical studies. However tumor cell resistance mechanisms towards this Aurora kinase inhibitor have not been yet established. We developed several HCT116 p53 wild-type and HCT116 p53 null resistant clones towards CYC116 by exposing the cells to high drug concentrations. In order to compare resistance mechanisms, another Aurora kinase inhibitor, ZM447439, was used as a reference compound. Here we present the preliminary data characterizing CYC116-resistant clones. In MTT cytotoxicity assays all the clones showed CYC116 resistance and cross resistance to other Aurora kinase inhibitors, and to some anticancer drugs, which suggest a multidrug resistance phenotype. However the degree of resistance is variable between the clones. All CYC116-resistant clones irrespective of their p53 background became tetraploid. This was not observed for the ZM447439-resistant clones. PH3 (ser10), an Aurora kinase B phosphorylation site, was not inhibited in all resistant clones, suggesting that this kinase is still active. DNA and RNA synthesis were also not inhibited in these clones. Flow cytometry based studies revealed no up regulation of PgP drug transporter in all CYC116-resistant clones, whereas two HCT116 p53 null ZM447439-resistant clones displayed an increase in PgP levels. Up regulation of MRP was only detected in one HCT116 p53 null CYC116-resistant clone, which expressed high levels of this drug transporter. From the initial data it is obvious that there were no common resistance mechanisms towards the studied Aurora kinase inhibitors. We are continuing the characterization of these resistant clones, which include microarray gene expression studies, 2-D electrophoresis and mass spectrometry studies, Aurora A and B sequencing (target mutations), and other drug transporter (e.g. BCRP &amp; LRP) expression studies. These will further help the understanding of the molecular basis of acquired tumor resistance to CYC116 and will aid us in predicting the clinical response as well as in designing combination treatment regimens for overcoming resistance hence furthering clinical development. This work was kindly supported by the Czech ministry of education. Grant number: MSM6198959216 and LC07017. 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 633.
S74 Increased plasma levels of syndecan-1 and sFlt-1 during cardiopulmonary bypass surgery: associations with sRAGE
Authors: J. Zhang, B. C. Creagh-Brown, S. Mumby, M. J. Griffiths, A. Burke-Gaffney
Journal: Thorax (2011)

<h3>Introduction and Objectives</h3> Endothelial barrier dysfunction contributes to the systemic inflammatory response syndrome (SIRS) for which cardiac surgery necessitating cardiopulmonary bypass (snCPB) is a human model. A growing body of evidence suggests that the receptor for advanced glycation end products (RAGE) is also implicated in the pathogenesis of SIRS. While RAGE activation, in vitro, is known to decrease barrier function of cultured endothelial cells, the role of RAGE in regulating vascular permeability in patients undergoing snCPB is unknown. We hypothesised that plasma levels of markers of endothelial barrier dysfunction, syndecan-1, an endothelial glycocalyx component; and sFlt-1, a soluble form of the vascular endothelial cell growth factor (VEGF) receptor-1, will increase during snCPB and levels relate to patient outcome. <h3>Methods</h3> ELISA measurements/western blotting was used to determine syndecan-1 and sFlt-1 levels in pre-, intra- and post-snCPB plasma samples; for comparison, glypican-1, another glycocalyx component and Robo4, an endothelial barrier stabilising protein, were also measured. Clinical indices: age, nature of operation, CPB time, ischaemic time, intensive care unit (ICU)/ hospital length of stay (LOS) were collected from electronic databases. <h3>Results</h3> Syndecan-1 was significantly higher during CPB (77.17±39.72 ng/ml) compared with pre-snCPB levels (35.26±25.81 ng/ml, n=14, p&lt;0.01). Plasma levels of sFLt-1 were significantly (p&lt;0.001) higher during (10 000 pg/ml±3601, n=10) and post-snCPB (4282±3271 pg/ml) compared with preoperative levels (69.68±35.22 pg/ml). Preoperative plasma syndecan-1 correlated positively with ICU LOS (r<sup>2</sup>=0.486, p=0.006); whereas, intraoperative sFlt-1 correlated negatively with ICU LOS (r<sup>2</sup>=0.406, p=0.048). Intraoperative syndecan-1 levels positively associated with ischaemic time (r<sup>2</sup>=0.383, p=0.018) and plasma sRAGE levels (r<sup>2</sup>=389, p=0.040); postoperative syndecan-1 levels correlated with sRAGE (r<sup>2</sup>=0.790, p=0.0003). Glypican-1 and Robo4 were also detected in snCPB plasma samples. <h3>Conclusion</h3> Plasma levels of syndecan-1 and sFlt-1 were highest during snCPB. A positive association between preoperative syndecan-1 and ICU LOS is consistent with a relationship between endothelial barrier dysfunction and outcome. By contrast, higher intraoperative sFlt-1 correlating with shorter ICU LOS implied a protective role of sFlt-1. Associations between syndecan-1 and sRAGE suggest a link between RAGE and endothelial barrier dysfunction that merits further investigation; as do the novel findings that glypican-1 and Robo4 were detected in plasma of patients undergoing snCPB.
AB1063 Assessment of Malnutrition Risk among Patients with Rheumatologic Diseases in the Outpatient Clinics of A Tertiary Government Training Hospital in the Philippines
Authors: J.R. Limgenco-Hipe, E. Salido, A. Magbitang
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Malnutrition is a frequently unaddressed confounding problemamong patients with chronic illnesses. It correlateswith decreased functionality and quality of life, and increased morbidity and mortality. The prevalence of malnutrition among patients with rheumatologic conditions ranges from 15-24%. Although there is a suspicion that malnutrition is common among Filipino patients with rheumatic diseases, there is no published data. The study will bridge this knowledge gap and hope to pave the way for a more holistic approach in the care of Filipino patients with rheumatic diseases. <h3>Objectives</h3> To assess the risk of malnutrition among patients with various rheumatologic conditions who attend the outpatient clinics of a tertiary training government hospital in the Philippines. <h3>Methods</h3> This is a cross sectional study of adult patients seen in a rheumatology out-patient clinic. After getting an informed consent, we collected data on demographics and disease characteristics then administered the Malnutrition Universal Screening Tool by getting their Body Mass Index, unplanned weight loss and acute disease effect score. Then we classified them according to malnutrition risk and managed accordingly. <h3>Results</h3> One hundred eighty-two patients are included (86% are female), with mean age of 45 years old (SD 16.65). The majority (54%) have low level of education and 76% are below minimum wage earners. Twelve percent are smokers and 16% are alcohol beverage drinkers. Thirty-nine percent have systemic lupus erythematosus (SLE), 15% have osteoarthritis (OA) and 14% have rheumatoid arthritis (RA). The average duration of illness is 75 months. Ten percent of our patients are at high risk of malnutrition while 18% and 72% are at moderate and low risk, respectively. Six percent of SLE patients have high risk and 24% are at moderate risk of malnutrition. Among patients with OA, 6.9% have high and 3.4% have moderate risk of malnutrition. While patients with RA, 19% and 16% have high and moderate risk of malnutrition, respectively. <h3>Conclusions</h3> Twenty-eight percent of patients with rheumatologic conditions being seen at the outpatient clinics of the Philippine General Hospital have moderate to high risk of malnutrition.The Malnutrition Universal Screening Tool can be used in the routine evaluation of our patients, identifying those who are at risk of malnutrition. This will allow for timely intervention and optimal care. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.3520
Analysis of plasma protein biomarkers from the CORRECT phase III study of regorafenib for metastatic colorectal cancer.
Authors: Heinz-Josef Lenz, Eric Van Cutsem, Alberto F. Sobrero, Salvatore Siena, Alfredo Falcone, Marc Ychou, Yves Humblet, Olivier Bouche, Laurent Mineur, Carlo Barone, Antoine Adenis, Josep Tabernero, Takayuki Yoshino, Richard M. Goldberg, Daniel J. Sargent, Frank Cihon, Andrea Wagner, Dirk Laurent, Michael Jeffers, Axel Grothey
Journal: Journal of Clinical Oncology (2013)

3514 Background: In the CORRECT phase III trial, the multikinase inhibitor regorafenib (REG) demonstrated significant improvement in overall survival (OS) and progression-free survival (PFS) vs placebo (Pla) in patients with metastatic colorectal cancer (mCRC) whose disease had progressed on other standard therapies. An exploratory biomarker subanalysis was conducted to identify protein biomarkers with potential predictive or prognostic value. Methods: Fifteen proteins of interest, many of which are involved in angiogenesis, were quantified by multiplex immunoassay or ELISA in baseline plasma samples collected at study entry from 80% (611/760) of patients. Potential predictive and prognostic effects were evaluated. Results: The biomarker subpopulation was representative of the overall study population in terms of OS and PFS. Using OS as the clinical endpoint, Tie-1 was the only protein whose level demonstrated significant correlation with efficacy (low protein group: REG/Pla, HR 0.87; high protein group, HR 0.56; interaction, p=0.035). Using PFS as the clinical endpoint, von Willebrand factor (VWF) was the only protein whose level demonstrated significant correlation with efficacy (low protein group: REG/Pla, HR 0.39; high protein group, HR 0.60; interaction, p=0.02). Following correction for multiple testing, neither Tie-1 nor VWF data retained statistical significance. Baseline levels of IL-8 and placental growth factor (PlGF) were found to have prognostic value for OS (IL-8: high/low protein levels, HR 3.48, p&lt;0.001; PIGF: HR 1.81, p=0.002). IL-8 was also prognostic for PFS (high/low protein levels: HR 1.63, p&lt;0.001). Conclusions: None of the plasma proteins examined showed significant predictive value for REG efficacy after multiple testing correction. The association between baseline levels of Tie-1/VWF and REG efficacy may be a hypothesis to be tested in further trials. Clinical trial information: NCT01103323.
BEST POST-SYSTOLIC SHORTENING TTE PARAMETERS FOR DETECTION OF LEFT VENTRICULAR ISCHEMIC SEGMENTS DETERMINED BY INVASIVE FRACTIONAL FLOW RESERVE
Authors: Koya Ozawa, Nobusada Funabashi, Takeshi Nishi, Masayuki Takahara, Hiroyuki Takaoka, Yoshihide Fujimoto, Yoshio Kobayashi
Journal: Journal of the American College of Cardiology (2016)
Commentary: Carcinogen Risk Assessment
Authors: Roy E. Albert
Journal: Environmental Health Perspectives (1989)

A molecular biological rationale for the linear nonthreshold dose-response pattern for carcinogenesis is presented based on the mutagenic activation of oncogens as the basis of initiation. The approach assumes that the linear nonthreshold dose pattern at very low doses applies only to tissues that are promoted by intrinsic and extrinsic agents other than the one being modeled, and that risk is charactertized on a relative rather than absolute basis in terms of aggregate tumor response.
A3.8 Extrathymic Autoimmune Regulator (AIRE) Expression in Rheumatoid Arthritis
Authors: AR Noort, KPM van Zoest, MC Lebre, PP Tak, SW Tas
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> AIRE is a transcription factor that is involved in the negative selection of self-reactive thymocytes in the thymus. Recently, AIRE protein has also been detected in peripheral lymphoid organs, predominantly in dendritic cells (DC). In these peripheral sites, AIRE was found to regulate the expression of a group of tissue-specific antigens that is distinct from those expressed in the thymus, suggesting that peripheral AIRE may play a complementary role in tolerance induction. It is currently unknown whether AIRE may play a role in inflamed tissues, such as rheumatoid arthritis (RA) synovial tissue (ST). <h3>Objective</h3> To document and further characterise extrathymic AIRE expressing cells in ST and paired peripheral blood (PB) mononuclear cells (MCs) as well synovial fluid (SF) MCs of RA patients. <h3>Methods</h3> ST was obtained via mini-arthroscopy from inflamed joints of RA or undifferentiated arthritis (UA) patients. Expression of AIRE was evaluated using IHC and IF microscopy. AIRE expression was also investigated in PB and SF DC using flow cytometry. <h3>Results</h3> AIRE expressing cells were detected in 80% of analysed RA ST and in contrast only in 25% of UA ST. Further characterisation using double-immunofluorescence microscopy revealed that these cells were predominantly CD1c+ myeloid (m)DC. Interestingly, a significantly higher percentage of CD1c+ mDC in RA SF expressed AIRE (55 ± 5%) compared to RA PB (20 ± 3%) and healthy PB (19.7 ± 2%). <h3>Conclusions</h3> Extrathymic AIRE expressing CD1c+ mDCs are present in RA ST and RA SF, suggesting a role in synovial inflammation. Extrathymic AIRE expression in RA synovial inflammation may be an attempt to control inflammation through the induction of peripheral tolerance to antigens involved in the perpetuation of the chronic inflammatory response.
Active management reduces bleeding in third stage of labour
Authors: Z. Kmietowicz
Journal: BMJ (1998)

Active rather than expectant management is the preferred treatment for the third stage of labour, according to the latest trial comparing the techniques in which midwives were skilled in both approaches.

Hospitals should recommend active management in their clinical guidelines, conclude the authors, although they should also ensure that midwives are trained in expectant management to allow women a choice of approaches ( Lancet 1998;351:693-9). Active management involves giving …
Lack of Uptake of Tagged Erythrocytes in a Large Hepatic Hemangioma
Authors: Douglas DeCORATO, Howard Finestone, Mitchell Horowitz
Journal: Clinical Nuclear Medicine (1999)

A 42-year-old man had intermittent right upper quadrant pain. Initial ultrasound examination showed a mass in the posterior segment of the right lobe of the liver. A tagged red blood cell scan was obtained to evaluate this lesion. No abnormal uptake was present on either planar or SPECT images. MR imaging showed that the lesion was hyperintense on heavily T2-weighted images and had a classic enhancement pattern (peripheral nodular pattern). Large nonthrombosed hepatic hemangiomas may be present despite the lack of uptake on a tagged red blood cell scan.
A Comparison of Low-Molecular-Weight Heparin with Unfractionated Heparin for Unstable Coronary Artery Disease
Authors: Marc Cohen, Christine Demers, Enrique P. Gurfinkel, Alexander G.G. Turpie, Gregg J. Fromell, Shaun Goodman, Anatoly Langer, Robert M. Califf, Keith A.A. Fox, Jerome Premmereur, Frederique Bigonzi, Jim Stephens, Beth Weatherley
Journal: New England Journal of Medicine (1997)

Antithrombotic therapy with heparin plus aspirin reduces the rate of ischemic events in patients with unstable coronary artery disease. Low-molecular-weight heparin has a more predictable anticoagulant effect than standard unfractionated heparin, is easier to administer, and does not require monitoring.
The Influence of Temperature and Fibril Stability on Degradation of Cartilage Collagen by Rheumatoid Synovial Collagenase
Authors: Edward D. Harris, Peter A. McCroskery
Journal: New England Journal of Medicine (1974)

Crude synovial collagenase, an enzyme that may affect joint cartilage in rheumatoid arthritis, can destroy whole articular cartilage. To study this phenomenon under more specific conditions, we purified collagenase synthesized by primary cultures of rheumatoid synovium and used it to degrade collagen fibrils purified from human articular cartilage. These highly cross-linked fibrils were resistant to solubilization in acetic acid-pepsin extracts and, in comparison with skin collagen fibrils reconstituted without intermolecular cross-links, were somewhat resistant to the collagenase as well. However, the rate of cartilage collagen lysis was affected by changes in reaction temperature. At temperatures found within rheumatoid knee joints (36°C) collagenolysis was four times greater than at temperatures found in normal knee joints (33°C). Part of the benefit from anti-inflammatory therapy in rheumatoid arthritis may be secondary to decreasing intra-articular temperatures, thereby decreasing the rate at which collagenase degrades cartilage collagen. (N Engl J Med 290: 1–6, 1974)
Contrast Material-Induced Renal Failure in Patients with Diabetes Mellitus, Renal Insufficiency, or Both
Authors: Patrick S. Parfrey, Sheila M. Griffiths, Brendan J. Barrett, Michael D. Paul, Margot Genge, John Withers, Nadir Farid, Patrick J. McManamon
Journal: New England Journal of Medicine (1989)

To determine the risk of nephrotoxicity induced by the infusion of radiographic contrast material, we undertook a prospective study of consecutive patients undergoing radiographic procedures with intravascular contrast material. There were three study groups: patients with diabetes mellitus and normal renal function (n = 85), patients with preexisting renal insufficiency (serum creatinine level, ≥150 μmol per liter) without diabetes (n = 101), and patients with both diabetes and renal insufficiency (n = 34). The control group consisted of patients undergoing CT scanning or abdominal imaging procedures without the infusion of contrast material who had diabetes mellitus (n = 59), preexisting renal insufficiency (n = 145), or both (n = 64). Clinically important acute renal failure (defined as an increase of >50 percent in the serum creatinine level) attributable to the contrast material did not occur in nondiabetic patients with preexisting renal insufficiency or in diabetics with normal renal function. The incidence of clinically important contrast-induced renal failure among the diabetic patients with preexisting renal insufficiency was 8.8 percent (95 percent confidence interval, 1.9 to 23.7 percent), as compared with 1.6 percent for the controls. The incidence of acute renal insufficiency, more broadly defined as an increase of >25 percent in the serum creatinine level after the infusion of contrast material, was 11.8 percent among all patients with preexisting renal insufficiency. After the exclusion of patients whose acute renal insufficiency could be attributed to other causes, the incidence was 7.0 percent (95 percent confidence interval, 3.2 to 12.8 percent), as compared with 1.5 percent in the control group. The risk of acute renal insufficiency attributable to the contrast material was therefore 5.5 percent, and the relative risk associated with the infusion of contrast material was 4.7. These rates were similar whether the osmolarity of the contrast material was high or low. We conclude that there is little risk of clinically important nephrotoxicity attributable to contrast material for patients with diabetes and normal renal function or for nondiabetic patients with preexisting renal insufficiency. The risk for those with both diabetes and preexisting renal insufficiency is about 9 percent, which is lower than previously reported. (N Engl J Med 1989; 320:143–9.)
Letter by Robinson Regarding Articles, “Bringing Back Targets to ‘IMPROVE’ Atherosclerotic Cardiovascular Disease Outcomes: The Duel for Dual Goals; Are Two Targets Better Than One?” and “Achievement of Dual Low-Density Lipoprotein Cholesterol and High-Sensitivity C-Reactive Protein Targets More Frequent With the Addition of Ezetimibe to Simvastatin and Associated With Better Outcomes in IMPROVE-IT”
Authors: Jennifer G. Robinson
Journal: Circulation (2016)

Bolula et al 1 report the rates of major cardiovascular events for groups of patients achieving low-density lipoprotein cholesterol (LDL-C) <70 mg/dL or ≥70 mg/dL and high-sensitivity C-reactive protein (hs-CRP) <2 mg/L or ≥2 mg/L after 1 month of follow-up for participants in the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT).The results not surprisingly are consistent with the reports of others, in that patients with both LDL-C <70 mg/dL and hs-CRP <2 mg/L on treatment are at lower risk than those with higher levels of either or both LDL-C and hs-CRP. 2 The accompanying editorial by Michos, Martin, and Blumenthal rightly points out that the lower cardiovascular event rates in the patients with an hs-CRP <2 mg/L is an observational association, rather than evidence of causality, and that this evidence is inadequate to support recommendations to titrate therapy to achieve specific hs-CRP goals. 3They note that residual confounding that could not be fully adjusted for in multivariate analyses, including starting with lower hs-CRP levels at baseline (6.5-7.5 mg/L in those with achieved hs-CRP <2.0 mg/L and 15.2-16.2mg/L in those with achieved hs-CRP ≥2.0 mg/L), could explain the association.However, it is erroneous to then assume that the lower event rates in those with LDL-C <70 mg/dL are causal and support a recommendation to titrate to an LDL-C goal <70 mg/dL.The randomization was to either ezetimibe or placebo added to background moderate-intensity statin therapy, not to an LDL-C target of <70 mg/ dL or ≥70 mg/dL.Therefore, the data for LDL-C are also observational and no stronger than those for hs-CRP, and prone to the same residual confounding as the hs-CRP association, including lower LDL-C levels at baseline (mean 79 mg/dL in the achieved LDL-C <70 mg/dL group and 92 mg/dL in the achieved LDL-C ≥70 mg/ dL group).Therefore, similar caution should be advised for both hs-CRP and LDL-C findings, and a clinical recommendation to titrate therapy to an LDL-C <70 mg and hs-CRP <2.0 mg/dL goal would be premature in the absence of a randomized trial comparing titrationto-goal strategies.
STABLE CORONARY DISEASE IN HIGH VASCULAR RISK PATIENTS AND QUALITY OF LIFE: INSIGHTS FROM THE LONG TERM RISK, CLINICAL MANAGEMENT AND HEALTHCARE RESOURCE UTILIZATION OF STABLE CORONARY ARTERY DISEASE (TIGRIS) REGISTRY
Authors: David B. Brieger, Shaun Goodman, Jose Carlos Nicolau, Tabassome Simon, Jiyan Chen, Satoshi Yasuda, Stefan Blankenberg, Stuart Pocock, Christopher Granger, Gema Requena, Andrew Maguire, Richard Grieve
Journal: Journal of the American College of Cardiology (2016)
68Ga Prostate-Specific Membrane Antigen Uptake in Renal Cell Cancer Lymph Node Metastases
Authors: Ingo Einspieler, Robert Tauber, Tobias Maurer, Markus Schwaiger, Matthias Eiber
Journal: Clinical Nuclear Medicine (2016)

68Ga prostate-specific membrane antigen (PSMA)-HBED-CC PET/CT in a patient with a history of both prostate cancer (PC) and renal cell cancer (RCC) shows high PSMA expression in the residual right seminal vesicle suggestive of local recurrence of PC as well as suspected PSMA-positive mediastinal, retroperitoneal, and iliac lymph nodes. Regarding the latter, biopsy revealed lymph node metastases from RCC excluding PC metastases. This case exemplarily demonstrates that high PSMA expression in RCC metastases can potentially mimic PC metastases. Thus, for accurate interpretation of imaging results in PC patients with additional primary tumors, knowledge of PSMA expression of non-PC tissue is necessary.