tbuckley/cabot-search huggingface dataset:
OT-304, a novel, anti-angiogenesis agent with multiple inhibitory effects on proliferation, angiogenesis, and tumor progression
Authors: S. A. Mousa, G. Patil, S. Thangirala, E. Dier, E. Dyskin, M. Yalcin, A. Rebbaa, F. R. Rickles
Journal: Journal of Clinical Oncology (2008)

14597 Background: Increased proinflammatory, proangiogenesis, and proliferative activities are among the major features of cancer. Thus, a comprehensive anti-tumor strategy would be to target these processes. The present study tested a novel, oral, small molecule dual inhibitor of NF-κB and ERG-1 mediated, oxidative stress activation pathways. Methods: Antitumor and antiangiogenesis efficacy of OT-304 were investigated in mouse xenograft, chick chorioallantoic membrane (CAM) and mouse matrigel models. The effect of OT- 304 was characterized using a human monocytic cell line (THP-1) and human endothelial cells using Affymetrix micro-array, RT-PCR, Western blot, ELISA and gel shift assays. Results: OT-304 was found to exert profound inhibitory effects on proliferation of various cancer cell lines. Analysis of underlying mechanism(s) indicated that OT-304 induces G0/G1 cell cycle arrest. OT-304 demonstrated potent inhibition of angiogenesis induced by various stimuli including basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), lipid hydroperoxide, angiotensin II, LPS, and bradykinin with an ED50 of 4.7 μg/CAM and 5.0 μg/mouse (bFGF- mediated angiogenesis). OT-304 demonstrated inhibition of LPS-induced NF-κB activation, nuclear translocation of p50/p65, degradation of IκBα and membrane lipid peroxidation (90% inhibition at 1.0 μM). In vivo studies using tumor xenografts in nude mice showed that OT-304 (10 mg/Kg, IP q3days) was able to inhibit the growth of doxorubicin-resistant breast cancer cells by more than 80%. In the CAM, OT-304 at 1–10 μg inhibited growth and angiogenesis of various tumor implants including breast, lung, pancreatic, glioma, osteosarcoma, neuroblastoma, and prostate cancer. Conclusions: These findings provide evidence that OT-304 acts through multiple mechanisms including the inhibition of oxidative stress pathways to prevent cancer progression. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Othera Pharmaceuticals Inc. Othera Pharmaceuticals Inc. Othera Pharmaceuticals Inc
Abstract 15066: The Influence of Cardiovascular Risk Factors on Coronary Flow Reserve Measured by Doppler Echocardiography in Women With Angina Pectoris and No Obstructive Coronary Artery Disease
Authors: Naja D Mygind, Adam A Pena, Marie M Michelsen, Nynne Dose, Jens Kastrup, Eva Prescott
Journal: Circulation (2014)

Background:  Coronary microvessel dysfunction (CMD) is a possible explanation for angina pectoris when no obstructive CAD can be diagnosed. CMD can be assessed by transthoracic Doppler echocardiography (TTDE) with measurement of coronary flow reserve (CFR). CFR≤2.0 is considered diagnostic for CMD, and is associated with an adverse prognosis despite the absence of obstructive CAD. The aim of this study was to investigate the correlation between traditional cardiovascular risk factors and CFR measured with TTDE.   Methods:  Women with angina pectoris assessed by CAG were invited to participate if the CAG revealed no significant stenosis. Assessment included demographic, clinical data, bloodsamples and TTE during rest and high-dose dipyridamole stress (0.84 mg/kg) with measurement of CFR by Doppler of the left anterior descending artery.   Results:  CFR was measured in 763 patients; median (IQR) 2.36 (2.00-2.76). When dividing patients into 3 groups, the CFR level was related to age, history of hypertension, duration of smoking and postmenopausal status (Table 1). Multiple linear regression with lnCFR as dependent variable gave the following results for the independent variables (constant=3.597): Age (p 2 =0.076. Parameter estimates are adjusted reflecting standard values for the independent variables in the regression equation.   Conclusions:  This is the largest study so far to describe microvascular function in women with angina pectoris and no obstructive CAD. CFR was impaired in a large proportion of the women, and associated with some traditional risk factors for CAD. CMD assessed by TTDE represents a relevant diagnostic and therapeutic target for strategies aiming at preventing adverse outcomes in women with angina pectoris and no obstructive CAD.
Abstract 18043: Factors That Influence the Decision for Ischemic Work-up in Hypertensive Emergency
Authors: Obiora Maludum, Kenechukwu Mezue, Sylvia Biso, Mary Rodriguez-Ziccardi, Talal Alnabelsi, Mahek Shah, Chinualumogu Nwakile, Vincent Figueredo
Journal: Circulation (2015)

Background: Hypertensive emergencies (HE) account for 3% of emergency room hospitalizations and it is estimated that 1-2% of America’s 50 million hypertensive patients will have at least one occurrence of HE in their lifetime. Recent studies have shown that cardiac troponin-I is elevated in a third of patients with HE, however the pathophysiology and significance of this elevation is still being explored. We tried to look at different factors that influence the decision to do ischemic work up in patients with HE. Method: Patients admitted to Albert Einstein Medical Center from 01/01/2005 to 08/30/2014 with a diagnosis of HE were included in this retrospective study. Patients were divided into two groups: those who had either cardiac catheterization or stress test, and those who had no ischemic work up. Demographic and clinical variables were collected. A cumulative risk score for coronary artery disease was calculated by assigning 1 point for each risk factor. Results: There were total of 187 patients with HE of which only 37 had ischemic work up. 20 out of the 37 patients who had ischemic work up had chest pain. Of the 20 patients only 3 were found to have significant coronary artery disease. Comparisons between the demographics and clinical predictors in both groups are shown in the table. Multivariate analysis shows chest pain to independently predict which patients were more likely to receive an ischemic work up (OR=4.7; 95% CI 1.6 to 7.6; p=0.001). Conclusion: In the setting of HE, our study shows that chest pain was the only single factor that independently predicts which HE patients are more likely to receive an ischemic work up. Elevated troponins or EKG changes alone were not found to independently predict the decision to perform an ischemic work up. This may reflect the pattern of clinical practice at our center. Large multi-center studies might be needed to explore this further and also assess the clinical outcomes of this decision making process.
Adenovirus-mediated interferon-β gene therapy combined with radiotherapy synergistically inhibits lung tumor growth in mice
Authors: M. Sebastian, J. Hast, N. Koplin, R. Buhl, R. Wiewrodt
Journal: Journal of Clinical Oncology (2004)

7340 Background: The outcome of non-resectable patients with advanced stages of lung cancer (LC) is not satisfying, despite improved chemotherapy and radiotherapy regimes. In other tumors immune-modulatory therapies using various interferons (IFN) delivered via viral vector, have shown some promise. We thus evaluated the use of a replication-deficient adenoviral (Ad) vector encoding for the murine IFN-β gene (Ad.muIFN-β) in mouse LC models in combination with radiotherapy. Methods: L1C2 cells (a mouse LC cell line syngeneic in immune competent BALB/c) were injected either subcutaneously (s.c.) or intraperitoneally (i.p.). Established tumors were treated with a single dose (109 pfu) of Ad.muIFN-β, a control Ad vector (Ad.HSVtk), or saline. Large s.c. flank tumors were additionally treated with radiotherapy (10Gy) at one timepoint. Results: 80% of animals with i.p. and s.c. tumors were cured after a single dose of Ad.IFN-β. However, in animals with large tumor burden (>5% body weight) this strategy was less successful. In large flank tumors, only the combination therapy of a single dose of Ad.muIFN-β and radiotherapy significantly reduced tumor size: With combination therapy, 60% of animals showed complete tumor eradication, whereas monotherapy with Ad.muIFN-β and radiation achieved an eradication rate of 0% and 20%, resp. Conclusions: Local delivery of the murine interferon-β gene via an adenoviral vector provided effective treatment for lung cancers established at various sites, as well as protective acquired immunity. Ad.muIFN-β gene therapy and radiotherapy acted synergistically in lung tumors in mice. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Fresenius Biotech
Phase IB randomized, double-blinded, placebo-controlled, dose-escalation study of polyphenon E in women with a history of hormone receptor-negative breast cancer.
Authors: K. D. Crew, P. Brown, H. Greenlee, T. B. Bevers, B. Arun, C. Hudis, H. L. McArthur, L. Vornik, T. L. Cornelison, D. L. Hershman
Journal: Journal of Clinical Oncology (2010)

TPS142 Background: Priorities in breast cancer (BC) chemoprevention include developing agents effective against hormone receptor (HR)-negative BC and validating intermediate biomarkers which correlate with BC risk. Numerous epidemiologic and preclinical studies support the anti- cancer and chemopreventive effects of green tea in BC. The main polyphenol of green tea, epigallacatechin gallate (EGCG), is a potent antioxidant which acts on multiple stages of carcinogenesis. The central hypothesis of this proposal is that the green tea polyphenol mixture, polyphenon E (Poly E), has activity for the secondary prevention of HR-negative BC. The primary objective of this phase IB trial is to demonstrate the safety of using Poly E over a 6- month period in patients with a history of HR-negative BC. Secondary exploratory objectives are to investigate the dose-related biologic effects of Poly E on breast tissue, radiographic, and serum-based biomarkers. Methods: This trial is a phase IB, randomized, double-blind, placebo-controlled study of oral Poly E 400 mg, 600 mg, or 800 mg bid for 6 months in 40 women with a history of stage I-III HR-negative BC (minimum of 6 months since completing chemotherapy, radiation therapy, or surgery; age 21-65). To date 40 patients have been enrolled. The primary endpoint of this dose escalation study is to determine the maximum tolerated dose of Poly E in this patient population according to the time-to-event continual reassessment method. Safety is assessed by monitoring clinical and laboratory parameters monthly for the duration of the study. Patients undergo a random core biopsy and mammogram of the contralateral breast at baseline and 6 months and serial blood/urine collections every 2 months. Laboratory correlates include breast tissue-based biomarkers (Ki-67, cleaved caspase-3, ER, EGFR, p53), mammographic density, serum hormone metabolites (estradiol, testosterone, IGF-I, IGFBP-3, SHBG), inflammatory and oxidative stress biomarkers (serum CRP, urine PGE-M, 8-OHdG, isoprostane). This study tests the safety and potential efficacy of a novel BC chemopreventive agent and evaluates a new approach for testing these agents. No significant financial relationships to disclose.
Abstract 15578: Effects of Low-Intensity Atrial Ganglionated Plexi Stimulation on Ventricular Electrophysiology in Normal Heart and after Acute Myocardial Ischemia
Authors: Bo He, Zhibing Lu, Wenbo He, Liu Wu, Bing Huang, Lilei Yu, Bo Cui, Xiaorong Hu, Hong Jiang
Journal: Circulation (2012)

Background: Atrial ganglionated plexus (GP) has been shown to modulate sinus rate, atrioventricular conduction and atrial electrophysiology. The aim of this study was to investigate the effect of l...
Lack of Fc-ε Receptors on Murine Eosinophils: Implications for the Functional Significance of Elevated IgE and Eosinophils in Parasitic Infections
Authors: Belen de Andres, Eva Rakasz, Michael Hagen, Mike L. McCormik, Allen L. Mueller, David Elliot, Ahmed Metwali, Matyas Sandor, Bradley E. Britigan, Joel V. Weinstock, Richard G. Lynch
Journal: Blood (1997)
Clinical risk factors for complications associated with ECG-guided portacath use in breast cancer patients.
Authors: L. Hanker, T. Karn, B. Linnemann, E. Lindhoff-Last, L. Mavrova, S. Afrashteh, P. Lazarova, R. Gaetje, M. Kaufmann, A. Rody
Journal: Journal of Clinical Oncology (2010)

e19647 Background: otally implanted venous access systems (portacath) are increasingly used in cancer patients in order to make the application of chemotherapy for patients more comfortable and safer. Nevertheless these portacaths are associated with short– and long-term complications. These vary between different types of malignancies. Complication rates in breast cancer patients have not yet been analyzed broadly. Methods: We performed a retrospective analysis at the universitiy hospital Frankfurt, Germany. Records from 405 breast cancer patients who had received an ECG- guided portacath insertion from years 2003 to 2009 were reviewed to evaluate risk factors for port associated complications. Two different insertion techniques were used: surgical cut down to the cephalic vein or if not possible direct puncture of the subclavian vein. The device was placed on the fascia pectoralis after ECG-guided positioning of the catheter tip. All patients were followed through December 2009 or until death, catheter failure, or catheter removal upon completion of chemotherapy. Beside clinical tumor parameters disease specific events have been evaluated. Results: Of 405 breast cancer patients 9 were excluded because of incorrect portacath insertions. Among the remaining 396 patients the most frequent complication was thrombosis (9.8%). Surgical complications were infrequent with catheter leakage (0.8%) and pneumothorax (0.5%). We found no significant correlations between the rate of thrombosis and several different clinical variables (primary vs. metastatic disease, tumor size, lymph node status, and histological grading). Moreover no differences were found regarding to the two applied insertion techniques or the chest side in which the portacath was placed. Interestingly, the rates of thrombosis were lower in patients older than 50 years (7.1% vs. 14.0%; p=0.037). Conclusions: The thrombotic complication rate in breast cancer patients is rare. We found younger age as the only patient-related risk factor for the development of port-related thrombosis. No significant financial relationships to disclose.
Phase II clinical trial of suberoylanilide hydroxamic acid (SAHA) in patients (pts) with recurrent and/or metastatic head and neck cancer(SCCHN)
Authors: G. Blumenschein, C. Lu, M. Kies, B. Glisson, V. Papadimitrakopoulou, R. Zinner, E. Kim, A. Gillenwater, J. Chiao, W. Hong
Journal: Journal of Clinical Oncology (2004)

5578 Background: SAHA is a potent histone deacetylase inhibitor that has excellent oral bioavailability. Preclinical studies demonstrated that SAHA has growth inhibitory and apoptosis-inducing activity in SCCHN cell lines in vitro. In a phase I trial of oral SAHA administered once a day or twice a day, a partial response was observed in a pt with metastatic laryngeal carcinoma. A phase II trial was initiated to assess the efficacy and safety of oral SAHA administered as 400 mg qd in pts with SCCHN. Methods: Eligible pts must have recurrent and/or metastatic SCCHN unresponsive to or intolerant of conventional chemotherapy (up to two prior chemotherapies including neoadjuvant, adjuvant, and concomitant chemotherapy/radiation); ECOG performance status 0–2; adequate hematologic, hepatic, and renal function; able to swallow capsules; have measurable disease; = 4 weeks from prior chemotherapy, radiation therapy, major surgery or investigational anticancer therapy and have recovered from prior toxicities. Study endpoints included response rate, duration of stable disease and progression-free survival. Results: 13 pts were enrolled (9 males, 4 females). 12 pts have received oral SAHA at 400 mg qd and were evaluable for response. 1 pt withdrew consent prior to starting therapy. Median age is 54 years (range 38–83). Prior therapies included radiation in 9 pts and chemotherapy in all 12 pts; 11 patients received platinum, 8 patients received both taxanes and platinum. No partial or complete responses were observed. Tumor shrinkage by CT scan (minor response) was seen in 1 pt. 4 pts had stable disease lasting 3 to 6 months. Toxicity has been acceptable with 1 pt discontinuing therapy for grade 3 anorexia. Other grade 3–4 drug-related toxicities included anemia (n=1), anorexia (n=1), back pain (n=1), fatigue (n=1), and thrombocytopenia (n=3). Conclusions: SAHA at 400 mg qd appears to be well tolerated and has modest single agent activity in this small group of heavily pre-treated pts. In view of the signs of activity and good tolerability, a dose intense schedule will be tested. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aton Pharma, Inc. Aton Pharma, Inc. Atom Pharma, Inc.
Triglyceride-Rich Lipoproteins and Atherosclerotic Cardiovascular Disease
Authors: Børge G. Nordestgaard
Journal: Circulation Research (2016)

Scientific interest in triglyceride-rich lipoproteins has fluctuated over the past many years, ranging from beliefs that these lipoproteins cause atherosclerotic cardiovascular disease (ASCVD) to being innocent bystanders. Correspondingly, clinical recommendations have fluctuated from a need to reduce levels to no advice on treatment. New insight in epidemiology now suggests that these lipoproteins, marked by high triglycerides, are strong and independent predictors of ASCVD and all-cause mortality, and that their cholesterol content or remnant cholesterol likewise are strong predictors of ASCVD. Of all adults, 27% have triglycerides >2 mmol/L (176 mg/dL), and 21% have remnant cholesterol >1 mmol/L (39 mg/dL). For individuals in the general population with nonfasting triglycerides of 6.6 mmol/L (580 mg/dL) compared with individuals with levels of 0.8 mmol/L (70 mg/dL), the risks were 5.1-fold for myocardial infarction, 3.2-fold for ischemic heart disease, 3.2-fold for ischemic stroke, and 2.2-fold for all-cause mortality. Also, genetic studies using the Mendelian randomization design, an approach that minimizes problems with confounding and reverse causation, now demonstrate that triglyceride-rich lipoproteins are causally associated with ASCVD and all-cause mortality. Finally, genetic evidence also demonstrates that high concentrations of triglyceride-rich lipoproteins are causally associated with low-grade inflammation. This suggests that an important part of inflammation in atherosclerosis and ASCVD is because of triglyceride-rich lipoprotein degradation and uptake into macrophage foam cells in the arterial intima. Taken together, new insights now strongly suggest that elevated triglyceride-rich lipoproteins represent causal risk factors for low-grade inflammation, ASCVD, and all-cause mortality.
Modulation of Idarubicin-Induced Apoptosis in Human Acute Myeloid Leukemia Blasts by All-Trans Retinoic Acid, 1,25(OH)2 Vitamin D3, and Granulocyte-Macrophage Colony-Stimulating Factor
Authors: Nicolas J. Ketley, Paul D. Allen, Stephen M. Kelsey, Adrian C. Newland
Journal: Blood (1997)
Surface Antigens on Marek's Disease Lymphoblastoid Tumor Cell Lines&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="fn3"&gt;3&lt;/xref&gt;
Authors: K A Schat, C L Chen, W R Shek, B W Calnek
Journal: JNCI Journal of the National Cancer Institute (1982)

A total of 32 Marek's disease virus (MDV)-induced cell lines, 1 avian leukosis virus-induced cell line, and 1 reticuloendotheliosis virus (REV)-induced lymphoblastoid cell line were investigated for the presence of Fc receptors, surface IgM, and Ia-like antigen. Surface IgM and Fc receptors could not be demonstrated on any of the cell lines. Ia-like antigen was detected on all MDV-induced cell lines and on the 1 REV-induced cell line. Ia-like antigen was unrelated to other antigens reported to be present on Marek's disease tumor cells. It was also unimportant as a target antigen for MDV-related, allogeneic cell-mediated cytotoxicity. The densities of the cells of 5 MDV-induced cell lines were established on continuous Percoll gradients. Most cells had densities between 1.05 and 1.06 g/ml.
KRAS mutations as predictive biomarker in patients with EGFR wild-type stage IV nonsquamous non-small cell lung cancer (NSCLC) recruited in a phase II clinical study with carboplatin-docetaxel-bevacizumab.
Authors: Manuel Domine, Yann Izarzugaza, Federico Rojo, Francisco Lobo, Maria Jesus Fernandez-Acenero, Victoria Casado, Gustavo Rubio, Juan Luis Arranz, Ana Leon, Jose Ignacio Martin-Valades, Gloria Serrano, Cristina Carames, Sharon Cordova, Juan Madoz, Sandra Zazo, Raul Rincon, Carmen Canadas, Angel Campos, Nuria Perez-Gonzalez, Jesus Garcia-Foncillas
Journal: Journal of Clinical Oncology (2012)

e18069 Background: KRAS mutation are harbored in ~30% of NSCLC patients, and have been described associated with an upregulation of genes involved in angiogenesis, including vascular endothelial growth factor/vascular permeability factor (VEGF/VPF). Bevacizumab (BVZ) is a recombinant monoclonal humanized antibody targeted against VEGF and added to carboplatin-paclitaxel chemotherapy has demonstrated to improve outcome in non-squamous NSCLC. The objectives of this study were to analyze the impact of KRAS mutations in response rate (RR) and time to progression (TTP) in a cohort of patients homogeneously treated with BVZ in combination with carboplatin-docetaxel. Methods: Patients treated with up to 6 cycles of carboplatin (AUC 5), docetaxel (75 mg/m2) and BVZ (7.5 mg/kg) on day 1, every 21 days. Patients with RR or stable disease continued maintenance BVZ (7.5 mg/kg) every 21 days until disease progression. KRAS mutations at codons 12, 13 and 61 were analyzed by COBAS KRAS Mutation Test (Roche) from DNA purified from diagnostic samples. Results: 30 patients were enrolled (24 male, 6 female); median age was 62 years (range 44-82); ECOG 1/2: 22/8. 27 were adenocarcinomas and 3, undifferentiated large cell carcinoma. Smoking habit: 1 non-smoker, 16 current-smoker, and 13 former-smoker. Seven patients were KRAS mutated (23.3%). Carboplatin-docetaxel-bevacizumab therapy showed a significant improved efficacy in KRAS wild-type compared to mutated patients (RR: 85.7% vs 14.3%, p=0.045; and TTP: 9.38 months vs 7.46 months, p=0.033), but did not impact on overall survival (12.4 months in wild type vs 11.06 months in KRAS mutated, p= 0.780). Conclusions: KRAS mutations predict RR and TTP in wild-type EGFR stage IV non-squamous NSCLC patients treated with bevacizumab-based therapy.