tbuckley/cabot-search huggingface dataset:
Abstract P2-16-03: C-Met is a potential therapeutic target for antibody-drug conjugates in breast cancer
Authors: Yanwen Fu, Edwige Gros, Alice Lee, Kimberly Johnson, Hong Zhang, Silpa Yalamanchili, Kouros Motamed, Gary Chen, Bryan Jones, David Miao, Gunnar F Kaufmann
Journal: Cancer Research (2015)

Abstract C-Met, a transmembrane receptor tyrosine kinase, plays a key role in malignant transformation of epithelial cells by activating signal transduction pathways essential for cellular proliferation, survival, migration and invasion. C-Met overexpression, with or without gene amplification, has been reported in primary breast cancers and correlate with poor prognosis. C-Met signaling inhibition, such as tyrosine kinase inhibitors (TKIs), usually not sufficient for sustained treatment efficacy, we believe that antibody drug conjugates (ADCs) offer the promise and potential of delivering potent anti tumor activity with the advantage of reduced side effects. We generated antibody drug conjugates containing a proprietary human anti-c-Met antibody (STI-D0606) with either a tubulin inhibitor or DNA damaging agent, such as doxorubicin analogs. STI-D0606, a fully human antibody (IgG1) selected from phage library was conjugated with the cytotoxin via site specific bioconjugation. The conjugates retained binding affinity and showed potent cell killing in a variety of c-Met positive cell lines. Progress will be reported in terms of in vivo efficacy in c-Met-positive human breast tumor xenograft in preclinical models. Citation Format: Yanwen Fu, Edwige Gros, Alice Lee, Kimberly Johnson, Hong Zhang, Silpa Yalamanchili, Kouros Motamed, Gary Chen, Bryan Jones, David Miao, Gunnar F Kaufmann. C-Met is a potential therapeutic target for antibody-drug conjugates in breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-16-03.
Phase II study of preoperative chemoradiation (CRT) with cetuximab, irinotecan and capecitabine in patients with locally advanced resectable rectal cancer
Authors: Y. S. Hong, D. Y. Kim, K. S. Lee, S. B. Lim, H. S. Choi, S. Y. Jeong, J. H. Kim, S. A. Im, T. W. Kim, K. H. Jung
Journal: Journal of Clinical Oncology (2007)

4045 Background: Preoperative CRT with irinotecan and capecitabine is effective and safe in rectal cancer. Cetuximab, an EGFR- targeted agent, is synergistic with chemotherapy and radiotherapy. We conducted this study to determine efficacy and safety of cetuximab, irinotecan, and capecitabine as a combined preoperative CRT in patients with locally advanced resectable rectal cancer. Methods: This is a non-randomized, open-label, multicenter phase II study with cetuximab 400mg/m 2 on D-6 (1 week before radiation) followed by cetuximab 250mg/m 2 and irinotecan 40mg/m 2 once a week (D1, 8, 15, 22, &amp; 29) and capecitabine 1650mg/m 2 /day for weekdays only during radiation. Radiotherapy was given to a total dose of 50.4 Gy/28 fractions starting on D1. Main eligibility criteria were histologically proven rectal adenocarcinoma; T3–4 lesions; age 18 - 75 years; ECOG PS 0 - 2; no prior chemotherapy or EGFR targeted therapy. Total mesorectal excision was planned to be performed 4–8 weeks after completion of CRT. Results: Between May 2006 and Dec 2006, 40 patients were enrolled; median age 56.5 years (34 - 72); M/F 32/8; PS 0–1/2 38/2; cT3/T4 36/4; cN0/N+ 8/32; median tumor location from anal verge 5.5cm (0 - 8.0); moderately-differentiated adenocarcinoma 29. At present, 21 patients completed preoperative CRT and were evaluable for toxicity. Grade 3/4 toxicities included leucopenia (2, 9.5%), neutropenia (1, 4.8%), anemia (1, 4.8%) and diarrhea (1, 4.8%). Grade 2 hypersensitivity reactions and skin rashes were observed in 2 (9.5%) and 9 patients (42.9%), respectively and no grade &gt;1 hand-foot syndrome was observed. Of 10 patients who underwent surgery (all R0 resection) till now, 9 were treated with sphincter saving procedure. Pathologic T0 and N0 were observed in 3 and 7 patients, respectively. Pathologic complete responses were observed in 2 patients and another 2 patients had only minimal microscopic residual tumor. Conclusions: Preoperative CRT with cetuximab, irinotecan and capecitabine showed promising preliminary pathologic responses with mild toxicity profiles. Study enrollment has now been completed and further results of efficacy and safety will be presented. No significant financial relationships to disclose.
Abstract 18385: Serum Amyloid A is an Evolutionary Conserved Apolipoprotein That Functions to “Fine Tune” Reverse Cholesterol Transport During the Acute-Phase Response
Authors: John B Ancsin
Journal: Circulation (2011)

In response to severe injury, the acute-phase protein, serum amyloid A (SAA) can replace apoA-I as the major apo-protein of HDL. The inclusion of SAA in HDL changes a number of HDL's properties. Our data indicates that SAA's presence reduces HDL's capacity to accept free cholesterol. SAA also increases HDL's binding affinity for macrophages and is dependent on the cell surface glycosaminoglycan, heparin sulfate (HS). SAA contains two HS binding sites and HS binding to SAA can cause it to dissociate from HDL, leaving behind lipid poor apoA-I rich oligomers, with enhanced cholesterol accepting potential. Under "amyloidogenic" condition this dissociated SAA can be readily converted into amyloid fibrils by macrophages and our data suggests this occurs largely on the cell surface. SAA can also be taken up by macrophages and once in the cytoplasm we have shown that it can stimulate neutral cholesteryl ester hydrolase (nCEH) and inhibit acetyl-coenzyme A acetyltransferase (ACAT) activities, respectively, with the net effect of mobilizing stored cholesteryl ester and making it available for export via the ABCA1/ABCG1 transporters. Under experimental conditions SAA can promote the export of over 70% of the cholesterol loaded into macrophages within 24 h. SAA's activities complement those of apoA-I/HDL by increasing the pool of exportable (de-esterified) cholesterol for efflux to an extracellular cholesterol acceptor like apoA-I/HDL and entry into the reverse cholesterol transport (RCT) pathway. The nCEH and ACAT modulating domains of SAA have been identified and as synthetic peptides have been also demonstrated to be potent promoters and inhibitors of nCEH and ACAT activities, respectively, with purified enzyme preparations, intact cells in culture and in vivo in mice, consistent with an allosteric mechanisms of action. When delivered in liposomes to a mouse apoE knockout model of atherosclerosis, these SAA peptides were shown to be highly effective in the prevention and regression of atherosclerotic lesions. We believe SAA has been evolutionary conserved to aid in the recycling of cellular cholesterol.
Autoinflation for treatment of glue ear
Authors: H. Kubba, D. D Reidpath, P. P Glasziou, C. Del Mar
Journal: BMJ (1999)

Editor—A review of nasal balloons is welcome, given the high prevalence of glue ear (otitis media with effusion) and the devices’ simplicity.1 The authors conclude from three studies that the balloon may be of benefit. The two published studies to which they refer merit closer attention.2,3 The studies suggest short term benefit, but it is not sustained. No significant differences could be found in either study between treated and control groups in tympanometric resolution at two or three months’ follow up. Compliance was poor in over half the children and got worse with time. Any benefit is lost after treatment is stopped.

Reidpath et al have included the two-week outcomes in one trial2 and the 12-week outcomes in the two others (Blanshard et al3 and the unpublished data), even though benefit decreases significantly with time, biasing the results in favour of the treatment. The greater prevalence of type B tympanometry in one untreated group3 is an additional source of bias, as is the lack of blinding and adequate randomisation in any study. The result is the conclusion that the treatment is effective, with an odds ratio of 3.5. Meta-analysis of poor research gives poor answers.

Reducing all the information in a paper to a single odds ratio can be a powerful tool but also hides much of the available information. Meta-analysis is not the best way to analyse three small studies of variable methodology. The conclusion is the inevitable refrain that “more/bigger/better studies are needed.” In his commentary on the paper Haggard mentions the need to prioritise research endeavour to maximise payback.1 Surely it is wrong to recommend that large, expensive, time consuming studies be done on an issue for which the answer is already available. The nasal balloon produces no sustained benefit in glue ear, and after three months’ watchful waiting no large difference can be expected in the number of children requiring surgery. This is the real issue.

Haggard mentions that nasal balloons may have a place as a temporising measure. Is he suggesting that although the device produces no worthwhile benefit, we can use it as a placebo while nature takes its course? This would be deception of the worst kind, since the balloon is not available on prescription in the United Kingdom and must be paid for by parents. Glue ear is associated with social deprivation, and we must not ask our poorest patients to pay for a worthless device simply to keep them amused.
The epidemiology of hepatitis C virus infection in Sweden
Authors: A Duberg, R Janzon, E Bäck, K Ekdahl, A Blaxhult
Journal: Eurosurveillance (2008)

In Sweden, infection with hepatitis C virus (HCV) has been a notifiable disease since 1990, when diagnostic methods became available. Blood donor screening indicated that about 0.5% of the Swedish population (9 millions) had been HCV infected. Here we present the Swedish hepatitis C epidemic based on data from all the HCV notifications 1990-2006. During this time about 42,000 individuals (70% men) were diagnosed and reported as HCV infected. The majority (80%) were born in 1950 or later, with a high percentage (60%) born in the 1950s and 1960s. Younger people, 15-24 years old at notification, were reported on the same level each year. The main reported routes of HCV transmission were intravenous drug use in 65%, blood transfusions/products in 6%, and sexual in 2%, though unknown or not stated in 26%. Approximately 6,000 of all notified individuals have died during the study period. To conclude, the Swedish HCV epidemic is highly related to the increase of intravenous drug use in the late 1960s and 1970s, with a high proportion of people now chronically infected for more than 25 years, resulting in an increase of severe liver complications in form of cirrhosis and hepatocellular carcinoma. Furthermore the unchanged number of notifications of newly infected younger people indicates an ongoing HCV epidemic.
Abstract 971: Beta Adrenergic Agonists and Sudden Death in Coronary Artery Disease
Authors: Dong Li, Kyndaron Reinier, Audrey Uy-Evanado, Carmen Teodorescu, Ronald Mariani, Karen Gunson, Jonathan Jui, Sumeet S Chugh
Journal: Circulation (2009)

Background: Recent observations have raised concerns regarding the cardiovascular safety of beta-adrenergic agonists, especially in patients with heart disease. At least one initial study indicated...
Different types of placebo response in patients receiving antidepressants
Authors: F M Quitkin, P J McGrath, J G Rabkin, J W Stewart, W Harrison, D C Ross, E Tricamo, J Fleiss, J Markowitz, D F Klein
Journal: American Journal of Psychiatry (1991)

The authors studied the responses of drug-treated patients in an attempt to validate observations about abrupt and gradual improvements in patients receiving placebo. Since previous data suggested that in the first 2 weeks of antidepressant treatment specific drug effects are unlikely, the authors hypothesized that this improvement is a placebo effect. Therefore, in the first 2 weeks of antidepressant treatment abrupt and gradual improvements should have the characteristics of their placebo counterparts.The subjects were 263 patients in controlled antidepressant trials lasting 6 weeks.The percentage of abrupt improvements that occurred in the first 2 weeks was higher than that for gradual improvements. Abrupt improvements during the first 2 weeks of drug treatment were also less persistent than gradual improvements with drug and no more persistent than improvements with placebo during the same period. However, in weeks 3, 4, and 5, abrupt and gradual improvements with drug were equally persistent and both were more persistent than abrupt improvements with placebo.These data support the authors' findings about placebo. Abrupt improvements during treatment with both drug and placebo are more likely during the first 2 weeks of treatment and are less likely to persist than gradual improvements. The fact that persistence of abrupt improvements with drug in weeks 1 and 2 appears different from that of gradual improvements but appears no different after week 3 suggests that the mechanism of action of abrupt improvement with drug changes after week 2.
Abstract 93: "Push Hard" Prompts Transiently Increase Depth of Chest Compressions on Manikins by Nurses
Authors: Isabelle L Banville, Ronald E Stickney, Fred W Chapman, Lars Wik
Journal: Circulation (2010)

Studies that have evaluated CPR quality show that most trained rescuers do not perform at the chest compression depth and rate recommended by international guidelines. Recent work has shown that CP...
Abstract 11449: Morphine Delays the Onset of Action of Prasugrel in Patients With Prior History of St Elevation Myocardial Infarction
Authors: Allison C Morton, Rashed Hossain, Rose Ecob, Jemma Walker, Julian Gunn, Heather M Judge, Robert F Storey
Journal: Circulation (2013)

Background:  Patients undergoing primary percutaneous coronary intervention (PPCI) for ST-elevation myocardial infarction (STEMI) receive loading doses of aspirin and a P2Y 12  inhibitor. Delays in onset of action of all P2Y 12  inhibitors are reported in PPCI patients and this may increase the risk of acute stent thrombosis. Morphine is known to delay the absorption of orally administered drugs.   Aim:  To determine whether morphine delays the onset of action of prasugrel in patients with previous PPCI for STEMI.   Methods:  This was an open-label, crossover study 12 aspirin-treated patients with a history of STEMI treated with PPCI for which prasugrel and morphine had been administered. Patients were randomly assigned to receive either morphine 5mg or saline intravenously followed by 60mg prasugrel. Blood samples were collected before and over 24 hours after drug administration and platelet function testing using VerifyNow P2Y12 assay and light transmittance aggregometry (LTA) was performed. After a washout period of 3 weeks, patients then crossed over. The primary endpoint of the study was platelet reaction units (PRU) assessed by VerifyNow P2Y12 assay at 2 hours post prasugrel.   Results:  11 patients completed the study. Mean PRU at 2h post prasugrel was 26 ± 36 PRU with saline and 104 ± 110 PRU with morphine (P = 0.027). Final LTA response to ADP 20 uM at 2h post prasugrel was 5 ± 12% with saline and 23 ± 28% with morphine (P = 0.033). The mean estimated time taken to achieve a PRU of 150 was 50 ± 34 mins with saline and 151 ± 181 mins with morphine. There was no difference in platelet reactivity at 24h post prasugrel with saline compared to morphine (20 ± 27 PRU saline vs 19 ± 29 PRU morphine).   Conclusions:  Morphine delays the onset of action of prasugrel in patients with a prior history of PPCI for STEMI. Intravenous drugs may be necessary to reduce the risk of acute stent thrombosis in morphine-treated STEMI patients undergoing PPCI.
Diabetes-induced cardiac dysfunction is rescued by endothelial cationic amino acid transporter 1 overexpression in mice
Authors: Rebecca H. Ritchie, Makhala M. Khammy, Marissa A. Bowden, Jennifer Irvine, Karen Andrews, Karina Huynh, Helen Kiriazis, David Kaye, Kylie Venardos
Journal: Circulation Research (2011)
Abstract 3062: Minimally Invasive Epicardial Injection Using a Miniature Crawling Robotic Device Through a Subxiphoid Approach
Authors: Takeyoshi Ota, Nicholas A Patronik, Cameron N Riviere, Marco A Zenati
Journal: Circulation (2007)

Itroduction: We have developed a miniature crawling robot (HeartLander) that navigates on the surface of a heart to dedicate minimally invasive intrapericardial interventions. We performed a series of epicardial injections with the HeartLander using a beating porcine heart through a closed chest subxiphoid approach. Hypothesis: The HeartLander can provide precise and safe epicardial injections under the minimally invasive approach. Methods: HeartLander consists of two articulated modules that adhere to the epicardium using suction. The modules are each 6.5 mm tall and 8 mm wide, and include two working channels for instrumentation. Vacuum pressure and wire actuation for inchworm-like locomotion are provided through the tether of the robot. The device uses 3-D magnetic tracking for navigation, and a joystick for control input. The control software also enables semi-automated navigation to a selected target location, as well as pre-planning of injection locations after the target is reached. In 8 porcine preparations, the device was inserted into the pericardial space through a subxiphoid approach. Epicardial injection on the ventricular wall was performed with a dedicated injection needle device through the working port. Results: The HeartLander could precisely be maneuvered to designated targets. Injections into left ventricles (i.e. anterior, lateral, posterior walls) were successfully accomplished in all cases. Mean depth of injection was 3.1 ± 0.34 mm. Mean path length was 48 ± 10 mm. Mean speed was 22 ± 7 mm/min. Mean suction pressure and force on wires during trials was 562 ± 26 mmHg and 4.1 ± 0.9 Newton, respectively. The magnetic tracking system provided adequate visualization. Mean deviation from the target path was 0.2 ± 1.0 mm. Target acquisition was within 2.1 ± 1.4 mm. No fatal arrhythmia and bleeding were noted during the trials. There were no injuries to the heart and surrounding structures due to the robot locomotion. A histological study verified no epicardial damage. Conclusions: The HeartLander demonstrated successful epicardial injection on a beating porcine heart through a closed chest subxiphoid approach. This approach may facilitate the cardiac cell transplantation therapy in the field of minimally invasive surgery.
Resting Skeletal Muscle Membrane Potential as an Index of Uremic Toxicity
Authors: James R. Cotton, Terry Woodard, Norman W. Carter, James P. Knochel
Journal: Journal of Clinical Investigation (1979)

Electrochemical disturbances of skeletal muscle cells in untreated uremia are characterized by an increase in the intracellular sodium and chloride content, a decrease in intracellular potassium, and a low resting membrane potential. In this study, we have reexamined the foregoing and, in addition, have examined the effects of hemodialysis. Three groups of patients were studied. In the first group of 22 uncomplicated uremic patients, whose creatinine clearance (Ccr) ranged from 2 to 12 cm3/min per 1.73 m2, resting transmembrane potential difference (Em) of skeletal muscle cells was measured. In each of the nine patients whose Ccr ranged between 6.3 and 12 cm3/min, the Em was normal (i.e., −90.8±0.9 mV, mean±SEM). However, as Ccr dropped below 6.3 cm/min, the Em became progressively reduced and assumed a linear relationship with the Ccr.
Intestinal Cholesterol Absorption, Treatment With Atorvastatin, and Cardiovascular Risk in Hemodialysis Patients
Authors: Günther Silbernagel, Günter Fauler, Bernd Genser, Christiane Drechsler, Vera Krane, Hubert Scharnagl, Tanja B. Grammer, Iris Baumgartner, Eberhard Ritz, Christoph Wanner, Winfried März
Journal: Journal of the American College of Cardiology (2015)
Abstract P194: Nulliparity is Associated with Greater Common Carotid Artery Intima Media Thickness and Adventitial Diameter in Overweight and Obese Young Women
Authors: Nancy A Niemczyk, Emma Barinas-Mitchell, Janet M Catov, Candace K McClure, James M Roberts, Ping G Tepper, Kim Sutton-Tyrrell
Journal: Circulation (2013)

Introduction:  Higher parity (number of births) is associated with increased subclinical cardiovascular disease (CVD) in mid-life and older women, and with increased risk of CVD overall. In the only study of reproductive age women, common carotid artery intima-media thickness was greater with each birth. These women were leaner than the US population (mean BMI 24 kg/m 2 ), and their fertility history was not assessed. Neither the relationship between parity and subclinical CVD in overweight and obese young women, nor the role infertility plays in this relationship, has been evaluated.   Hypothesis:  We hypothesized that increased parity would be associated with increased intima-media thickness (IMT) and adventitial diameter (AD) in overweight and obese young women without known fertility problems.   Methods:  The Slow Adverse Vascular Effects (SAVE) trial provided 349 adults, aged 25-45 years old, BMI 25-39.9 kg/m 2 , with intensive weight loss interventions. Participants were normotensive and non-diabetic. B-mode ultrasound was used to measure IMT and AD at baseline. An ancillary study obtained reproductive histories of 73% (191 of 261) of the women in the trial. Linear regression was used to estimate the relationship between parity and IMT and AD. Demographic, cardiovascular and reproductive risk factors were covariates in the multivariate models.   Results:  There were 70 nulliparous (age 34.9 ± 7.1) and 102 parous women (age 39.5 ± 4.9). Parous women (parity 2.0 ± .7) had decreased common carotid artery AD and IMT than nulliparous women after adjustment for age, race and cardiovascular disease risk factors (Table 1). No other reproductive factors were statistically significant.   Conclusions: Contrary to our hypothesis, this analysis demonstrates that parity is associated with markers of healthier common carotid arteries in a sample of disease-free, overweight or obese young women. This may represent a beneficial effect of pregnancy or indicate overall better health in overweight women who are capable of childbearing.
Abstract 15815: Developing a Protocol Utilizing Non-Invasive Respiratory Volume Monitoring to Identify Patients at Risk for Opioid Induced Respiratory Depression
Authors: C. Marshall MacNabb, Jordan Brayanov, Jenny Freeman, Edward George
Journal: Circulation (2013)

Introduction: Respiratory compromise, often due to opioid administration, is a contributor or main cause of >1/3 of hospital cardiopulmonary arrests. Opioids are routinely used for pain management ...
Birth Control. Facts and Responsibilities. A Symposium Dealing with this Important Subject from a Number of Angles.
Authors: Adolf Meyer
Journal: JAMA (1926)

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