tbuckley/cabot-search huggingface dataset:
In vitro schedule-dependent interaction and gene expression modulation by gemcitabine and pemetrexed in non-small cell lung cancer (NSCLC) cell lines.
Authors: Elisa Giovannetti, Valentina Mey, Romano Danesi, Luca Marini, Fulvio Basolo, Mario Del Tacca
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

2028 

Gemcitabine is a pyrimidine analogue that inhibits ribonucleotide reductase (RR) as well as DNA synthesis and is now an established effective agent in the treatment of NSCLC. The present study investigates whether pemetrexed, a new multitargeted antifolate that blocks folate metabolism and DNA synthesis, would be synergistic with gemcitabine against A549, Calu-1 and Calu-6 NSCLC cell lines. Cells were treated with gemcitabine (1 h), and pemetrexed (24 h), and the 50% inhibitory concentrations on cell growth (IC50) were respectively 0.13±0.02 and 0.25±0.03 (A549), 5.28±1.25 and 34.13±5.78 (Calu-1) and 1.66±0.36 and 4.84±1.10 μg/ml (Calu-6). The analysis by the combination index demonstrated synergism mainly with the sequence pemetrexed-gemcitabine in A549 and Calu-6 cells, while in Calu-1 cells the degree of synergism observed with the gemcitabine-pemetrexed sequential exposure was considerably greater than that observed with the reverse sequence. To asses the role of drug metabolism on gemcitabine cytotoxicity, further studies were performed with inhibitors of the gemcitabine activating enzyme deoxycytidine kinase (dCK), and the inactivating enzymes 5’-nucleotidase (5’-NT), and cytidine deaminase (CDA). The crucial role of dCK in gemcitabine citotoxicity was confirmed by a significant increase in IC50 by adding the dCK inhibitor 2’-deoxycytidine in all cell lines, while there was a modest increase in cytotoxicity by inhibition of 5’-NT and CDA, with diethylpyrocarbonate and tetrahydrouridine, respectively. Cell cycle analysis by flow cytometry demonstrated that pemetrexed increased cell population in S phase (from 6.0 to 32.5% [A549], from 25.7 to 38.4% [Calu-1] and from 23.3 to 39.8% [Calu-6]), which is the most sensitive phase of cell cycle to gemcitabine. Furthermore, all the pemetrexed-gemcitabine combinations significantly enhanced the occurence of apoptosis, as detected by fluorescence microscopy. Finally, quantitative PCR analysis demonstrated that pemetrexed, at the IC50 level, significantly enhanced expression of dCK in A549 (+92.40%), potentially facilitating gemcitabine activation, while gene expression was not apparently modulated in Calu-1 cells. These data provide evidence that the combination of gemcitabine and pemetrexed displays schedule-dependent synergistic cytotoxic activity against NSCLC cells, associated with favorable modulation of cell cycle, induction of apoptosis and inducible dCK gene expression.
Abstract 12991: Knockdown of USF1 Leads to a Beneficial Metabolic Profile in Mice
Authors: Pirkka-Pekka Laurila, Jarkko Soronen, Essi Kaiharju, Christian Ehnholm, Leena Peltonen, Matti Jauhiainen
Journal: Circulation (2011)

Metabolic derangements in the body are tightly linked with cardiovascular disease. We have earlier established the association between genetic variants of USF1 with familial combined hyperlipidemia...
Abstract 3021: Fatigue as a symptom of Acute Myocardial Infarction
Authors: Ann Eckhardt, Michelle Fennessy, Anne Fink, Jessica Jones, Kathryn Szigetvari, Donna Kruse, Laura Tucco, Cathy Ryan, Julie J Zerwic
Journal: Circulation (2007)

Purpose: Fatigue may be a commonly experienced symptom of acute myocardial infarction (AMI); however, there is a disturbing lack of data about the fatigue that occurs among men and women at the time of AMI. The purpose of this study was to characterize the fatigue experienced among men and women during AMI using three validated fatigue questionnaires. Method: Ninety AMI patients were recruited from six Midwestern hospitals. The Profile of Mood States (POMS), Fatigue Severity Index (FSI), and the Short Form 36 Health Survey (SF-36) were completed by each hemodynamically stable subject. Results: The sample included 76% men (mean age = 61, SD = 10), 24% women (mean age = 59, SD = 13); 78% non-Hispanic white. Subjects scored 1.7 on the POMS fatigue subscale (0 = none, 4 = extremely), 47.3 on the SF-36 vitality subscale (0 = most, 100 = least), and 6.4 on the “most fatigued” item of the FSI (0 = not fatigued at all, 10 = as fatigued as I could be). Scores from AMI subjects were compared to published scores in other populations. Compared to older adult male subjects, AMI subjects had higher levels of fatigue on the POMS fatigue subscale (M = 0.71, t = 7.2, p &lt; 0.001) and the SF-36 vitality subscale (M = 51.0, t = 2.85, p &lt; 0.01). In addition, AMI patients were more fatigued on the “most fatigued” item of the FSI compared to cancer patients in active treatment (M = 5.5, t = 2.28, p = 0.05). Men and women reported similar levels of fatigue across all three measures; however, women reported that fatigue caused more disruption of activities of daily living (p &lt; 0.001), more difficulty with physical activities (p &lt; 0.01), poorer rating of general health (p &lt; 0.05), and more interference with social activities (p &lt; 0.05). Conclusion: To date, fatigue as a symptom of AMI has focused on using qualitative methods in women. This study used three well-established measures of fatigue to demonstrate that fatigue is commonly experienced by both men and women and at levels that are higher than a healthy older adult sample and cancer patients. Interestingly, fatigue had a greater negative impact on women’s lives.
Abstract 19267: Time Dependency of Edema-based Assessment of Area-At-Risk in Reperfused Acute Myocardial Infarction: A Serial Assement with Cardiac Magnetic Resonance Imaging
Authors: Veronica L Rundell, Xiangzhi Zhou, Ying Liu, Avinash Kali, Richard L Tang, Rachel A Klein, Andreas Kumar, Rohan Dharmakumar
Journal: Circulation (2010)

Introduction: Relative edema volume, computed from Cardiac MR images, has been used to define the Area-At-Risk in myocardial infarction and subsequently in the determination of salvagable myocardiu...
Anaesthetic machines and anti-hypoxia devices
Authors: J. M Fielden
Journal: BMJ (2002)

Editor—Saunders and Meek point out that anaesthetic machines without hypoxic guards confer an appreciable risk.1 Many latent errors in the health system are solved only after tragedies. As the authors say, in an underfunded system the replacement of such machines, at considerable cost (£8000-£40 000 depending on the type of machine), has to compete with many other high priorities for small capital funds. Awaiting replacement leaves patients at risk and is thus unacceptable.

An interim solution could be used in most situations. It is perfectly possible to deliver an anaesthetic without giving nitrous oxide at all; indeed, there are several benefits from avoiding the use of nitrous oxide. Furthermore, the use of nitrous oxide outside operating theatres is of dubious benefit (other than when Entonox is given; this comes premixed with 50% oxygen, thus removing the risk of hypoxia in normal conditions).

In the short term it is thus perfectly possible to prevent this latent risk outside theatre by removing all nitrous oxide cylinders and pipeline supplies and capping their connections. This is a quick and cost effective safety measure that can be instituted within days in most hospitals. In operating theatres most anaesthetic monitoring is of high enough standard to detect a hypoxic mix before it becomes a problem. When monitoring is inadequate these machines should be withdrawn, thus enforcing change and removing a latent error.
Abstract 9107: Pim-1 Kinase Increases Non-Random Chromatid Segregation in Cardiac Progenitor Cells
Authors: Balaji Sundararaman, Daniele Avitabile, Mathias Konstandin, Natalie Gude, Christopher T Cottage, Mark A Sussman
Journal: Circulation (2011)

Rationale: A cell has DNA strands of different replication ages because DNA replication is semi-conservative. Double-stranded DNA molecules possess one DNA strand that is one generation older than the other. Non-sister chromatids containing newly synthesized DNA and ‘old’ DNA strands are non-randomly partitioned between mother and daughter cells. Stem cells are presumed to non-randomly segregate chromatids to determine cell fate of daughter cells, although experimental evidence is lacking. Resident cardiac progenitor cells (CPC) present in the adult heart have been used for cell-based treatment of myocardial damage but the factors determining the stemness and lineage commitment of these cells are poorly understood. Cardio protective kinase Pim-1 increases asymmetric cell division in vivo, proliferation and commitment of CPCs after adaptive transfer in pathological injury model but its role in non-random segregation is unknown. Objective: Establish role of Pim-1 on non-random chromatid segregation and correlate with daughter cell fate determination in cardiac progenitor cells. Methods and Results: Non-random segregation was tracked by incorporation of bromodeoxyuridine (BrdU), a thymidine analogue labeling newly synthesized DNA strands. For label retention assay, cells were labeled for many generations and blocked in second cytokinesis during chase in BrdU free media. Two daughter nuclei within a cell body had different BrdU intensity. Density measurements showed that 4.6% of CPCs outside the 95% confidence interval for equal BrdU intensity between daughter nuclei indicating non-random segregation of BrdU labeled chromatids. Genetic engineering of CPCs to express Pim-1 kinase greatly enhanced non-random segregation (12.6% vs 5.6% GFP expressing cells). Non-random segregation was further confirmed by asymmetric BrdU segregation in anaphase cells from second mitotic shake off during chase. Conclusions: CPCs non-randomly segregate chromatids as demonstrated by selective segregation of BrdU labeled chromatids which is twofold increased in cells overexpressing Pim-1 kinase. Future Directions: The relationship of non-random chromatid segregation to identity of stem cells fate remains to be determined.
A double blind phase II study of BIBF 1,120 in patients suffering from relapsed advanced non-small cell lung cancer (NSCLC)
Authors: J. Von Pawel, R. Kaiser, C. Eschbach, M. Stefanic, J. Love, U. Gatzemeier, M. Reck
Journal: Journal of Clinical Oncology (2007)

7635 Background: Vascular endothelial-(VEGF), platelet derived- (PDGF), and fibroblast growth factor (FGF) with their receptors compose critical cellular pathways controlling angiogenesis. BIBF 1120 is an oral potent triple angiokinase inhibitor targeting VEGFR, PDGFR, FGFR kinases. Methods: In this double blind multi-center trial, patients with an ECOG score of 0–2 with locally advanced or metastatic (stage IIIB/IV) relapsed NSCLC after failure of first or second line chemotherapy were randomly assigned to daily treatment with 2x250 mg or 2x150 mg of BIBF 1,120 until progression. In the event of dose limiting toxicity, a single dose reduction to open label treatment with 2x150 or 2x100 mg of BIBF 1,120 was allowed. Patients with stable brain metastases or squamous cell carcinoma were not excluded. Primary endpoints were progression free survival (PFS) and objective tumor response (RECIST, determined every 6 weeks). Results: Seventy three of 74 patients enrolled received BIBF 1120 (61% males, median age: 64 years, range 36–80). The most common histology was adenocarcinoma (55%), followed by squamous cell carcinoma (23%). The median PFS of all patients (n= 73) was 1.6 months without significant difference between both treatment arms. The stable disease rate was 48% without objective tumour responses. However, patients with an ECOG performance status of 0 or 1 (n= 57) had a median PFS of 2.9 months and a three- and 5 months PFS rate of 46% and 31%, without any difference between both treatment arms. The stable disease rate was 59%. Patients treated with 2x250 mg per day had more dose limiting CTCAE Grade 3 and 4 toxicities compared with patients treated with 2x150 mg (27% versus 2.8%, p=0.006, two-sided Fisher-test). The most frequent adverse events irrespective of relatedness observed in 73 patients were of CTCAE Grade 1 or 2 and included nausea (41%), diarrhoea (41%), vomiting (33%), fatigue (29%) and abdominal pain (22%). Grade 3 and 4 toxicities included nausea (8%), diarrhoea (7%), vomiting (4%), abdominal pain (4%) and AST and/or ALT elevations (5.4%). Conclusions: BIBF 1120 is safe and well tolerated and showed promising efficacy data in ECOG 0–1 patients. A high disease control rate of 59% could be observed. [Table: see text]
Abstract 3713: Five Year Follow Up Of The Pci Vs. Exercise Training In Stable Coronary Artery Disease-Pilot Trial (Pet-pilot)
Authors: Sven Möbius-Winkler, Claudia Walther, Axel Linke, Sandra Erbs, Stephan Gielen, Karsten Lenk, Rainer Hambrecht, Gerhard C Schuler
Journal: Circulation (2007)

Coronary revascularisation by percutaneous techniques is widely used in the treatment of patients (pts) with coronary artery disease (CAD). Among non-pharmacological therapeutic options for pts with stable CAD, regular physical exercise training (ET) is known to improve functional work capacity, myocardial perfusion and the 1 year event free survival rate. Aim of this study was to compare stent angioplasty (SA) with a conservative strategy including daily ET with regard to event-free survival after a 5 year follow up and clinical status. Method: 101 pts with stable CAD were randomly assigned either to SA or to the ET-group. Pts in both groups received optimised medical standard therapy. Initially and at follow up visits, clinical status was assessed using the Canadian Cardiovascular Society classification (CCS). The primary endpoint was the composite of death from any cause, non-fatal myocardial infarction, cerebrovascular accident, need for any revascularization procedure due to unstable angina pectoris (UA) and hospitalisation due to worsening of angina pectoris. Results: The event free survival rate for the combined primary endpoint was 63 % (32 patients out of 51) in the exercise training group and 40% (20 patients out of 50) in the stent group (p=0.037) . Within the five years of follow up, 36 cardiovascular events occurred in 19 patients of the training group as compared to 55 cardiovascular events in 30 patients of the stent group. Conclusion: At long-term follow up of 5 years, daily exercise training additionally to a optimal medical treatment in stable CAD patients leads to a better event free survival rate compared with stent angioplasty.
Abstract 4450: Does the Evidence Support Guideline Recommendations for Clopidogrel Pretreatment?
Authors: Shervin Eshaghian, Stanley Chou, Jayanta Das, George A Diamond, Prediman K Shah, Sanjay Kaul
Journal: Circulation (2008)

Although few concrete data exist about the optimal timing and dose of clopidogrel pretreatment, the ACC/AHA &amp; ESC guidelines endorse pretreatment with 300 – 600 mg of clopidogrel at least 2– 6 hours before PCI as Class IA (ACS) and Class IC (elective PCI) recommendation. To evaluate the current evidence base in support for clopidogrel pretreat-ment. Five trials examining the impact of clopidogrel pretreatment in stable and unstable CAD were evaluated: PCI-CURE, PCI-CLARITY, CREDO, PRAGUE-8, ARMYDA-5. Because of substantial clinical heterogeneity in trial design and population, concomitant therapies (glycoprotein 2b/3a inhibitors, thrombolysis, etc), loading dose, pretreatment duration and analysis plan between PCI-CURE, PCI-CLARITY and the rest, a formal meta-analysis was confined only to CREDO, PRAGUE-8, ARMYDA-5. The key data are summarized in the Table . Clopidogrel pretreatment was associated with significant reduction in ischemic outcomes without a significant increase in major bleeding in two out of the 5 trials (PCI-CURE and PCI-CLARITY). Both these trials utilized nonrandomized subgroup comparisons with pretreatment duration longer than that typically encountered in clinical practice (&lt;48h). A meta-analysis of the 3 trials demonstrated a nonsignificant 23% odds reduction in efficacy (P=0.1) and a nonsignificant 29% odds increase in major bleeding (P=0.24). No significant heterogeneity was observed for pooled efficacy (P=0.79) or bleeding (P=0.77) outcomes. Pretreatment hypothesis is currently not validated in rigorous prospective assessments, thereby calling into question the Class I recommendation (benefit &gt;&gt;&gt;risk) endorsed by the guidelines. Clearly, further clinical data regarding dose, time course of pretreatment and associated benefit are warranted to provide unequivocal support. Until then, it is prudent to rule out surgical CAD before pretreatment to avoid bleeding risk. Trials Assessing Clopidogrel Pretreatment
Identification of OXA-23-producing Acinetobacter baumannii in Greece, 2010 to 2011
Authors: A Liakopoulos, V Miriagou, E A Katsifas, A D Karagouni, G L Daikos, L S Tzouvelekis, E Petinaki
Journal: Eurosurveillance (2012)

We report on the sequence type and beta-lactamase content of 174 carbapenem-resistant Acinetobacter baumannii isolates recovered from clinical specimens during 2010 and 2011 in a tertiary care hospital in central Greece. Carbapenem resistance was associated mainly with carriage of the bla(OXA-23) gene (in 72.4% of the isolates). To our knowledge, this is the first description of A. baumannii strains producing OXA-23 in Greece. During 2011, in our hospital they rapidly ‘replaced’ the previously predominant OXA-58- positive A. baumannii strains.
Abstract 20575: An Alpha-1A Adrenergic Receptor Agonist Prevents and Treats Heart Failure
Authors: Megan D Montgomery, Trevor Chan, Raj Dash, Philip M Swigart, Bat-Erdene Myagmar, Anthony J Baker, Paul C Simpson
Journal: Circulation (2014)

INTRODUCTION:  The neurohormonal hypothesis that sympathetic activation in heart failure (HF) is toxic to the heart led to class I recommended drugs. However, contrary data suggest that sympathetic blockade in HF has limits, such as the negative effects of alpha-1-adrenergic receptor (a1-AR) blockade in humans in ALLHAT and V-HeFT. Conversely, a1-agonists protect myocytes and hearts of multiple species in multiple models through pleiotropic mechanisms, but this is untested in HF in vivo.   HYPOTHESIS:  We hypothesized that a1-AR agonism can treat HF in vivo.   METHODS:  We screened drugs in neonatal rat and adult mouse ventricular myocytes (NRVM, AMVM), measured telemetry blood pressure (BP), and did subcutaneous infusion in mice with HF from cardiotoxin (doxorubicin, DOX) and pressure overload (TAC).   RESULTS:  In NRVMs, the a1A agonist A61603 (A6) was the most efficacious and potent of 10 a1 agonists in ERK activation (EC50 6±1 nM, Emax 22±7) and protein synthesis (EC50 10±1 nM, Emax 1.7±0.1), and EC50s matched a1A binding affinity. In AMVMs, A6 activated ERK (EC50 39±5 nM) and protected against DOX (EC50 15±8 nM, Emax 35±6), an effect lost in the a1A KO. In isolated hearts, A6 activated ERK target genes. A6 10 ng/kg/d infused sc for 7 days had no effect on BP, but increased cardiac pERK (EC50 0.1±0.1 μg/kg/d). With DOX, A6 10 ng/kg/d started at the same time enhanced survival (A6+DOX 84%, n=21; Veh+DOX 34%, n=49). A6 also preserved function (A6 FS 61±2% vs. Veh 49±3%), and reduced serum CK (571±67 vs. 1204±98), TUNEL staining (0.5±0.1 vs. 1.3±0.2), and Sirius Red staining (25±1 vs. 32±1) (n=3-5). A6 effects on survival and FS after DOX were lost in the a1A KO. With TAC (gradient 109 mmHg), FS fell over 2 weeks to 40±1%. A6 from weeks 2 to 4 increased FS (to 51±2%, n=30), while FS remained low with Veh (39±2%, n=24). A6 after TAC did not change heart or myocytes size, but did increase pERK and bMyHC, and reduced cardiac troponin I (A6 5±2 vs. 11±2), cleaved caspase 3 (77±7% of Veh), collagens I and III (46±5% and 56±8% of Veh), and Sirius Red staining (5±4% vs. 9±8%) (n=3-22).   CONCLUSIONS:  The high affinity a1A-AR agonist A61603, at a low dose that does not change BP, prevents cell death and fibrosis and improves function and mortality in two mouse models of HF. a1A-AR agonists might be potential HF therapies.
Abstract 1146: Vitamin A Status Regulates Glucose and Lipid Homeostasis in Rats
Authors: Guoxun Chen, Wei Chen, Rui Li, Yan Zhang
Journal: Circulation (2009)

Since elevation of hepatic vitamin A (VA, retinol) content in diabetic patients was observed before, we hypothesized that VA status may play a role in glucose and lipid homeostasis. Recently, we ob...
A phase I/II study to assess the safety, tolerability and pharmacokinetics (PK) of intravenous (IV) infusion of MB07133 in subjects with unresectable hepatocellular carcinoma (HCC)
Authors: B. Ma, W. Forbes, A. P. Venook, D. M. Bissell, C. Peterson, I. Niculae, D. Bullough
Journal: Journal of Clinical Oncology (2006)

2054 Background: MB07133 is a novel cytarabine (araC) prodrug that uses the HepDirect technology to target production of the active form of araC, araC triphosphate (araCTP), to the liver. The study objectives were to determine the maximum tolerated dose, toxicity profile (NCI-CTC 2.0), PK &amp; antitumor activity of MB07133 in patients (pts) with unresectable HCC. MB07133 was given as a continuous IV infusion at escalating doses during the first 7 days of a 28-day cycle until disease progression or unacceptable toxicity occurred. To date, 22 pts with Child-Pugh Class A liver function have been enrolled in 4 cohorts (300, 600, 1200, 1800 mg/m 2 /d, D1–7), with 3–6 pts/cohort. Enrolled pts had a median age of 57 yrs (range 20–67) &amp; consisted of 21 males, 1 female, 19 Asians &amp; 3 Caucasians. A total of 66 cycles have been administered (maximum 10 cycles in 1 pt) with no dose-limiting toxicities associated with therapy. Most drug-related toxicities (67%) were mild to moderate (gr 1–2 neutropenia, thrombocytopenia &amp; increased ALT). There was 1 gr 3 ascites unrelated to study drug and no gr 4 toxicity. Six pts experienced 10 serious adverse events, all unrelated or unlikely related to study drug. The very low araC concentrations in the plasma (see table ) were consistent with previous animal studies, which demonstrated MB07133 to target araCTP production in the liver. 36% of pts who had ≥ 2 cycles of MB07133 had disease stabilization. Conclusions: MB07133 is well tolerated at doses up to 1800 mg/m 2 /d in pts with unresectable HCC. Enrollment of a 2400 mg/m 2 cohort is ongoing. The disease stabilization observed in this study, although preliminary, warrants further investigation in Phase 2. [Table: see text] [Table: see text]
Abstract 2859: Catheter Contact Force During Ablation of Atrial Flutter and Atrial Fibrillation: Results From the TOCCATA Multi-Center Clinical Study
Authors: Vivek Reddy, Petr Neuzil, Philippe Ricard, Boris Schmidt, Dipen Shah, Pierre Jais, Josef Kautzner, Andrea Natale, Gerhard Hindricks, Claudia Herrera, Yury Vanekov, Hendrik Lambert, Karl-Heinz Kuck
Journal: Circulation (2009)
SHP1 Suppression In Diffuse Large B Cell Lymphoma Is Regulated Through Promoter Hypermethylation At Novel CpG2 Island and H3K27 Trimethylation Histone Mark
Authors: Mamta Gupta, Guangzhen Hu, Linda E Wellik, Jing Jing Han, Mary Stenson, Ahmet Dogan, Thomas E Witzig
Journal: Blood (2013)