tbuckley/cabot-search huggingface dataset:
A multicenter sequential phase IV study of oxaliplatin (Oxa) and capecitabine (Cap) followed by irinotecan (Iri) and capecitabine in first line advanced colorectal cancer (ACC). Preliminary results
Authors: L. De La Cruz, A. Albero, M. M. Barros, A. Moreno, J. A. Virizuela, M. J. Sánchez, R. De Toro, M. Portillo, J. C. Toral, A. Duque
Journal: Journal of Clinical Oncology (2004)

3652 Background: we pretend to evaluate effectiveness and safety of a sequential schedule of chemotherapy (CT) with 3 drugs highly active in ACC. Method: open label, multicenter, phase IV trial with phase II design. Patients with ACC non suitable for curative surgery, measurable disease, not CT for advanced disease or adjuvant CT in the last 6 months, ECOG PS ≤ 2 and without age limits, were treated with Oxa 130 mg/m2 iv d 1 and oral Cap 1000 mg/m2/12 hs d 2–15, q3wk, 4 cycles, following with Iri 240 mg/m2 iv d 1 and oral Cap 1000 mg/m2/ 12 hs d 2–15, q3wk, until disease progression or unacceptable toxicity. Primary objective, rate of response (CR +PR, RECIST criteria). Secondary objectives, time to progression, overall survival and toxicity (CTC system 2.0 vs). Results: From april 2003, 20 patients have been enrolled of 54 planned (end of recruitment, september 2004). Median age: 63 years (49–80). Male/female: 11/9. After 4 cycles 10 patients have been evaluated, with 5 PR, 4 SD and 1 PD and 7 patients after 7 cycles with 2 CR, 1 PR and 4 SD. Severe toxicicity (G 3/4) per cycle: diarrhoea (16,1%), nausea (11,1%), vomiting (11,1%), asthenia (10%), anorexia (5%), transient neuropathy (5%) and febrile neutropenia (5%). 5 patients have persistent neuropathy after Oxa. Withdrawal of 3 patients, impairment of performance status (1), self decision (1) and digestive toxicity (1). One patient died for non treatment related causes. Unexpected toxicity observed: beard alopecia in men and MCV increased in red corpuscles in almost all cases with Iri and Cap. Conclusion: This sequential schedule seems to be effective and manageable. Although data are inmature, the results fit with the outcome expected. To minimize secondary effects of treatment seems important reducing oxaliplatin to 4 cycles (avoiding persistent neurotoxicity) and assure a good application of oral treatment, adjusting doses when necessary. No significant financial relationships to disclose.
Abstract 18309: Integration of Quantitative Measures of Stenosis Severity With Morphologic Atherosclerotic Plaque Characteristics Improves Discrimination of Coronary Lesions that Cause Ischemia: Results from a Prospective Multicenter International Trial
Authors: Hyung-Bok Park, Nakazato Ryo, Ran Heo, Iksung Cho, Heidi Gransar, Hyuk-Jae Chang, James K Min
Journal: Circulation (2014)

Background: Beyond stenosis severity, coronary computed tomographic angiography (CCTA) enables morphologic evaluation of atherosclerotic plaque characteristics (APCs), including aggregate plaque volume, positive arterial remodeling (PR), low attenuation plaque (LAP) and spotty calcification (SC), features associated with global myocardial ischemia and acute coronary syndromes. We determined whether the combination of stenosis severity plus APCs would improve the discrimination of coronary lesions that cause ischemia. Method: 252 patients from 17 centers in 5 countries [mean age 63 years, 71% males] underwent CCTA and invasive angiography, with invasive fractional flow reserve (FFR) performed for 407 coronary lesions. Stenosis severity was determined by luminal diameter reduction (%DS). Aggregate plaque volume (APV) was defined as the plaque volume from ostium to distal end of the lesion, with APV percent (%APV) defined as APV divided by total vessel volume. Other APCs by CCTA were defined as: (1) PR, lesion diameter/reference diameter &gt;1.10; (2) LAP, any voxel &lt;30 HU; and (3) SC, nodular calcified plaque &lt;3 mm. Lesion ischemia was defined by invasive FFR ≤0.8, which was employed as the reference standard. Results: Coronary stenosis severity and APCs demonstrated good discrimination for lesion ischemia: %DS, (Area under the receiver operating characteristics curve [AUC] of 0.72 (95% CI 0.68-0.77), APV (AUC 0.69, 95% CI 0.64-0.73), and %APV (0.75, 98% CI 0.70-0.79). Over %DS alone, the addition of %APV improved the discrimination of lesion-specific ischemia (0.79, 95% CI 0.75-0.83, p&lt;0.001), with further improvement with increasing APC number (0.86, 95% CI 0.82-0.89, p&lt;0.001) [Figure]. Conclusion: In this prospective multicenter international study, the combination of quantitative measures of stenosis severity with morphologic features of atherosclerotic plaque by CCTA resulted in improved discrimination of coronary lesion-specific ischemia.
First-line treatment with bevacizumab (B) and high dose (HD) bolus aldesleukin (IL-2) in metastatic renal cell carcinoma (mRCC) patients (Pts)
Authors: M. S. Ernstoff, M. M. Regan, D. F. McDermott, J. A. Sosman, J. P. Dutcher, J. I. Clark, T. S. Crocenzi, A. Ochoa, M. B. Atkins
Journal: Journal of Clinical Oncology (2007)

15524 Background: The rationale for combining HD IL-2 with B includes potential synergistic immune interactions, non-overlapping toxicities, and potential for added clinical benefit. We have initiated a multi-center phase II study designed to estimate the efficacy of combination therapy of standard HD IL-2 and B therapy in mRCC pts. Methods: Pts with histologically confirmed mRCC, predominantly clear cell histology, measurable or evaluable disease, KPS of =80%, adequate end organ function for HD IL-2, and no underlying coagulopathy or thrombotic event are eligible for this study. One cycle consists of 84 days. B (10 mg/kg) IV is given every 2 wks beginning 2 wks prior to the first dose of IL-2. B is dosed 1 hr prior to initiating IL-2 on days IL-2 is given. HD IL-2 (600,000 IU/kg) IV Q8 hours (maximum 28 doses) is given during two 5-day courses separated by 9 days (starting on day 15 and 29). Results: We report the results of the first 15 of a planned 60 pts. The median age is 54 (range 40–73) with 9 men and 6 women. 14 pts have a MSKCC intermediate prognostic score, one pt has a poor prognostic score. In the first cycle, the median number of B doses was 7 of a planned 7 (range 2–7) and the median number of IL-2 doses was 17 of a planned 28 (range 6–26). There has been one treatment related death from unresponsive hypotension which occurred during the second cycle. Typical IL-2 toxicities have been noted thus far. Among a variety of correlative studies, we evaluated the serum L- ornithine (L-O) level, a byproduct of arginase-mediated arginine metabolism that has been shown to inversely correlate with TCR? chain expression. L-O level are significantly elevated in RCC pts possibly due to VEGF stimulation of arginase production. In 4 patients tested to date, peripheral blood L-O levels have dramatically decreased over the course of therapy. Conclusions: HD IL-2 and B can be given safely and may impact on immune regulatory pathways. [Table: see text]
Abstract 19600: Inhibition of Increased Thrombin Receptor Activity Attenuated Monocrotaline-induced Pulmonary Hypertension in Rats
Authors: Yukimitsu Kuwabara, Kohtaro Abe, Mayumi Hirano, Yoshitaka Hirooka, Katsuya Hirano, Kenji Sunagawa
Journal: Circulation (2014)

Background and Objectives:  Thrombin contracts the normal pulmonary artery (PA), while it relaxes the normal systemic artery endothelium-dependently. This unique property of pulmonary artery may contribute to the pathogenesis of pulmonary artery hypertension (PAH), because it frequently associated with thrombus formation and thrombotic pulmonary arteriopathy. However, the responsiveness to thrombin and its role in PAH remain unknown. We investigated, in monocrotaline (MCT)-induced PH in rats, the contractile responsiveness to thrombin and explored a therapeutic potential of antagonizing the thrombin receptors.   Methods and Results:  Three weeks after a single subcutaneous injection of MCT (60 mg/kg), MCT increased right ventricular (RV) systolic pressure (SP) (Normal: 23±3 vs. MCT: 74±4 mmHg, n=6~10, p   Conclusions:  This study provides the first evidence that the contractile response of PA to thrombin is increased in PAH. We conclude that antagonizing the increased thrombin receptor activity in PAH may serve as a novel therapeutic target.
Design, synthesis, and molecular modeling study of novel non-camptothecin DNA-topoisomerase 1 inhibitors for development of anticancer agents
Authors: Sang Kook Lee, Suh-Hee Lee, Chenghai Quan, Thy My Hue Van, Won-Jea Cho
Journal: Cancer Research (2008)

LB-145  DNA topoisomerase 1 (top 1) is considered an important enzyme to relax supercoiled DNA for transcription, replication and mitosis. Elevation of the top 1 levels in solid tumors compared to normal tissue has made top 1 a promising target for antineoplastic drugs.  Since topotecan and irinotecan were launched as promising anticancer agents, camptothecin derivatives have been studied well over a last decade. Camptothecin analogs must be infused for long periods for cancer treatment as they reverse the CPT-trapped cleavage complexes within minutes and their inactive decomposed carboxylates are in equilibrium with active lactone forms under physiological conditions. Moreover, these analogs can cause resistance because the drugs are also substrates for the efflux transporters. For overcoming these critical drawbacks of camptothecin drugs, the development of novel non-camptothecin top 1 inhibitors has been actively pursued.  As a part of our ongoing effort to develop isoquinoline antitumor agents as for alternative camptothecin derivatives, we designed indenoisoquinolines as constrained forms of 3-arylisoquinolines. Generally, constrained structures are considered to have little conformational entropy compared to flexible forms and can be more efficiently fitted into the active site of a receptor. Potent top 1 and cytotoxic activity of indenoisoquinolines led us to explore the structure-activity relationships study based on the x-ray structure of indenoisoquinone into DNA-top 1 complex.  Through this study, an intramolecular cycloaddition reaction was employed to efficiently generate 11-hydroxyindenoisoquinlines. The cytotoxic activity of these analogs was then measured in various cancer cells with top 1 inhibition activity. The alkoxy derivatives displayed higher cytotoxicity and top 1 inhibitory activity than the 11-hydroxy and 11-keto compounds. Although the reason for these higher cytotoxicities and top 1 activity is presently not clear, the top 1 activity could be explained by a docking study using FlexX in the Sybyl program.
Abstract 330: Impact of High-Volume, Continuous Venovenous Hemofiltration on Survival of Rats Resuscitated by Cardiopulmonary Bypass After Cardiac Arrest
Authors: Koichiro Shinozaki, Tai Yin, Wei Zhang, Tong Da, Junhwan Kim, Joshua Lampe, Shigeto Oda, Hiroyuki Hirasawa, Lance B Becker
Journal: Circulation (2014)

Introduction:  Some groups have reported a favorable impact of continuous venovenous hemofiltration (HF) on victims suffering lethal CA, yet whether it is better to use higher or standard volumes of HF is unclear.   Objective:  To demonstrate the effects of two differing volumes of HF on post cardiac arrest syndrome (PCAS) and mortality in rodent models.   Methods:  Twenty-four rats were randomly assigned into 3 groups; control, standard volume HF, or high volume (HV) HF. Animals were subjected to asphyxial CA for 12min, and then cardiopulmonary bypass (CPB) was employed for 30min as a resuscitation method. No inotropic and vasoactive drugs were injected. HF was employed with CPB and maintained for 6hr under normothermic conditions. The filtration volume was set at 35-45mL/kg/h in standard volume HF group and 105-135mL/kg/h in HV-HF group. Survival time was the primary outcome, and neurological deficit score at 7hr, hemodynamical status, blood levels of IL-6, TNFα, and lactate were measured as the secondary outcomes. Blood samples were obtained at baseline, 30min, 1hr, 2hr, 3hr, and 6hr after CPB.   Results:  All animals gained ROSC by CPB and survived over 6hr but died within 24hr. There were no significant differences in survival time (long rank, control vs. HF; p=0.89, control vs. HV-HF; p=0.33) and in neurological deficit score (ANOVA, p=0.14). Mean TNFα levels increased but peaked out over time (peak was at 1hr, 78±57pg/mL, 82±85pg/mL, and 122±131pg/mL in control, HF, and HV-HF group), while mean IL-6 levels continued increasing over time (maximum was at 6hr, 3,795±6,401pg/mL, 9,839±11,720pg/mL, and 8,132±11,717pg/mL, respectively). IL-6 levels in HF and HV-HF groups were slightly higher than control group, however there were no significant differences in either cytokine levels. Blood pressure during and after CPB increased in all animals at 15min through 45min after CPB resuscitation. Mean blood pressure of control and HF groups were significantly higher than HV-HF group (p   Conclusions:  Neither standard volume nor high volume HF after CA had any effect on mortality, TNFα, nor IL-6 levels in severe PCAS models.
Abstract 20459: Epigenetic Activation of Phosphodiesterase Subtypes Lead to Compromised Beta-Adrenergic Signaling in Induced Pluripotent Stem Cell-Derived Cardiomyocytes From Dilated Cardiomyopathy Patients
Authors: Haodi Wu, Jaecheol Lee, Mingxia Gu, Feng Lan, Jared Churko, Veronica Sanchez-Freire, Elena Matsa, Antje Ebert, Karim Sallam, Joseph Gold, Joseph Wu
Journal: Circulation (2014)

Introduction: Familial dilated cardiomyopathy (DCM) has been modeled by human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). However, the mechanisms of compromised signaling transduction and contractile function in DCM iPSC-CMs are still not well understood. Methods and Results: Beating iPSC-CMs were generated from healthy individuals and DCM patients. RNA-seq and real-time PCR showed strict regulation of the main beta-adrenergic signaling proteins in iPSC-CMs during maturation. Confocal imaging of spontaneous calcium activity and hydrogel-based traction force microscopy (TFM) technology demonstrated beta-adrenergic stimulation induced both inotropic and chronotropic regulation in the contractility of iPSC-CMs. Following extended in vitro maturation of iPSC-CMs, we observed a transition in the beta-adrenergic receptor (beta-AR) subtype dependence from beta-2 AR dominance at early stage (day 30) to beta-1/2 AR co-existence at late stage (day 60). Comparison of the beta-adrenergic responsiveness between iPSC-CMs from DCM patients and their familial controls showed compromised beta-adrenergic signaling in DCM cells. Microarray data and expression profiling indicated up-regulated phosphodiesterases (PDE) 2A, 3A and 5A in DCM iPSC-CMs, which impaired cAMP generation and blunted the beta-adrenergic response. By blocking PDE2A, 3A or 5A, beta-adrenergic signaling reactivity and contractile function in DCM iPSC-CMs were both greatly improved. To further elucidate underlying mechanism of PDE regulation, we conducted chromatin immunoprecipitation (CHIP) assays, which showed significant up-regulation of activation histone marker and down-regulation of repressive histone marker in the PDE promoters during maturation process of DCM iPSC-CMs, which closely recapitulated the epigenetic modulation in the ventricle tissues harvested from DCM patients. Conclusions: Patient-specific DCM iPSC-CMs recapitulated impaired beta-adrenergic responsiveness and contractility in diseased heart. Studies on iPSC-CM model revealed a novel epigenetic mechanism that underlies PDE subtype specific regulation and signaling deficiency in DCM pathogenesis, which may serve as a new therapeutic target in the future.
Effects of imatinib on breast cancer cell biology in vitro
Authors: C. Mundhenke, M. Weigel, S. R. Schmidt, I. Meinhold-Heerlein, C. Schem, D. O. Bauerschlag, W. Jonat, N. Maass
Journal: Journal of Clinical Oncology (2005)

3210 Background: New targeted therapies for solid tumors are currently investigated in pre-clinical and clinical studies. For Imatinib mesylate activities in inhibiting selected tyrosine kinase receptors, including PDGF-R and c-Kit, have been reported. These receptors and their downstream effectors trigger signal transduction cascades regulating processes like proliferation, differentiation and survival. Inhibition of these mechanisms could lead to growth reduction in breast cancer. Effects of Imatinib on breast cancer cell biology in vitro are evaluated. Methods: Expression patterns of PDGF-R-β and c-Κit in human breast cancer cell lines MCF-7, ZR-75–1, MDA MB 231 and T47D are detected by PCR. The IC50 of Imatinib is determined in proliferation assays and used in further experiments. Changes in PDGF-R- β phosphorylation and expression during Imatinib treatment are investigated by immunohistochemistry. In MDA MB 231 receptor activation is also detected by western blot. To investigate potential synergistic effects with cytotoxic agents, cells are treated with Imatinib combined with variable concentrations of Vinorelbine. Apoptotic effects of single Imatinib or combined with Vinorelbine are observed by TUNEL assay. Results: MCF-7 and ZR-75–1 express PDGF-R-β and c-Kit, MDA MB 231 and T47D are PDGF-R-β positive only. Imatinib mono leads to growth inhibition in breast cancer cells in a clinical tolerated dose. Combination of Imatinib and Vinorelbine shows a significantly stronger growth inhibition than Vinorelbine alone (0,5 to 6nM). TUNEL assay clearly demonstrates apoptosis in Imatinib treated breast cancer cells. Apoptosis caused by Vinorelbine can be enhanced by adding Imatinib. Immunohistochemistry shows a dose depended inhibitory effect of Imatinib on PDGF-R-β activation (phosphorylation). A change in receptor expression does not occur. In MDA MB 231 cells this data has been confirmed by western blot. Conclusions: Imatinib has an anti-proliferatory effect on breast cancer cells which is caused by inducing apoptosis and PDGF-R-β inactivation. Moreover Imatinib increases growth inhibition of vinorelbine. This may lead to new options in breast cancer therapy combining targeted and cytotoxic agents. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis
In vitro study of the antioxydant properties of nonsteroidal anti-inflammatory drugs by chemiluminescence and electron spin resonance (ESR)
Authors: Yves Henrotin, Ange Mouithys-Mickalad, SX Zheng, G Deby-Dupont, C Deby, Maurice Lamy, Jean-Yves Reginster
Journal: Annals of the Rheumatic Diseases (2000)
Abstract 18083: Does 6-Minute-Walk Distance Correlate With Right Ventricular Function in Patients With Pulmonary Arterial Hypertension?
Authors: Karima Addetia, Nicole M Bhave, Benjamin H Freed, Mardi Gomberg-Maitland, Victor Mor-Avi, Kirk T Spencer, Karin Dill, Roberto M Lang, Amit R Patel
Journal: Circulation (2013)

Background: The majority of treatments available for pulmonary arterial hypertension (PAH) have been approved based on improvement in 6-minute walk distance (6MWD), shown to be an independent predictor of prognosis in these patients. Meanwhile, right ventricular (RV) size and function are also important prognosticators in these patients. We sought to determine whether RV indices on cardiovascular magnetic resonance imaging (CMR) correlated with 6MWD in patients with PAH. Methods: Same-day CMR and 6MWD were performed in 35 PAH patients (51±14 yrs, 32 females, BSA=1.8±0.3/m 2 ). 22 patients had repeat testing at 7±1 months. Consecutive short-axis cines spanning the entire RV were used to measure ejection fraction (RVEF) and indexed end-diastolic volume (EDVI). Patients who declined to perform the 6MWD test claiming inability were assigned 6MWD=0. Results: Mean RVEF, EDVI and 6MWD at baseline were 36±14%, 134±47mL and 349±152m. Four patients were unable to perform 6MWD at baseline and 3 at follow-up. Poor correlation was observed between baseline RV indices and 6MWD (r=0.10 for EDVI and r=0.14 for RVEF; p&lt;0.0001). Patients classified as WHO class III showed significantly worsened mean 6MWD than those classified as WHO class I (296m vs.469m; p&lt;0.01). However, WHO class did not correlate with RVEF or EDVI. Even when 6MWD was categorized into recommended thresholds for predicting prognosis, namely ≤250m (n=7) and &gt;440m (n=8), there was no significant difference in mean RVEF and EDVI between these 2 groups. Finally, when comparing changes in RVEF and 6MWD from baseline to follow-up, 10/24 patients showed concordant changes, while the remaining 12/24 patients showed discordant changes (p=0.59, Figure). Conclusions: Since 6MWD does not appear to correlate with RV function in this patient population, further studies are needed to determine the optimal parameters to study disease progression in these patients.
p53 is a direct transcriptional regulator of pro-apoptotic hCLCA2
Authors: vijay walia, Sumit Kumar, Ming Ding, Randolph Elble
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

2790 

The breast tumor suppressor hCLCA2 gene is a putative chloride regulator that is expressed in normal breast epithelial tissues but frequently downregulated in breast cancers. We showed previously that hCLCA2 is induced by DNA damaging agents such as doxorubicin and aphidicolin, more strongly in p53 positive cell lines. We now report that p53 is a direct transcriptional regulator of hCLCA2. The expression of hCLCA2 was induced by an adenovirus encoding p53. ChIP analysis showed that p53 binds directly to the hCLCA2 promoter between -157 and -359bp upstream of translation initiation site. This segment was required for the p53-dependent expression of an hCLCA2-luciferase fusion gene. Point mutation of the p53 consensus binding motif abolished this induction. Doxorubicin induction of hCLCA2 in MCF-7 cells was inhibited by pifithrin, indicating that p53 activates the endogenous hCLCA2 promoter in response to DNA damage. An adenovirus encoding hCLCA2 induced a cell cycle lag in G0/G1 phase, decreased intracellular pH from 7.49 to 6.7, caused Bax and Bad translocation to mitochondria, activated caspases and promoted apoptosis. These results reveal the molecular mechanism of hCLCA2 induction and downstream events that may provide protection from tumorigenesis.
Abstract 10911: Management of First Onset Supraventricular Tachycardias in adults with Congenital Heart Disease
Authors: Zeliha Koyak, Bart Kroon, Joris R De Groot, Berto J Bouma, Lodewijk J Wagenaar, Arie J Van Dijk, C A Roel, Isabelle C Van Gelder, Marco C Post, Barbara J Mulder
Journal: Circulation (2012)

Background Supraventricular tachycardias (SVT) are a major cause of morbidity in adults with congenital heart disease (CHD). Few data exist on the efficacy of anti-arrhythmics in this population. O...
Evaluation of three biochemical markers for serially monitoring the therapy of small-cell lung cancer.
Authors: P A Ganz, P Y Ma, H J Wang, R M Elashoff
Journal: Journal of Clinical Oncology (1987)

A number of biochemical markers have been proposed for monitoring the therapy of small-cell lung cancer (SCLC). This report reviews the experience at a single institution using three biochemical markers, alpha-1-acid glycoprotein (AGP), carcinoembryonic antigen (CEA), and lactate dehydrogenase (LDH), for serially monitoring the therapy of patients with SCLC. AGP measurements identified limited-disease patients more frequently than LDH or CEA, and a combination of markers (AGP and LDH) improves the accuracy of correctly classifying patients with active disease. Each of the markers correctly tracked the clinical response to therapy in approximately two thirds of the subjects. The use of a combination of markers should be considered for monitoring the therapy of SCLC in future clinical trials.