tbuckley/cabot-search huggingface dataset:
Final results of a phase II pharmacokinetic/pharmacodynamic (PK/PD) study of combination voreloxin and cytarabine in patients with relapsed or refractory acute myeloid leukemia.
Authors: G. J. Roboz, J. E. Lancet, L. D. Cripe, F. Ravandi Kashani, A. F. List, J. A. Fox, G. Michelson, J. E. Karp
Journal: Journal of Clinical Oncology (2010)

6526 Background: Voreloxin (VOR), an anticancer quinolone derivative that inhibits topoisomerase II, is active in ovarian cancer and acute myeloid leukemia (AML). Nonclinical studies showed synergistic activity of VOR and cytarabine (ara-C) (Scatena Cancer Chemother Pharmacol 2010). Methods: Phase (ph) Ib results were presented previously (Proc ASCO 2009). Ph II expansions in first relapse (frel) and primary refractory (pref) AML were at 80 mg/m2 VOR/400 mg/m2 ara-C by 24-hr CIV in schedule A (A) and 90 mg/m2 VOR/1 g/m2 ara-C by 2-hr IV infusion in schedule B (B). VOR dosing days 1, 4; ara-C daily ×5. Up to 4 cycles allowed. Response determined by IWG criteria. Blood, urine, and bone marrow aspirate (BMA) collected for PK or PD analysis. Ph II populations pooled and subset analysis of pref/early frel (efrel) outcome performed as safety/efficacy results were comparable in A and B. Results: CR+CRp+CRi (ORR) was 32% (12/37) frel and 25% (8/32) pref; most were CR (17 of 20). Fourteen ph II patients went to transplant (12 responders, 1 partial responder, 1 treatment failure). Preliminary median overall survival (OS) was 7.8 months (mo) (95% CI 4.7-10.2). All-cause mortality was 3% (2/69) at 30 days and 8% (5/63) at 60 days. Activity was similar in patients with efrel (CR1 ≤ 12 mo) and pref (ORR 28%, OS 7.3 mo [95% CI 6-9.9]), a patient group with poor outcomes. Nonhematologic grade ≥ 3 adverse events > 10% at VOR 70–90 mg/m2: aggregated (ag) upper GI mucositis 17%; ag lower GI mucositis 9%; febrile neutropenia 37%; ag sepsis/bacteremia 23%, ag infections 15%, and ag pneumonia 10%; hypokalemia 19%. PK/PD: VOR PK was dose proportional and unaffected by ara-C. DNA damage PD response seen with increased pDNA-PKcs/pCHK2 in BMA of 15/23 patients at ≥ 34 mg/m2 VOR/ara-C. Conclusions: Activity of combination VOR with intermediate dose ara-C is promising, warranting further study in a randomized setting. Safety and activity profile in pref and efrel (CR1 ≤ 12 mo) patients: ORR (28%), 30- and 60-day all-cause mortality (5% average), and OS (7.3 mo) compares favorably with recent data for other AML therapies (Litzow BJH 2009; Giles Blood 2009). Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Sunesis Pharmaceuticals Sunesis Pharmaceuticals Sunesis Pharmaceuticals
Abstract 5454: Wogonin overcomes cisplatin resistance of head and neck cancer by targeting antioxidant defense mechanisms
Authors: Ji Won Kim, Eun Hye Kim, Jin Young Park, Minsu Kwon, Jong-Lyel Roh
Journal: Cancer Research (2015)

Abstract Background: Cisplatin is a first-line chemotherapeutic agent for head and neck cancer (HNC). However, the main limitation to clinical usefulness of cisplatin is the high incidence of chemoresistance causing one of major failures in cancer management. This may suggests the necessity of combination therapies of cisplatin with other drugs to circumvent chemoresistance. Wogonin, one of major natural flavonoids, is known to reverse multidrug resistance in several types of cancers, however, which has been rarely tested in HNC cells. Therefore, the present study investigated the ability and molecular mechanisms of wogonin overcoming cisplatin resistance in HNC cells. Methods: Two cisplatin-resistance HNC cell lines (AMC-HN4R and -HN9R) and their parental and other human HNC cell lines were used. The effect of wogonin, alone and in combination with cisplatin, was assessed in HNC cells and normal cells by measuring cell viability, cell cycle and death assays, reactive oxygen species (ROS) production, and protein expression, and in preclinical tumor xenograft mouse models. Results: Wogonin selectively killed HNC cells but spared normal cells. It inhibited NF-E2-related factor 2 (NRF2), P-glycoprotein, and glutathione S-transferase P (GSTP), overexpressed in cisplatin-resistant HNC cells, resulting in the increased ROS accumulation in HNC cells, an effect that can be blocked by the antioxidant N-acetyl-L-cysteine. Wogonin also induced selective cell death by targeting the antioxidant defense mechanisms enhanced in the resistant HNC cells and subsequently, effectively activating cell death pathways involving PUMA and PARP. Therefore, wogonin significantly sensitized the resistant HNC cells to cisplatin in vitro and in vivo. Conclusions: Wogonin might be the promising anticancer candidate by inducing ROS accumulation and selective killing HNC cells, thus contributing to overcome the cisplatin-resistance of HNC cells. Citation Format: Ji Won Kim, Eun Hye Kim, Jin Young Park, Minsu Kwon, Jong-Lyel Roh. Wogonin overcomes cisplatin resistance of head and neck cancer by targeting antioxidant defense mechanisms. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5454. doi:10.1158/1538-7445.AM2015-5454
Pharmacokinetics, Clinical Efficacy and Safety of Plasma-Derived Nanofiltered C1 Inhibitor Concentrate for Treatment of Hereditary and Acquired Angioedema.
Authors: J. J. Hofstra, E. van Twuyver, I. Kleine-Budde, C. W. Choi, M. Levi, F. W.G. Leebeek, J. G.R. de Monchy, P. F. Ypma, A. D. Huitema, A. Nienhuis, P. F. Strengers
Journal: Blood (2008)
Impact of epidermal growth factor receptor (EGFR) pathway alterations on the outcome of non-small cell lung cancer (NSCLC) patients (pts) treated with first-line chemotherapy (CHT)
Authors: A. Gelibter, F. Buttitta, C. Nuzzo, P. Visca, A. M. Cianciulli, M. Rinaldi, E. Terzoli, I. Sperduti, A. Ceribelli, F. Cognetti
Journal: Journal of Clinical Oncology (2007)

7607 Background: Molecular alterations along the EGFR pathway have been proposed to be the major determinant of clinical outcome in response to EGFR tyrosine kinase inhibition in NSCLC pts. However, their potential impact on sensitivity to CHT has not been studied in detail. Methods: Advanced NSCLC pts undergoing CHT were screened for EGFR gene mutations (by SSCP and sequencing) and/or increased copy number (by FISH), EGFR protein expression (by IHC), and HER-2, phosphorylated AKT (pAKT), and total AKT protein expression (by IHC). Correlation between specific molecular alterations and clinical outcome (ORR, PFS, and OS) was then retrospectively explored using both the Cox regression model as well as classification and regression trees (CART) analysis. Results: One hundred and twenty seven pts were screened and 93 received 1st-line CHT. The frequency of EGFR pathway alterations is shown in Table 1 . At a median follow up of 13 mos, survival analysis revealed that true EGFR gene amplification is the only significant predictor of worst OS (p=0.004). No significant correlation was found with PFS. ORR was significantly worse in HER-2-positive pts (p=0.03). CART analysis confirmed that true EGFR gene amplification negatively affect OS, followed by EGFR gene mutation and chromosome 7 polysomy in non-amplified and non-amplified/non-mutated pts, respectively. Conclusions: EGFR pathway alterations significantly impact on outcome following 1st-line CHT for advanced NSCLC. HER-2 overexpression negatively impacts on ORR, but not on PFS and OS. This information maybe useful in selecting appropriate treatment algorithm for advanced NSCLC pts. No significant financial relationships to disclose. [Table: see text]
Marked synergism in a preclinical model of ovarian cancer with the combination of a histone deacetylase inhibitor and either topotecan or gemcitabine: Potential clinical implications
Authors: V. S. John, D. R. Budman, A. Calabro
Journal: Journal of Clinical Oncology (2008)

16573 Background: Gemcitabine is an active agent in ovarian cancer but relapses are common.How to combine this agent with other drugs remains unclear. Histone deacetylase inhibitors demonstrate clinical activity in human tumors; affect numerous proteins involved in signal transduction, and tolerable toxicity. Therefore the panDACI, panobinostat (LBH589), combined with gemcitabine, conventional cytotoxics and/or fluvastatin (a prenylation inhibitor) were evaluated in a preclinical screen.Median effect analysis, followed by curve shift analysis and apoptosis assays were used to identify combinations for further development. Methods: The human ovarian cancer cell lines SK-OV-3 and OvCa-432 were obtained from ATTC (Rockville, MD), fluvastatin and pano from Novartis Pharma (West Caldwell, NJ), and the other agents from Sigma-Aldrich (St. Louis, MO). The IC50 of the single agent was determined by a 72 hr incubation of log growth cells using a MTT assay and the EZ-ED50 program (Perrella Scientific, Conyers, CA). The dosages of all agents were at clinically achievable concentrations and applied concurrently. All reported values were the means of at least 3 experiments with each study using 4 wells per point. For isobologram analysis, a minimum of 10 concentrations of drug mixtures were studied above and below the IC50. Median effect CI values less than 1 are synergistic. Fa50 is the 50% cytotoxic point of the combination. Results: See Table. Results were confirmed by curve shift analysis (p <0.01) and apoptosis assay. Conclusion: A doublet may have a higher therapeutic effect over a single agent with both gemcitabine or topotecan combined with panobinostat demonstrating the highest synergism. The addition of platinum to the doublet gave CI@Fa50 of close to 1, which suggests additivity. Further studies of the doublet are indicated. COMBINATION SK-OV-3 CI@Fa50 OvCa-432 CI@Fa50 pano+Gem 0.3 ± .05 0.3 ± .03 pano+Fluvastatin 0.1 ± .07 0.4 ± .09 pano+Doxo 1.03 ± .10 0.5 ± .07 panot+Docetaxel 0.5 ± .04 0.9 ± .13 pano+Paclitaxel 0.7 ± .05 0.2 ± .04 pano+Carbo 1.0 ± .07 1.0 ± .07 pano+Topo 0.4 ± .01 0.2 ± .04 pano+Paclitaxel+Carbo 1.3 ± .07 0.5 ± .08 pano+Gem+Carbo 1.0 ± .20 0.9 ± .07 pano+Doxo+Carbo 0.5 ± .06 0.3 ± .05 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Eli Lilly
Endovascular Thrombectomy for Ischemic Stroke
Authors: Steven Warach, S. Claiborne Johnston
Journal: JAMA (2016)

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The new IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification
Authors: William D Travis, Elisabeth Brambilla, Masayuki Noguchi, Kim Geisinger, David Beer, Charles A Powell, Bruce Johnson, Gregory J Riely, Valerie Rusch, Hisao Asamura, Kavita Garg, John Austin, Denise Aberle, Christian Brambilla, Douglas Flieder, Wilbur Franklin, Adi Gazdar, Michael Gould, Philip Hasleton, Douglas Henderson, Fred Hirsch, Rudolf M Huber, Yuichi Ishikawa, James Jett, Keith Kerr, David Johnson, Keiko Kuriyama, Jin Soo Lee, Vincent Miller, Tetsuya Mitsudomi, Andrew Nicholson, Iver Petersen, Victor Roggli, Rafael Rosell, Nagahiro Saijo, Montserrat Sanchez-Cespedes, Giorgio Scagliotti, Jean-Paul Sculier, Takashi Takahashi, Erik Thunnissen, Ming Tsao, Masahiro Tsuboi, Paul E Van Schil, Johan Vansteenkiste, Yasushi Yatabe, Ignacio Wistuba, Pan-Chyr Ynag
Journal: Journal of Thoracic Oncology (2009)
Patient-Derived Xenograft Establishment from Human Malignant Pleural Mesothelioma
Authors: Licun Wu, Ghassan Allo, Thomas John, Ming Li, Tetsuzo Tagawa, Isabelle Opitz, Masaki Anraku, Zhihong Yun, Melania Pintilie, Bethany Pitcher, Geoffrey Liu, Ron Feld, Michael R. Johnston, Marc de Perrot, Ming-Sound Tsao
Journal: Clinical Cancer Research (2016)

Abstract Purpose: Malignant pleural mesothelioma (MPM) is a rare but aggressive disease with few therapeutic options. The tumor–stromal interface is important in MPM, but this is lost in cell lines, the main model used for preclinical studies. We sought to characterize MPM patient-derived xenografts (PDX) to determine their suitability as preclinical models and whether tumors that engraft reflect a more aggressive biological phenotype. Experimental Design: Fresh tumors were harvested from extrapleural pneumonectomy, decortication, or biopsy samples of 50 MPM patients and implanted subcutaneously into immunodeficient mice and serially passaged for up to five generations. We correlated selected mesothelioma biomarkers between PDX and patient tumors, and PDX establishment with the clinical pathologic features of the patients, including their survival. DNA of nine PDXs was profiled using the OncoScan FFPE Express platform. Ten PDXs were treated with cisplatin and pemetrexed. Results: A PDX was formed in 20 of 50 (40%) tumors implanted. Histologically, PDX models closely resembled the parent tumor. PDX models formed despite preoperative chemotherapy and radiotherapy. In multivariable analysis, patients whose tumors formed a PDX had significantly poorer survival when the model was adjusted for preoperative treatment (HR, 2.46; 95% confidence interval, 1.1–5.52; P = 0.028). Among 10 models treated with cisplatin, seven demonstrated growth inhibition. Genomic abnormalities seen in nine PDX models were similar to that previously reported. Conclusions: Patients whose tumors form PDX models have poorer clinical outcomes. MPM PDX tumors closely resemble the genotype and phenotype of parent tumors, making them valuable models for preclinical studies. Clin Cancer Res; 23(4); 1060–7. ©2016 AACR.
P0732 : Impact of old schistosomiasis infection on the use of fibroscan for staging of fibrosis in chronic HCV patients
Authors: I. Ramzy, R. Fouad, M. ElRaziky, A. Elsharkawy, W. ElAkel, H. Abdelhafez, M. Elsayed, H. Khattab, M. Shehata, A. Radwan, G. Esmat
Journal: Journal of Hepatology (2015)
Letter by Koh Regarding Article, “Long-Term Effectiveness and Safety of Pravastatin in Patients With Coronary Heart Disease: 16 Years of Follow-Up of the LIPID Study”
Authors: Kwang Kon Koh
Journal: Circulation (2016)

Hague et al 1 reported that, in the LIPID (Long-term Intervention with Pravastatin in Ischemic Disease) study, the absolute survival benefit from 6 years of pravastatin treatment appeared to be maintained for the next 10 years, with a similar risk of death among survivors in both groups after the initial period.Treatment with pravastatin does not influence cancer or death from noncardiovascular causes during long-term follow-up.Statins are important to prevent cardiovascular events, and nowadays guidelines recommend using high-intensity statins.Pravastatin is weakest on potency but relatively safer than others and also improves insulin sensitivity and prevents the new onset of type 2 diabetes mellitus. 2,3Indeed, we reported that atorvastatin dose-dependently worsened insulin sensitivity by reducing plasma levels of adiponectin in humans. 4 A recent genetic analysis from patients participating in the randomized trials reported that the increased risk of type 2 diabetes mellitus noted with statins is explained, at least in part, by 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibition. 5 Randomized clinical trials to compare the benefits of cardiovascular reduction and the risk of developing type 2 diabetes mellitus are needed urgently.Genetic and pharmacogenetic testing approaches are also needed to define who is more vulnerable to developing type 2 diabetes mellitus.In particular, more information is required regarding the metabolism of statins and their off-target or unknown actions.These different metabolic effects of specific statins are important to consider when formulating optimal therapeutic strategies with statins for patients to help reduce overall morbidity and mortality.
Low-dose hydralazine prevents fibrosis in a murine model of acute kidney injury–to–chronic kidney disease progression
Authors: Björn Tampe, Ulrike Steinle, Désirée Tampe, Julienne L. Carstens, Peter Korsten, Elisabeth M. Zeisberg, Gerhard A. Müller, Raghu Kalluri, Michael Zeisberg
Journal: Kidney International (2016)
miRNA 125b Enhances the differentiation and Functionality of in Vitro Generated Human Hematopoietic Progenitor Cells
Authors: Julian Pulecio, Emmanuel Nivet, Marianna Vitaloni, Ignacio Sancho Martinez, Leire Abalde, Leopoldo Laricchia-Robbio, Juan Carlos Izpisua Belmonte
Journal: Blood (2012)
The Average Baseline BCR-ABL Levels Are Significantly Higher in Patients with Resistance to Dasatinib As First-Line Treatment for Early Chronic Phase Chronic Myeloid Leukemia
Authors: Cristian Tomasetti, Hagop M. Kantarjian, Ritesh Ramchandani, Elias Jabbour, Alfonso Quintás-Cardama, Giovanni Parmigiani, Jorge E. Cortes
Journal: Blood (2012)
FLT3 Mutations in a Large Series of Patients with Acute Promyelocytic Leukemia Treated with All-Trans Retinoic Acid and Anthracycline Monochemotherapy.
Authors: Pau Montesinos, Marcos Gonzalez, Maria Calasanz, Pascual Bolufer, Dolors Colomer, Jose Roman, Maria Teresa Gomez, Joaquin Martinez, Elena Amutio, Miguel Sanz
Journal: Blood (2006)
Exercise capacity, physical activity and obesity in adults with repaired aortic coarctation
Authors: Roselien Buys, Werner Budts, Christophe Delecluse, Luc Vanhees
Journal: Circulation (2012)

BACKGROUND Patients with aortic coarctation (COA) have a reduced exercise capacity and seem to be more prone to adopt a sedentary lifestyle. During clinical practice, we often observe that patients seem to be overweight. However, data on physical activity and weight status in this population are currently not available. OBJECTIVE This study aimed to describe weight status, self-reported physical activity levels, and self-perceived health status in adults with repaired COA in comparison with healthy counterparts and to investigate the relationships among exercise capacity, physical activity, weight status, and perceived health status. METHODS We studied 103 COA patients who underwent cardiopulmonary exercise testing and who completed the Flemish Physical Activity Computerized Questionnaire and the short-form 36 health survey questionnaire. RESULTS Patients with COA show a significantly lower exercise tolerance than what would be expected in healthy persons (P < .0001). Weight status was similar to the overall Belgian population, but a tendency toward higher body mass index was present. Patients with COA report a lower level of habitual physical activity (P < .05) as well as reductions in perceived vitality, general health, and mental health (P < .05). Parameters of habitual physical activity are related to exercise capacity (total energy expenditure: r = 0.278, P = .0015). The more active COA patients report higher scores of perceived physical functioning, general health, and mental health. Overweight patients did not perform significantly different than patients with a healthy weight did. CONCLUSIONS Adults with repaired COA have a reduced exercise tolerance, which is related to low physical activity levels. Up to one-third of the COA patients we studied are overweight. As a poor exercise capacity identifies patients at risk for hospitalization and death and obesity might adversely influence the development of cardiovascular disease, it is important to improve the exercise capacity in these patients. Guiding patients toward more physical activity in daily life might therefore be the number 1 preventive measure to be taken in this patient group.
Phenotypic Rescue Of Induced Pluripotent Stem Cells From Dyskeratosis Congenita Patients By Ectopic Expression Of DKC1 But Not TERC
Authors: Bai-wei Gu, Jason A. Mills, Marisa Apicella, Jian-meng Fan, Deborah L. French, Monica Bessler, Philip J. Mason
Journal: Blood (2013)
The pressure-dependent air leak after partial lung resection
Authors: Amit Chopra, Peter Doelken, Marc A Judson, Terrill Huggins
Journal: Thorax (2016)

A 72-year-old man with a right middle lobe lung adenocarcinoma underwent lobectomy with removal of tube thoracostomy 3 days after the thoracic surgery. He presented approximately 3 weeks after surgery with increasing dyspnoea. A chest X-ray (CXR) revealed a moderately large, loculated basilar pneumothorax (figure 1A). A small bore tube thoracostomy was placed with reduction of the pneumothorax. However, a moderate-sized pneumothorax with a persistent air leak persisted for approximately 2 weeks after chest tube placement requiring ongoing hospitalisation (figure 1B). Pleural manometry was performed sequentially, first with the chest tube open to water seal and then with chest tube clamped demonstrating that the air leak was pressure-dependent. Based on the manometric findings (figure 2), the chest tube was clamped and the pneumothorax remained radiographically stable. The tube thoracostomy was removed and the patient was discharged home. At 1-year follow-up, his CXR showed stable pneumothorax (figure 3).



Figure 1 
Chest X-ray. (A) Right basilar loculated pneumothorax …