tbuckley/cabot-search huggingface dataset:
Abstract 4277: Development and validation of a novel IDH1-mutant astrocyte cell line as a model for high-grade gliomas
Authors: Nathaniel D. Robinson, Karin R. Purshouse, Nathan R. Fons, Gregory A. Breuer, Stefan Pusch, Andreas von Deimling, Ranjini K. Sundaram, Ranjit S. Bindra
Journal: Cancer Research (2016)

Abstract High-grade gliomas (HGGs) are devastating malignancies of the central nervous system, and few treatment options are available for these tumors. In the most malignant form of the disease, glioblastoma multiforme (GBM), over 90% of patients will succumb to their tumor within 5 years after standard of care treatment, consisting of surgery, radiation therapy, and temozolomide chemotherapy. It is now clear that gliomas are molecularly heterogeneous entities, with mutations in tumor suppressors and oncogenes defining many distinct sub-types with important therapy implications. However, almost all HGGs are treated with a limited array of initial therapies, regardless of these molecular differences. Isocitrate dehydrogenase-1 (IDH1), a gene recently found to be mutated in many gliomas, is involved in the conversion of isocitrate to 2-oxoglutarate in cells. The IDH1 R132H mutant enzyme converts 2-oxoglutarate to the oncometabolite (R)-2-hydroxyglutarate (D2HG), which leads to profound metabolic alterations in tumor cells. In addition, recent studies indicate that mutations in IDH1 may also induce altered DSB repair, differential sensitivities to chemo-radiotherapy, and substantial changes in chromatin modifications. Here, we present the creation of a novel astrocyte cell line harboring an engineered heterozygous IDH1 R132H mutation at the endogenous gene locus using CRISPR/Cas9 gene editing. We confirmed expression of the engineered mutation at the protein level, and we have characterized this cell line in a comprehensive panel of functional assays. In particular, we demonstrated that our mutant cell clones secrete high levels of D2HG, and we confirmed that the levels of this oncometabolite can be suppressed with small molecule inhibitors of mutant IDH1. We also characterized the DNA damage response network in IDH1-mutant cells using high-content DNA damage foci assays recently developed by our group, and also in clonogenic survival assays. To our knowledge, this is the first report of an astrocyte cell line harboring an engineered, heterozygous R132H mutation at the endogenous locus. This novel cell line represents a new model system for studying gliomas and has tremendous applications for further cell characterization, mechanistic studies, and drug screening. Citation Format: Nathaniel D. Robinson, Karin R. Purshouse, Nathan R. Fons, Gregory A. Breuer, Stefan Pusch, Andreas von Deimling, Ranjini K. Sundaram, Ranjit S. Bindra. Development and validation of a novel IDH1-mutant astrocyte cell line as a model for high-grade gliomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4277.
Discontinuation of echinocandin and azole treatments led to the disappearance of an FKS alteration but not azole resistance during clonal Candida glabrata persistent candidaemia
Authors: S. Imbert, L. Castain, A. Pons, S. Jacob, I. Meyer, M. Palous, C. Vezinet, O. Langeron, C. Hennequin, A. Monsel, A. Fekkar
Journal: Clinical Microbiology and Infection (2016)
Recombinant Chimeric IgA1 and IgA2 Antibodies for Tumor Immunotherapy.
Authors: Michael Dechant, Thomas Beyer, Stefan Lohse, Tanja Schneider-Merck, Wencke Weisner, Sven Berger, Matthias Peipp, Jan G.J. van de Winkel, Thomas Valerius
Journal: Blood (2007)
290P Rituximab plus CHOP dramatically improved outcome of newly diagnosed diffuse large b-cell lymphoma in China: results of long-term follow-up from Sun Yat-sen University Cancer Center (SYSUCC)
Authors: H.Q. Huang, Y. Xia, Y. Gao, X.X. Wang, Q.Q. Cai, Z.J. Xia, L. Zhimin, B. Bai, T.Y. Lin, W. Zhao, Z. Yan, W. Jiang
Journal: Annals of Oncology (2015)
Abstract 144: Gene expression analysis of HPV negative and HPV positive penile cancer
Authors: María Sánchez-Vázquez, Krizia Rohena-Rivera, Carlos Pérez-Ruiz, Antonio Puras-Báez, Carmen Cadilla, Magaly Martínez-Ferrer
Journal: Cancer Research (2016)

Abstract Penile cancer is a disease with a high morbidity and mortality among developing countries. Although penile cancer is a relatively uncommon cancer in developed countries, its incidence is nearly four times higher in Puerto Rico when compared with other racial and ethnic groups in the United States. Approximately 40% to 45% of penile cancers are HPV-related. The etiology of penile cancers is not completely understood and additional research is necessary to fully delineate the sequence of molecular events involved in both HPV mediated and non-HPV mediated pathways leading to penile cancer. The objective of this study is to determine the genome-wide expression profiles in HPV mediated and non-HPV mediated penile cancer. Penile cancer fresh tissue was obtained from surgically intervened cases. The global gene expression profile was identified and analyzed using the Affymetrix GeneChip® Human Gene 2.0 array. Microarray analysis showed a total of 158 genes differentially expressed between HPV mediated and non-HPV mediated penile cancer. Ingenuity Pathway Analysis (IPA) revealed alterations in the celular movement, cancer, lipid metabolism, carbohydrate metabolism, interleukin, TGF-B, integrin, PI3-kinase and MMP signaling pathways. The microarray results were confirmed by quantitative real-time PCR for some representative genes. Functional and pathway annotation using bioinformatics tools helped to identify specific pathways. Knowledge of the biological pathways and networks of the genes that are significantly expressed or altered are pertinent to understanding the molecular basis of the penile cancer. Citation Format: María Sánchez-Vázquez, Krizia Rohena-Rivera, Carlos Pérez-Ruiz, Antonio Puras-Báez, Carmen Cadilla, Magaly Martínez-Ferrer. Gene expression analysis of HPV negative and HPV positive penile cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 144.
Passive Sampling for Indoor and Outdoor Exposures to Chlorpyrifos, Azinphos-Methyl, and Oxygen Analogs in a Rural Agricultural Community
Authors: Jenna L. Gibbs, Michael G. Yost, Maria Negrete, Richard A. Fenske
Journal: Environmental Health Perspectives (2016)

Recent studies have highlighted the increased potency of oxygen analogs of organophosphorus pesticides. These pesticides and oxygen analogs have previously been identified in the atmosphere following spray applications in the states of California and Washington.We used two passive sampling methods to measure levels of the ollowing organophosphorus pesticides: chlorpyrifos, azinphos-methyl, and their oxygen analogs at 14 farmworker and 9 non-farmworker households in an agricultural region of central Washington State in 2011.The passive methods included polyurethane foam passive air samplers deployed outdoors and indoors and polypropylene deposition plates deployed indoors. We collected cumulative monthly samples during the pesticide application seasons and during the winter season as a control.Monthly outdoor air concentrations ranged from 9.2 to 199 ng/m3 for chlorpyrifos, 0.03 to 20 ng/m3 for chlorpyrifos-oxon, < LOD (limit of detection) to 7.3 ng/m3 for azinphos-methyl, and < LOD to 0.8 ng/m3 for azinphos-methyl-oxon. Samples from proximal households (≤ 250 m) had significantly higher outdoor air concentrations of chlorpyrifos, chlorpyrifos-oxon, and azinphos-methyl than did samples from nonproximal households (p ≤ 0.02). Overall, indoor air concentrations were lower than outdoors. For example, all outdoor air samples for chlorpyrifos and 97% of samples for azinphos-methyl were > LOD. Indoors, only 78% of air samples for chlorpyrifos and 35% of samples for azinphos-methyl were > LOD. Samples from farmworker households had higher indoor air concentrations of both pesticides than did samples from non-farmworker households. Mean indoor and outdoor air concentration ratios for chlorpyrifos and azinphos-methyl were 0.17 and 0.44, respectively.We identified higher levels in air and on surfaces at both proximal and farmworker households. Our findings further confirm the presence of pesticides and their oxygen analogs in air and highlight their potential for infiltration of indoor living environments. Citation: Gibbs JL, Yost MG, Negrete M, Fenske RA. 2017. Passive sampling for indoor and outdoor exposures to chlorpyrifos, azinphos-methyl, and oxygen analogs in a rural agricultural community. Environ Health Perspect 125:333-341; http://dx.doi.org/10.1289/EHP425.
Abstract 12719: Expression of DHRS7c, A Novel Cardiomyocyte-expressed Gene Affected by Adrenergic Stimulation, is Strongly Associated With Ventricular Reverse-remodeling in Dilated Cardiomyopathy
Authors: David P Kao, Brian D Lowes, Edward M Gilbert, Wayne Minobe, Leslie K Meyer, Robert A Quaife, Michael R Bristow
Journal: Circulation (2015)

Background: The molecular mechanisms by which β-blockers produce ventricular reverse-remodeling in nonischemic dilated cardiomyopathy (NDCM) are incompletely understood. DHRS7C is a short chain dehydrogenase/reductase of uncertain functional significance expressed preferentially in the myocardium and down-regulated in heart failure or with α- and β-adrenergic stimulation. The objective of this study was to determine the association of DHRS7C with DCM and reverse-remodeling in heart failure patients taking β-blockers. Methods and Results: Forty-seven NDCM patients were randomized to metoprolol succinate, metoprolol + doxazosin, or carvedilol for 18 months. Ejection fractions (EFs) were measured by radionuclide ventriculography, and myocardial biopsy was performed at baseline, 3, and 12 months. Transcriptome-wide myocardial mRNA expression was measured using the Affymetrix HGU133 plus 2.0 GeneChip. DHRS7C expression was significantly reduced in DCM patients compared with 4 non-failing controls (7.3±0.2 vs. 9.0±0.7, p=0.03). Thirty-one (66%) patients had a reverse-remodeling response defined as improvement of 8 LVEF units at 12 months or if not available, 5 LVEF units at 3 months. DHRS7C was significantly more up-regulated in responders vs. non-responders (4.1±0.6 vs. 2.2±0.7 fold change, p=0.03). Change in gene expression was significantly correlated with change in LVEF (r=0.52, p&lt;0.001), RVEF (r=0.40, p&lt;0.001), and heart rate (r=-0.38, p&lt;0.01). These correlations were comparable to other genes associated with reverse-remodeling. Conclusions: Myocardial expression of DHRS7C is significantly down-regulated in human NDCM. As expected, expression increases in response to β-AR blockade and is strongly correlated with both EF and heart rate response to beta-blockers comparable to MYH6 and ADRB1/2 . Although its function is unclear, DHRS7C may be an important biomarker or mechanistically important for ventricular reverse-remodeling.
Split dose gemcitabine/ cisplatin (GC) in urothelial carcinoma of the bladder: Review of toxicity and response.
Authors: Laura Elizabeth Sellers, Alex Harper, Mark David Linch, Reena Davda, Rowan Miller, Heather Payne, Anita Mitra, Basu Suprotim, Zanab Wasim, Stephen John Harland, Ursula Brigid McGovern
Journal: Journal of Clinical Oncology (2016)

e16018 Background: UK guidelines for treatment of bladder cancer recommend Gemcitabine/Cisplatin (GC) or MVAC (Methotrexate, Vinblastine, Doxorubicin and Cisplatin). Outcomes are similar but reported toxicity is less in patients receiving the GC doublet. Most UK centers use 3 weekly cisplatin dosing (70mg/m2). However, split dose Cisplatin weeks 1 and 2 (35mg/m2) with gemcitabine, allows shorter infusion times whilst maintaining efficacy. Methods: We conducted retrospective case note review of patients' receiving split dose GC for urothelial carcinoma (UC) of the bladder at UCLH since 2009, including radiological and pathological response rates and toxicity assessment during treatment. Results: 58 patients received split dose GC (15 females, 43 males). Median age was 59. 94% were pure UC or had UC as the main histological subtype. 32 patients (55%) were treated neo-adjuvantly. 69% (22/32) are disease free and 78% (25/32) remain alive. 28/32 (87%) completed all 3 planned cycles. Grade 3/4 toxicities were: neutropenia (37.5%) neutropenic fever (6%), thrombocytopenia (3%), anaemia (6%) and VTE (15%). 29/32 (90%) proceeded with planned definitive treatment – 20/29 (69%) cystectomy and 9/29 (31%) radiotherapy/chemoradiotherapy. 3/20 (15%) of patients had pCR at the time of cystectomy. Only 2 patients (6%) had evidence of radiological progression. 26 patients received split dose GC for metastatic disease. Radiologically, 4/23 (17%) had a CR, 8/23 (35%) PR, 3/23 (13%) SD and 8/23 (35%) PD. With 16.8 months median follow up, the OS was 15.2 months and PFS 8 months. 16/26 (62%) received all 6 cycles (mean = 4). G3/4 toxicities were neutropenia (23%), anaemia (38%), thrombocytopenia (4%), VTE (8%). Conclusions: Split dose GC has comparable response rates in metastatic disease to other platinum containing regimens but has a favourable toxicity profile and considerably less time burden on day care facilities. Although we report a lower pCR in the neo-adjuvant setting than others, long-term survival outcomes are comparable. Split dose GC is well tolerated in all settings and should be considered as an alternative to the longer more toxic regimens, particularly in metastatic disease.
Incidence of advanced neoplasia during surveillance in high- and intermediate-risk groups of the European colorectal cancer screening guidelines
Authors: Joaquín Cubiella, Fernando Carballo, Isabel Portillo, José Cruzado Quevedo, Dolores Salas, Gemma Binefa, Núria Milà, Cristina Hernández, Montse Andreu, Álvaro Terán, Eunate Arana-Arri, Akiko Ono, María Valverde, Luis Bujanda, Vicent Hernández, Juan Morillas, Rodrigo Jover, Antoni Castells
Journal: Endoscopy (2016)

<b>Background and study aims:</b> The European guidelines for quality assurance in colorectal cancer (CRC) screening have established high-risk (≥ 5 adenomas or an adenoma ≥ 20 mm) and intermediate-risk (3 – 4 adenomas or at least one adenoma 10 – 19 mm in size, or villous histology, or high grade dysplasia) groups with different endoscopic surveillance intervals. The aim of this study was to evaluate the difference in the incidence of advanced neoplasia (advanced adenoma or CRC) between the two risk groups. <b>Patients and methods:</b> This retrospective group study included patients meeting high- or intermediate-risk criteria for adenomas detected in CRC screening programs and the COLONPREV study before European guidelines were adopted in Spain (June 2011) with a 3-year surveillance recommendation according to Spanish guidelines. The primary outcome measure was the incidence of advanced neoplasia in patients undergoing surveillance. The secondary outcome measure was the CRC incidence. We used an adjusted proportional hazards regression model to control confounding variables. <b>Results:</b> The study included 5401 patients (3379 intermediate risk, 2022 high risk). Endoscopic surveillance was performed in 65.5 % of the patients (2.8 ± 1 years). The incidence of advanced neoplasia in the high- and intermediate-risk groups was 16.0 % (59.0 cases/1000 patient-years) and 12.3 % (41.2 cases/1000 patient-years), respectively. The CRC incidence was 0.5 % (1.4 cases/1000 patient-years) and 0.4 % (1 case/1000 patient-years), respectively. The advanced neoplasia and CRC attributable risk to the high risk group was of 3.7 % and 0.1 %, respectively. In the proportional hazards analysis, the risk of advanced neoplasia was greater in the high-risk group (hazard ratio [HR] 1.5, 95 % confidence interval [CI] 1.2 – 1.8), with no significant differences in the CRC incidence (HR 1.6, 95 %CI 0.6 – 3.8). <b>Conclusions:</b> Patients meeting high-risk criteria have a higher incidence of advanced neoplasia during endoscopic surveillance. No differences were found in the CRC incidence at a 3-year surveillance recommendation.
Abstract 2468: Combined targeting of the EWS/ETS transcriptional program by BET bromodomain and PI3K pathway inhibition blocks tumorigenicity and increases apoptosis in Ewing sarcoma
Authors: Tim Hensel, Chiara Giorgi, Fiona Becker-Dettling, Julia Calzada-Wack, Frauke Neff, Thorsten Buch, Oxana Schmidt, Beat W. Schäfer, Stefan Burdach, Günther HS Richter
Journal: Cancer Research (2016)

Abstract Ewing sarcomas (ES) are highly malignant bone or soft tissue tumors. Genetically, ES are defined by balanced chromosomal EWS/ETS translocations that give rise to chimeric proteins (EWS-ETS), which generate an oncogenic transcriptional program associated with altered epigenetic marks throughout the genome. By use of an inhibitor (JQ1) blocking BET bromodomain binding proteins (BRDs) we strikingly observed a strong down-regulation of the predominant EWS-ETS protein EWS-FLI1 in a dose dependent manner. This was further enhanced by co-treatment with an inhibitor (BEZ235) of the PI3K pathway. Microarray analysis revealed JQ1 treatment to block a typical ES associated expression program. The effect on this expression program was mimicked by RNA interference of BRD3 or BRD4 expression but not by BRD2 blockade, indicating that the EWS-FLI1 mediated expression profile is at least in part mediated via such epigenetic readers. JQ1 treatment not only suppressed an ES specific expression profile but also blocked contact dependent and independent proliferation of different ES lines. But subsequent analysis of proliferation after transient knockdown of either BRD3 or BRD4 did not recapitulate inhibition of proliferation as observed after JQ1 treatment, indicating the necessary simultaneous blockade of both proteins. However, inhibition of proliferation after JQ1 treatment was due to a partial G1 arrest and S phase elongation of the cell cycle. In addition, induction of apoptosis as demonstrated by PARP1-, CASP7-cleavage and increased CASP3 activity significantly contributed to the reduction of the proliferative ability of ES lines. Single or combination treatment with the PI3K/mTOR inhibitor BEZ235 increased apoptosis of ES cell lines although single treatment with BEZ235 was less effective than JQ1 application. Consequently, tumor development was dose dependently suppressed with increased formation of apoptotic bodies in a xeno-transplant model in immune deficient mice, overall indicating that ES may be susceptible to treatment with epigenetic inhibitors blocking BET bromodomain activity and the associated pathognomonic EWS-ETS transcriptional program. Citation Format: Tim Hensel, Chiara Giorgi, Fiona Becker-Dettling, Julia Calzada-Wack, Frauke Neff, Thorsten Buch, Oxana Schmidt, Beat W. Schäfer, Stefan Burdach, Günther HS Richter. Combined targeting of the EWS/ETS transcriptional program by BET bromodomain and PI3K pathway inhibition blocks tumorigenicity and increases apoptosis in Ewing sarcoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2468.
A randomized phase Ib/II study evaluating the safety and efficacy of olaratumab (IMC-3G3), a human anti-platelet-derived growth factor α (PDGFRα) monoclonal antibody, with or without doxorubicin (Dox), in advanced soft tissue sarcoma (STS).
Authors: William D. Tap, Robin L Jones, Bartosz Chmielowski, Anthony D. Elias, Douglas Adkins, Brian Andrew Van Tine, Mark Agulnik, Matthew M. Cooney, Michael B. Livingston, Gregory K. Pennock, Amy Qin, Ashwin Shahir, Robert L. Ilaria, Ilaria Conti, Jan Cosaert, Gary K. Schwartz
Journal: Journal of Clinical Oncology (2015)

10501 Background: Options for patients (pts) with unresectable/metastatic STS are limited. While Dox is standard of care, Dox combinations have yet to improve overall survival (OS) over Dox alone. Olaratumab (IMC-3G3), a fully human monoclonal antibody, selectively binds PDGFRα (a signaling pathway implicated in STS), blocks ligand binding, and enhances Dox activity in preclinical sarcoma models. Methods: We conducted a phase Ib, open-label, randomized phase II study of Dox ± olaratumab in unresectable/metastatic STS (NCT01185964). Pts received Dox (75 mg/m2 Day 1) with (Arm A) or without (Arm B) olaratumab (15 mg/kg Days 1 and 8, every 21 days), a dose and schedule confirmed safe in phase Ib, for up to 8 cycles. In Arm A, olaratumab monotherapy continued after Dox until disease progression; in Arm B, pts could cross over to olaratumab at progression. The primary endpoint was progression-free survival (PFS; target hazard ratio [HR] = 0.67, 80% power, α = 0.2) with OS as a secondary endpoint. Results: Of 133 pts randomized, 129 (97%) were treated (64, Arm A; 65, Arm B). Demographics were balanced. Final PFS analysis (103 events) revealed medians of 6.6 months (Arm A) and 4.1 months (Arm B) (stratified HR; 95% confidence interval [CI]: 0.672 [0.442-1.021]; p = 0.0615). Interim OS analysis (83 deaths) revealed medians of 25.0 months (Arm A) and 14.7 months (Arm B) (HR = 0.44; p = 0.0005). Objective response rates were 18.8% (Arm A) and 12.3% (Arm B) (p=0.3407). The following Grade ≥ 3 adverse events (AEs) occurred in ≥ 5% of the population: Arm A > Arm B, neutropenia (51.5% vs 33.8%), anemia (12.5% vs 7.7%), fatigue (9.4% vs 3.1%), thrombocytopenia (9.4% vs 7.7%); Arm A < Arm B, febrile neutropenia (12.5% vs 13.8%), infections (6.3% vs 10.8%). Conclusions: This study of olaratumab in combination with Dox met its primary PFS endpoint and achieved an improvement of 10.3 months in median OS that was highly statistically significant (HR = 0.44; p = 0.0005). Olaratumab is the first agent added to Dox to improve OS in advanced/metastatic STS in a randomized trial. Clinical trial information: NCT01185964.
Implications of the Bystander and Abscopal Effects of Radiation Therapy
Authors: Vivek Verma, Steven H. Lin
Journal: Clinical Cancer Research (2016)

Siva and colleagues have demonstrated that localized thoracic radiation resulted in DNA damage at out-of-field sites. Although these interesting findings require validation, we discuss the important clinical implications of these data, especially in the era of immune therapies. Clin Cancer Res; 22(19); 4763-5. ©2016 AACRSee related article by Siva et al., p. 4817.
BT062, An Antibody-Drug Conjugate Directed Against CD138, Shows Clinical Activity in Patients with Relapsed or Relapsed/Refractory Multiple Myeloma
Authors: Sundar Jagannath, Asher Chanan-Khan, Leonard T. Heffner, David Avigan, Todd M. Zimmerman, Sagar Lonial, Robert J. Lutz, Andre Engling, Christoph Uherek, Frank Osterroth, Markus Ruehle, Michelle A. Beelitz, Gabriele Niemann, Andrea Wartenberg-Demand, Thomas Haeder, Kenneth C. Anderson, Nikhil C. Munshi
Journal: Blood (2011)