tbuckley/cabot-search huggingface dataset:
Abstract 443: Prognostic significance of CXCL12 protein levels in high-grade serous ovarian carcinoma
Authors: Laurence Buisseret, Vincent Delisle, Laudine Communal, Sandra Pommey, John Stagg
Journal: Cancer Research (2016)

Abstract Signals mediated by the C-X-C chemokine ligand 12 (CXCL12; stromal-derived factor 1) and its receptor CXCR4 have been implicated in cancer progression through multiple tumorigenesis processes, including cancer cell proliferation, survival, invasion and tumor angiogenesis. In vitro and murine models recently demonstrated that this axis is also involved in the mechanism of tumor immune evasion and resistance to immune checkpoint inhibitors. In human ovarian cancer, this axis has been associated with ascites, nodes and peritoneal metastasis. We investigated the prognostic value of CXCL12 protein expression and association with CD8+ T cell infiltration in a cohort of 203 patients diagnosed with a high-grade serous ovarian carcinoma (HGSC). Quantitative immunofluorescence allowed us to evaluate the frequency and level of expression of CXCL12 and CD8+ cell density in the epithelial and stromal tumor compartments. CXCL12 expression in the epithelial tumor compartment was significantly higher than in the stromal compartment (p&amp;lt;0.0001). Strikingly, high levels of tumoral CXCL12 expression were significantly associated with a worse progression-free survival (PFS) and overall survival (OS) (log-rank test, p = 0.007 &amp; p = 0.006, respectively). The Kaplan-Meier median PFS and OS were respectively of 17±1.5 and 42±6.9 months in patients with high levels and of 18±3.6 and 61±7.5 months in patients with low levels of CXCL12. Notably, multivariate analysis showed that CXCL12 levels were associated with a worse outcome independent of FIGO stage and residual disease. No correlation was observed between CXCL12 expression levels and CD8+ T cell density. Intriguingly, in CD8+ subgroup analyses, the prognostic value of CXCL12 levels was restricted to tumors with low intraepithelial CD8+ T cell densities. Flow cytometry and quantitative real-time PCR results suggest that CXCL12 promotes a mesenchymal phenotype and increased expression of cancer stem cells markers on human ovarian cancer cells. In conclusion, modulation of the CXCL12/CXCR4 axis is a promising approach in HGSC that may potentiate immunotherapies and may act on epithelial-to-mesenchymal transition. Our study highlights the rationale to evaluate in the clinical setting treatments targeting the CXCL12/CXCR4 in HGSC, specifically in patients lacking CD8+ T cell tumor infiltration. Citation Format: Laurence Buisseret, Vincent Delisle, Laudine Communal, Sandra Pommey, John Stagg. Prognostic significance of CXCL12 protein levels in high-grade serous ovarian carcinoma. [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 443.
The Potential to Advance Health Care in the US Criminal Justice System
Authors: Newton E. Kendig
Journal: JAMA (2016)

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Proteinase-activated receptor 2 (PAR2) in hepatic stellate cells – evidence for a role in hepatocellular carcinoma growth in vivo
Authors: Franziska Mußbach, Hendrik Ungefroren, Bernd Günther, Kathrin Katenkamp, Petra Henklein, Martin Westermann, Utz Settmacher, Lennart Lenk, Susanne Sebens, Jörg P. Müller, Frank-Dietmar Böhmer, Roland Kaufmann
Journal: Molecular Cancer (2016)

Previous studies have established that proteinase-activated receptor 2 (PAR2) promotes migration and invasion of hepatocellular carcinoma (HCC) cells, suggesting a role in HCC progression. Here, we assessed the impact of PAR2 in HCC stromal cells on HCC growth using LX-2 hepatic stellate cells (HSCs) and Hep3B cells as model. PAR2 expression and function in LX-2 cells was analysed by RT-PCR, confocal immunofluorescence, electron microscopy, and [Ca2+]i measurements, respectively. The impact of LX-2-expressed PAR2 on tumour growth in vivo was monitored using HCC xenotransplantation experiments in SCID mice, in which HCC-like tumours were induced by coinjection of LX-2 cells and Hep3B cells. To characterise the effects of PAR2 activation in LX-2 cells, various signalling pathways were analysed by immunoblotting and proteome profiler arrays. Following verification of functional PAR2 expression in LX-2 cells, in vivo studies showed that these cells promoted tumour growth and angiogenesis of HCC xenografts in mice. These effects were significantly reduced when F2RL1 (encoding PAR2) was downregulated by RNA interference (RNAi). In vitro studies confirmed these results demonstrating RNAi mediated inhibition of PAR2 attenuated Smad2/3 activation in response to TGF-β1 stimulation in LX-2 cells and blocked the pro-mitotic effect of LX-2 derived conditioned medium on Hep3B cells. Furthermore, PAR2 stimulation with trypsin or a PAR2-selective activating peptide (PAR2-AP) led to activation of different intracellular signalling pathways, an increased secretion of pro-angiogenic and pro-mitotic factors and proteinases, and an enhanced migration rate across a collagen-coated membrane barrier. Silencing F2RL1 by RNAi or pharmacological inhibition of Src, hepatocyte growth factor receptor (Met), platelet-derived growth factor receptor (PDGFR), p42/p44 mitogen activated protein kinase (MAPK) or matrix-metalloproteinases (MMPs) blocked PAR2-AP-induced migration. PAR2 in HSCs plays a crucial role in promoting HCC growth presumably by mediating migration and secretion of pro-angiogenic and pro-mitotic factors. Therefore, PAR2 in stromal HSCs may have relevance as a therapeutic target of HCC.
Circulating tumor cell (CTC) and CA2729 as predictors of outcome in patients with metastatic breast cancer (MBC) in the prospective TBCRC 005 biomarker study.
Authors: A. Bardia, P. Huang, Z. Zhang, L. Sokoll, J. N. Ingle, L. A. Carey, N. U. Lin, R. Nanda, K. Visvanathan, A. C. Wolff
Journal: Journal of Clinical Oncology (2010)

1001 Background: Limited data support using circulating tumor markers (e.g., CA2729) as adjuncts to clinical/imaging studies to monitor MBC during active Rx (Harris, JCO 2007). CTC independently predicts survival (Cristofanilli, NEJM 2004), and an ongoing randomized trial is testing its clinical utility. However, the joint and comparative contribution of these two assays as outcome predictor(s) have yet to be tested. Methods: TBCRC 005 is an IRB-approved prospective trial testing the predictive role of serum DNA methylation in MBC patients starting new Rx. CA2729 (local labs, high if ≥ 38 units/mL serum) was collected at baseline and repeated if high in wk 3-4. CTC (CellSearch, high if ≥ 5 CTC/7.5 mL blood) was collected at baseline and at wk 3-4. Logistic regression/ROC and Cox regression tested marker association with progressive disease (PD) at first restaging (8-12 wks) and with PFS/OS, respectively. Results: Baseline CTC (52% or 59 high) and CA2729 (82% or 93 high) were available in 113 women (median age 56; white 86%; < 2 prior Rx 31%; ER+ 66%, HER2+ 21%, triple neg 18%). High CTC (but not high CA2729) was associated with worse PFS/OS. In 82 women with high baseline CA2729, this assay was repeated at wk 3-4 and in 60 of them CTC was also repeated. Change in CTC (but not in CA2729) was highly correlated with baseline CA2729 and CTC. Change in CA2729 (but not in CTC) independently predicted PD/PFS/OS (p=0.02/0.0003/0.002, n=60) after adjusting for known prognostic factors (age, prior Rx, race, number of disease sites, and phenotype), and remained an independent predictor for PD/PFS/OS when model rerun in those with at least baseline CTC (p values > 0.001/0.003/0.002, n=82). Therefore, ROC analysis for PD was done in patients with just baseline CTC and showed that PD prediction was significantly improved when baseline and change in CA2729 added to the prediction model with CTC (AUC 0.84, 95% CI 0.76-0.93 vs. AUC 0.69, 95% CI 0.58-0.81, p=0.006, n=82). Conclusions: Overall, CTC is an informative prognostic marker as per prior reports. In women with high baseline CA2729, CA2729 change is independently and more strongly associated with outcome than CTC or CTC change. These new findings must now be externally validated. No significant financial relationships to disclose.
Abstract 3019: High throughput drug screening identified spleen tyrosine kinase as a novel therapeutic target in head and neck cancer with potent in vitro and in vivo activity
Authors: Morgan Black, Laurie Ailles, Ren Sun, Alessandro Datti, Frederick Vizeacoumar, Nicole Pinto, Kara Ruicci, John Yoo, Kevin Fung, Danielle MacNeil, David A. Palma, Eric Winquist, Joe S. Mymryk, Paul C. Boutros, John W. Barrett, Anthony C. Nichols
Journal: Cancer Research (2016)

Abstract Background and Significance: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, and survival remains poor highlighting the need for novel treatments for the treatment of HNSCC. High throughput drug screening has shown the potential to discover novel therapeutics in other cancers. Methods: Twenty-eight HNSCC cell lines, including 5 HPV-positive lines, were characterized with whole exome sequencing and copy number arrays and screened with 1505 potential anti-cancer agents on a robotic liquid handling platform at a single dose (4uM). The most potent hits were confirmed with 10-point dose response curves. Novel therapeutic targets were further investigated with mechanistic and xenograft studies. Results: Drug screening identified 10 agents with broad activity across our cell line panel. One of the most potent agents was ER27319 maleate, reported to be a spleen tyrosine kinase (Syk) inhibitor. We confirmed that this molecule inhibited Syk phosphorylation specifically at tyrosine residues 525/526. Additionally, ER27319 maleate as well as a more clinically relevant Syk inhibitor, Fostamatinib, were observed to significantly impaired cellular migration and invasion. Additionally, siRNA knockdown of Syk in HNSCC cells was found to decrease HNSCC cell line growth. Finally, inhibition of Syk was observed to control HNSCC tumour growth in vivo in cell line-derived xenografts. Conclusions: High throughput drug screening of HNSCC cell lines identified Syk as a novel target and confirmed potent in vitro and in vivo activity. Further preclinical evaluation is planned with a panel of patient-derived xenografts. Should these results yield significant activity, we will aim to repurpose approved Syk inhibitors to improve outcomes for patients suffering from HNSCC. Citation Format: Morgan Black, Laurie Ailles, Ren Sun, Alessandro Datti, Frederick Vizeacoumar, Nicole Pinto, Kara Ruicci, John Yoo, Kevin Fung, Danielle MacNeil, David A. Palma, Eric Winquist, Joe S. Mymryk, Paul C. Boutros, John W. Barrett, Anthony C. Nichols. High throughput drug screening identified spleen tyrosine kinase as a novel therapeutic target in head and neck cancer with potent in vitro and in vivo activity. [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 3019.
P0731 : Ledipasvir (LDV)/sofosbuvir (SOF) treatment of hepatitis C virus (HCV) is associated with reduction of serum apolipoprotein levels
Authors: Z. Younossi, E. Elsheikh, M. Stepanova, L. Gerber, F. Nader, D. Brainard, J.G. McHutchinson
Journal: Journal of Hepatology (2015)
Real-time monitoring of magnetic drug targeting using fibered confocal fluorescence microscopy
Authors: Jie Bai, Julie Tzu-Wen Wang, Kuo-Ching Mei, Wafa T. Al-Jamal, Khuloud T. Al-Jamal
Journal: Journal of Controlled Release (2016)

Magnetic drug targeting has been proposed as means of concentrating therapeutic agents at a target site and the success of this approach has been demonstrated in a number of studies. However, the behavior of magnetic carriers in blood vessels and tumor microcirculation still remains unclear. In this work, we utilized polymeric magnetic nanocapsules (m-NCs) for magnetic targeting in tumors and dynamically visualized them within blood vessels and tumor tissues before, during and after magnetic field exposure using fibered confocal fluorescence microscopy (FCFM). Our results suggested that the distribution of m-NCs within tumor vasculature changed dramatically, but in a reversible way, upon application and removal of a magnetic field. The m-NCs were concentrated and stayed as clusters near a blood vessel wall when tumors were exposed to a magnetic field but without rupturing the blood vessel. The obtained FCFM images provided in vivo in situ microvascular observations of m-NCs upon magnetic targeting with high spatial resolution but minimally invasive surgical procedures. This proof-of-concept descriptive study in mice is envisaged to track and quantify nanoparticles in vivo in a non-invasive manner at microscopic resolution.
Abstract LB-328: Subtypes of urothelial carcinoma of the urinary bladder defined by genomic alteration combinations predict clinical characteristics
Authors: Alyna Khan, Alex Fichtenholtz, Jeffrey Ross, Garrett Frampton, Eric Neumann, Siraj M. Ali, Phil J. Stephens
Journal: Cancer Research (2016)

Abstract Introduction: At least 70,000 patients will be diagnosed with bladder urothelial carcinoma (UC) in the United States this year. Current pathologic staging divides UC into muscle invasive (MIBC) and non-muscle invasive bladder cancer (NMIBC). Existing molecular classifications reveal a heterogeneous mutational landscape especially in the MIBC group, with studies finding that UC breaks down to anywhere from two to six classes defined by molecular features. These studies have utilized either select somatic alterations or high-dimensional mRNA expression data. Classifications of UC based on comprehensive genomic profiling (CGP) and subsequently detected somatic tumor alterations are conspicuously absent. Methods: To create this CGP-based classification, 638 cases of mostly refractory or metastatic UC patients were assayed with CGP in the course of clinical care sequencing the coding exons of 287 cancer-related and 47 introns of 19 genes frequently rearranged in cancer and analyzing base-pair substitutions, indels, copy number alterations, and select gene fusions. Hierarchical latent class analysis (HLCA) a mixed-model classification method that finds highly statistically significant combinations of gene alterations, was applied to the resultant alteration profiles. Results: HLCA detected the structure of somatic alteration combinations in UC, finding two main super classes driven by either CDKN2A/B co-deletion or TP53 and RB1 mutations, and subclasses further defined by altered genes in signal transduction (FGFR3, ERBB2, PIK3CA) and chromatin modifying (KDM6A, MLL2, ARID1A) pathways. These classes are predictive of clinical characteristics and tumor progression, and outperform existing molecular-based UC classifiers. Conclusions: Identifying robust molecular subtypes of UC allows for appropriate assignment of patients to relevant clinical trials and can aid in electing suitable therapeutic strategies. Investigating the clinical context and targeted and immunotherapy implications of these subclasses will be essential for diagnostic, prognostic and therapeutic purposes. Citation Format: Alyna Khan, Alex Fichtenholtz, Jeffrey Ross, Garrett Frampton, Eric Neumann, Siraj M. Ali, Phil J. Stephens. Subtypes of urothelial carcinoma of the urinary bladder defined by genomic alteration combinations predict clinical characteristics. [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 LB-328.
Expression, Role in Transformation and Prognostic Significance of the Transcription Factor Yin Yang 1 (YY1) in Non-Hodgkin’s Lymphoma: Analyses in NHL Tissues by Experimental and Bioinformatic Approaches
Authors: Massimo Libra, Giancarlo Castellano, Stavroula Baritaki, Sara Huerta-Yepez, Giovanni Ligresti, Loredana Militello, Grazia Malaponte, Franca Stivala, Silvana Canevari, Benjamin Bonavida
Journal: Blood (2008)
Narrow-band imaging vs. high definition white light for optical diagnosis of small colorectal polyps: a randomized multicenter trial
Authors: Peter Klare, Bernhard Haller, Sandra Wormbt, Ellen Nötzel, Dirk Hartmann, Jörg Albert, Johannes Hausmann, Henrik Einwächter, Andreas Weber, Mohamed Abdelhafez, Roland Schmid, Stefan von Delius
Journal: Endoscopy (2016)

The aim of the study was to compare the latest narrow-band imaging (NBI) device with high-definition white light (HDWL) endoscopy for accuracy of real-time optical diagnosis of small colorectal polyps.We conducted a randomized, prospective, multicenter trial at three study sites in Germany. In the NBI arm, endoscopists used NBI for the prediction of polyp pathology on the basis of the NBI International Colorectal Endoscopic classification. In the HDWL arm, NBI was not used for optical classification of polyp histology. The primary outcome was accuracy of optical diagnoses (neoplastic vs. non-neoplastic) in small polyps measuring < 10 mm. Secondary end points included sensitivity and negative predictive value (NPV).A total of 380 patients were randomized 1:1 to either the NBI or HDWL arm. A total of 421 polyps measuring < 10 mm were detected (55.8 % neoplastic, 44.2 % non-neoplastic). Accuracy, sensitivity, and NPV were 73.7 %, 82.4 %, and 75.5 %, respectively, in the NBI arm and 79.2 %, 79.8 %, and 73.4 %, respectively, in the HDWL arm (P = 0.225, P = 0.667, P = 0.765). More polyps were assessed with high confidence in the HDWL arm (82.6 %) than in the NBI arm (73.7 %; P = 0.038). The NPV of the prediction of neoplastic histology in diminutive polyps (≤ 5 mm) rated with high confidence was 90.3 % in the NBI arm. We detected significant differences between the participating study sites in the performance data of predictions.The levels of accuracy for real-time prediction of polyp histology (< 10 mm) did not differ between NBI and HDWL for optical diagnosis. Variation in the performance of optical diagnosis was apparent between study centers.ClinicalTrials.gov (NCT02009774).
Abstract 2508: A red-shifted fluorescent substrate for aldehyde dehydrogenase, AldeRed 588-A, for labeling viable ALDH-positive cells
Authors: Nick Asbrock, Vi Chu, Martin Pomper
Journal: Cancer Research (2016)

Abstract Normal and cancer stem cells can be isolated based upon the enzymatic activity of aldehyde dehydrogenase I (ALDH1), a detoxifying enzyme responsible for oxidation of hazardous aldehyde byproducts. ALDH1 has been used to isolate cancer stem cells from various human malignancies including bladder, breast, cervical, colon, head and neck, liver, lung, pancreas, prostate and ovary. Currently, the ALDEFLUOR assay, is the only commercially available reagent for ALDH detection in live cells. The substrate used in this assay primarily emits in the green region of the electromagnetic spectrum (512nm). For researchers with valuable cell and transgenic animal models in which the target gene of interest has been tagged with eGFP, ALDEFLUOR therefore cannot be used. Selection of cells positive for aldehyde dehydrogenase (ALDH) activity from a green fluorescent background is thus difficult with existing reagents. We now describe a red-shifted fluorescent substrate for ALDH, AldeRed 588-A, that provides additional flexibility for utilizing ALDH as a marker for stem cell and cancer stem cell isolation. The activity of AldeRed 588-A was compared with the ALDEFLUOR reagent and demonstrated similar ability to fractionate ALDHpos cells in a number of cell lines tested. Citation Format: Nick Asbrock, Vi Chu, Martin Pomper. A red-shifted fluorescent substrate for aldehyde dehydrogenase, AldeRed 588-A, for labeling viable ALDH-positive cells. [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 2508.
Pharmacokinetic Results Of a Feasibility and Phase II Study (ITCC 021) On Bortezomib (BTZ) In Pediatric Relapsed ALL: Lack Of Significant Penetration Of BTZ In The Cerebrospinal Fluid
Authors: Gertjan Kaspers, Ron Mathot, Satianand Ramnarain, Denise Niewerth, Franco Locatelli, Eveline S.J.M De Bont, Franca Fagioli, Pierre Rohrlich, Arend von Stackelberg, Michel Zwaan
Journal: Blood (2013)
Abstract 2156: Targeting estrogen receptor mutations for treatment of endocrine therapy resistance in breast cancer
Authors: Prasanna G. Alluri, Jose Larios, Rohit Malik, James Rae, Arul M. Chiinaiyan
Journal: Cancer Research (2016)

Abstract Approximately 70% of all breast cancers express the Estrogen Receptor (ER) and inhibition of the ER signaling remains the mainstay of systemic therapy in such cancers. The advent of endocrine therapies (ET) have contributed significantly to reduction in the incidence, recurrence and mortality associated with breast cancer. However, approximately one-third of patients with ER-positive breast cancer do not benefit from adjuvant ET, and nearly all patients with ER-positive metastatic breast cancer (MBC) ultimately become refractory to all known ETs. While several mechanisms of resistance to ET have been proposed, there are currently no clinically effective treatments for ET resistance. Thus, ET resistance remains a major obstacle to the effective treatment of a significant subset of ER-positive breast cancers. We have recently reported recurrent somatic mutations in the ligand binding domain (LBD) of the Estrogen Receptor gene (ESR1) in metastatic breast cancer patients with a history of prior treatment with ET. The ESR1 mutations result in constitutive activation of the ER and confer ET resistance when ectopically expressed in ER-positive cell lines. In an attempt to develop novel therapeutic strategies to treat ET-resistant breast cancer, we have evaluated OTX015, a clinical bromodomain and extraterminal (BET) domain inhibitor, in pre-clinical models of ET resistance due to ESR1 mutations. Our studies suggest that BET inhibition may serve as an attractive strategy for treatment of ET resistance due to ESR1 mutations. Citation Format: Prasanna G. Alluri, Jose Larios, Rohit Malik, James Rae, Arul M. Chiinaiyan. Targeting estrogen receptor mutations for treatment of endocrine therapy resistance in breast 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 2156.