tbuckley/cabot-search huggingface dataset:
Abstract 92: Epigenetic inhibitors targeting colon cancer stem cells
Authors: Yufeng Chen
Journal: Cancer Research (2015)

Abstract Colon cancer is one of the top leading causes of death in the world. Even after surgery and chemotherapy, there are still many patients who will experience relapse. Cancer stem or initiating cells (CSCs) are a small subset of self-renewing and highly tumorigenic cells, which are resistant to existing chemotherapy. In addition, CSCs are often enriched following chemotherapy, and are responsible for relapse and subsequent metastasis. One mechanism that possibly leads to chemotherapeutic failure is epigenetic changes which involve aberrant chromatin modifications in cancer and CSCs. Here, we performed microarray to investigate the gene expression profiles of CSCs and non-CSCs populations identified by ALDEFLUOR assay. Several genes were found to be highly expressed in CSCs in different colon cancer cell lines. Then we performed inhibitor screening to identify small molecules which can inhibit CSCs. Several compounds inhibiting histone methylations were found to be effective in reducing the CSCs population and expression of CSCs’ related genes. These results support the use of epigenetic inhibitors together with chemotherapy in refractory colon cancer. Citation Format: Yufeng Chen. Epigenetic inhibitors targeting colon cancer stem cells. [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 92. doi:10.1158/1538-7445.AM2015-92
OC-024 Spinning through the small bowel: first report of the UK (multicentre) experience of spiral enteroscopy
Authors: E J Despott, S Hughes, P Marden, C Fraser
Journal: Gut (2010)

<h3>Introduction</h3> This decade has witnessed a revolution in small bowel (SB) endoscopy. Balloon assisted enteroscopy (double-balloon and later single-balloon) has dramatically expanded the capacity to endoscopically manage SB pathology. More recently, a novel device assisted enteroscopy named spiral enteroscopy (SE) is a promising alternative method of deep enteroscopy. SE uses a pliable plastic spiral threaded onto a flexible overtube (Spirus, Endoase Discovery SB, Spirus Medical, Massachusetts, USA). Rotational torque applied to the overtube allows the spiral thread to engage the SB. This advances the overtube and enteroscope deeper into the small bowel. <h3>Methods</h3> We report an early multicentre experience of SE since its introduction to the UK in November 2008. <h3>Results</h3> 23 procedures (12 male) were done at two tertiary referral centres. Mean age was 58 years (19–81 years). 11 procedures were done under conscious sedation while the remaining 12 were under general anaesthesia. 22 procedures were performed via the oral route; 1 procedure was done via the rectal route. Carbon dioxide was used as an insufflating gas in 13 procedures while air was used for rest. The most common indication for SE was mid-gut bleeding (n=17). Other indications included SB polyposis (n=5) and direct percutaneous endoscopic jejunostomy (DPEJ) feeding tube replacement (n=1). 22 procedures were continued to the maximal point of insertion until forward advancement of the enteroscope ceased. One oral procedure was aborted due to the presence of gastric contents despite a 14-hour fast. Mean duration of procedures was 42±12 min. In one patient, where the spiral engaged the SB throughout the procedure, pan-enteroscopy was achieved in 65 min. In the patient undergoing rectal SE, SB intubation distance was estimated to be 50 cm proximal to the ICV. Eight patients were treated with argon plasma coagulation for angioectasias and one patient had multiple polypectomies. In one patient, the overtube induced some minor submucosal bruising; the patient remained well after the procedure. No other complications ensued. The main limitation to SE was related to occasional inability of the spiral to engage the SB. In another two patients, the SE failed to reach the location of SB tattoos placed at previous DBEs. In another patient, SE failed to reach a proximal ileal polyp (subsequently reached by DBE in the same session). <h3>Conclusion</h3> The initial UK experience with SE suggests that where SB engagement readily occurs, deep SB intubation can be achieved in a relatively short time. Anecdotally, the SE also appears to provide a stable platform for therapeutic interventions. Further comparative studies would be helpful.
Abstract 5357: Inhibition of collagen receptor discoidin domain receptor-1 (DDR1) tyrosine kinase enhances cytotoxicity of anti-mesothelin immunotoxin for cancer therapy
Authors: Fatima G. Ali-Rahmani, David Fitzgerald, Scott Martin, Paresma Patel, Craig Thomas, Ira Pastan
Journal: Cancer Research (2015)

Abstract Discoidin domain receptor 1 (DDR1) is an emerging anti-cancer target that belongs to the family of tyrosine kinases that are activated by collagen, the most abundant component of extracellular matrix (ECM). Collagen mediated induction of DDR1 facilitates cell adhesion, migration, proliferation and matrix remodeling. The collagen/DDR1 axis is also thought to modulate tumor-stromal interaction and potentially can affect tumor response to therapy. Mesothelin is a cell-surface tumor-associated antigen over-expressed in several human cancers including mesothelioma, ovarian, lung, breast, and pancreatic cancers with limited expression on normal cells. RG7787 is a clinically optimized recombinant immunotoxin (RIT) being developed in collaboration with Roche that should enter clinical trials late this year. It consists of a humanized anti-mesothelin Fab fused to domain III of Pseudomonas exotoxin A in which immunogenic B cell epitopes are silenced. Activation of tyrosine kinase mediated signaling in tumor cells has been shown to modulate the activity of RITs. Therefore, we hypothesized that DDR1 regulates RIT activity and its inhibition might enhance the activity of RG7787. Knockdown of DDR1 by siRNA or its inhibition with a novel and specific inhibitor, ‘7rh’, synergistically enhanced the cytotoxic activity of RG7787 in several cancer cell lines. Investigation into the mechanism of action showed the knockdown of DDR1 increased mesothelin expression, internalization of RG7787, and enhanced inhibition of protein synthesis. Furthermore, stimulation of DDR1 activity by collagen treatment protected cancer cells from killing by RG7787. However, this collagen mediated resistance of cancer cells to RIT therapy can be overcome by addition of 7rh. Combination of 7rh with RG7787 synergistically inhibited growth of A431/H9 tumors in nude mice. In conclusion, we report that collagen protects cells from killing by RITs through DDR1 and that lowering DDR1 protein or inhibiting DDR1 kinase activity enhances the cytotoxic activity of RITs. Our data suggest that the combination of ‘7rh’ and RG7787 represents a novel therapeutic strategy to target mesothelin-expressing cancers. These data also provide insight into how tumor stroma might be protecting cancer cells from therapy. Citation Format: Fatima G. Ali-Rahmani, David Fitzgerald, Scott Martin, Paresma Patel, Craig Thomas, Ira Pastan. Inhibition of collagen receptor discoidin domain receptor-1 (DDR1) tyrosine kinase enhances cytotoxicity of anti-mesothelin immunotoxin for cancer therapy. [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 5357. doi:10.1158/1538-7445.AM2015-5357
Defibrotide Counteracts the Modifications of Anti-Thrombotic Phenotype of Endothelial Cells Induced by Thalidomide.
Authors: Cinara Echart, Barbara Graziadio, Cinzia Repice, Mario Boccadoro, Antonio Palumbo, Constantine Mitsiades, Kenneth Anderson, Paul Richardson, Massimo Iacobelli
Journal: Blood (2007)
Acute Portal Vein Thrombosis (PVT) Causing Acute on Chronic Liver Failure: Is There a Role for Liver Transplantation?
Authors: Madhusudhanan Jegadeesan, Hitendra Kumar Garg, Shaleen Agrawal, Neerav Goyal, Subash Gupta
Journal: Clinical Gastroenterology and Hepatology (2016)
546. Development of MFP-Inducible System for AAV5 Gene Therapy of Chronic Diseases in the Liver
Authors: Jolanda Liefhebber, Raygene Martier, Richard vanLogtenstein, Harald Petry, Pavlina Konstantinova
Journal: Molecular Therapy (2016)

Introduction: Gene therapy offers long term solutions for chronic diseases, whereby the transgene is continuously expressed upon single vector administration. However in some cases it would be desirable to tightly regulate or switch off transgene expression. Methods: We are investigating regulated gene expression based on the mifepristone (MFP)-inducible GeneSwitch system. The GeneSwitch protein comprises yeast Gal4 DNA-binding domain, a human p65 activation domain and a MFP controlled domain derived from the human progesterone receptor. The classical GeneSwitch system consists of two expression cassettes on two separate vectors; one containing the GeneSwitch sequence and one containing the transgene. We compared this two-vector system to a single-vector system, where the two cassettes were put into one vector for efficacy in vitro and in vivo. Results: We show inducible expression of EPO, IGF and GNDF obtained in vitro upon addition of MFP to cells transfected with plasmids containing GeneSwitch and the gene expression cassette. The kinetics of EPO mRNA and protein expression followed a dose dependent fashion in the range of 0.1 to 10 nM MFP and reached a plateau at higher MFP concentrations. Surprisingly, the GeneSwitch protein expression decreased 48h after MFP induction. The indicibility of the single versus the two-vector system of GeneSwitch-EPO was compared. Both systems were equally inducible based on total amount of EPO produced in the presence of MFP and related to background expression in the absence of MFP. In vivo proof of concept was obtained for EPO in the liver. EPO is characterized by clear expression kinetics in plasma and raises blood hematocrit, hence provides a reliable in-life read-out for gene inducibility. Mice were injected with different doses of AAV5-AAT-GeneSwitch-EPO and gene expression was induced in two separate rounds at 4 and 8 weeks p.i. EPO plasma levels increased approximately 2-logs in the single or two-vector system-injected mice, compared to un-induced groups. Moreover in the absence of MFP background expression of EPO was lower in the single-vector system and hematocrit levels were unaffected. Measurements of MFP in tissue matrices and in plasma by mass spectrometry show the presence of MFP in plasma and liver, validating applicability of the GeneSwitch system in the liver. Conclusion: Overall, our data indicate that transgene expression can be repeatedly regulated in the liver using the GeneSwitch system and provides us with a novel AAV5 vector for further development.
Real World Data of Daclatasvir and Asunaprevir Combination Therapy for HCV Genotype 1b Infection in Patients With Renal Dysfunction
Authors: Masatoshi Ishigami, Kazuhiko Hayashi, Takashi Honda, Teiji Kuzuya, Yoji Ishizu, Tetsuya Ishikawa, Isao Nakano, Fumihiro Urano, Takashi Kumada, Kentaro Yoshioka, Hidemi Goto, Yoshiki Hirooka
Journal: Clinical Gastroenterology and Hepatology (2016)
Colchicine delays hepatocellular carcinoma
Authors: D. Domville, O. Arrieta, J. L. Rodríguez, V. Rosas, S. Ponce de León, D. Kershenobich, X. Gómez-Roel, E. León-Rodríguez
Journal: Journal of Clinical Oncology (2005)

4169 Background: Hepatocellular carcinoma (HCC) is a malignant neoplasia that is associated with liver cirrosis in up to 60–80% of the cases. The incidence of HCC varies between 3 and 9% and it is one of the principal causes of death in patients with cirrhosis. The viral causes of liver cirrhosis, particularly by infection of hepatitis C virus, are associated with a greater risk of HCC, the pathologic mechanisms involved are probably a consequence of the inflammatory reaction. Colchicine is an anti-inflammatory agent, which inhibits the formation of intracellular microtubules, causing disturbances in the process of mitosis and in the formation of fibrosis. Diverse random studies have failed to demonstrate if colchicine has any benefit over mortality in patients with liver cirrhosis of any etiology. Methods: We made a retrospective study of a cohort of 350 patients with postnecrotic liver cirrhosis, to evaluate the effect of the administration of colchicine over the time of HCC development. We analyzed the clinical and pathological factors that are associated with the presence of hepatocarcinoma. Results: The average follow-up was of 84+/- 2.8 months. Two hundred and twenty patients received 1mg during 5 days per week of colchicine and 130 patients just received symptomatic treatment. The patients who received colchicine had the same Child- Pugh classification that the group that didn’t. Colchicine didn’t affect the progression of the Child score, during the first three years of follow-up. The percentage of patients that develop HCC was significantly less in the group who received colchicine in comparison with those that didn’t receive it (26 vs 10.3% p=0.0001). With the multivariate analysis we found that age greater than 52 and having less than 116 000 platlelets at the moment of diagnosis, as well as not receiving treatment with colchicine, were associated with developing HCC in lesser time. The protective mechanisms of colchicine over the development of HCC could be related with it’s effect as an anti-inflammatory drug and mithosis inhibition. Conclusions: Colchicine prevents the development of HCC, independently from the liver reserve nor the patient’ s age. No significant financial relationships to disclose.
Evaluation of Prospective Detection of PML-RARA and RARA-PML Fusion Transcripts by Real-Time Quantitative PCR (RQ-PCR) To Direct Pre-Emptive Therapy with Arsenic Trioxide (ATO) in Acute Promyelocytic Leukemia (APL) Patients Treated in the UK MRC AML15 Trial.
Authors: David J. Grimwade, J. Jovanovic, R. Hills, E. Nugent, Y. Patel, R. Flora, D. Diverio, K. Jones, H. Aslett, E. Sellwood, E. Solomon, F. Lo Coco, K. Wheatley, A. Burnett
Journal: Blood (2007)
On-target activity of neoadjuvant cixutumumab and combined androgen deprivation therapy for high-risk prostate cancer: A phase II trial.
Authors: J. P. Dean, R. B. Montgomery, J. Wan, P. Cohen, K. Haugk, J. M. Corman, W. J. Ellis, B. L. Dalkin, D. L. Ludwig, S. R. Plymate
Journal: Journal of Clinical Oncology (2011)

153 Background: IMC-A12 (cixutumumab) is a fully human monoclonal antibody which targets the insulin-like growth factor receptor 1. Preclinical data suggests that the combination of androgen deprivation and IMC-A12 is much more effective than either treatment alone. This clinical trial tests the effectiveness of the combined treatment in a neoadjuvant fashion before radical prostatectomy. We have assayed serum samples from the first 18 patients to identify signs of on-target activity in this setting. Methods: Eligible men with high risk localized prostate cancer are defined by one of the following: Gleason score ≥ 8, PSA ≥ 20, Clinical Stage T2c-T3, or a risk for relapse exceeding 50% as defined by the Kattan nomogram. Men are treated for 3 months with goserelin, bicalutamide, and biweekly IMC-A12 infusions (10 mg/kg). The primary objective of the trial is to determine the rate of pathological complete response with an accrual goal of 28 men. Using samples from the first 18 patients on study, serum protein markers were assayed by ELISA and serum PSA and glucose levels were determined by clinical laboratory analysis. Results: Significant increases in c-peptide (1.7-fold, p&lt;0.01), IGF-I (4.1-fold, p&lt;0.01), IGF-II (1.32-fold, p&lt;0.001), IGFBP-3 (1.9-fold, p&lt;0.01), growth hormone (8-fold, p&lt;0.01) were noted after initiation of ADT+IMC-A12, compared to pre-treatment levels. Non-significant increases of insulin (1.9-fold), IGFBP-1 (2-fold), and glucose (1.24-fold) levels were seen. Stratification of patients by nadir PSA levels correlated with residual tumor volume, likelihood of positive surgical margins and likelihood of lymph node metastases. Interestingly, patients with lower nadir PSA levels had smaller increases in c-peptide (50%, p&lt;0.01), insulin (66%, p&lt;0.02) and blood sugar (21%, P&lt;0.01) compared to the patients with higher nadir PSA levels. Conclusions: Combined with ADT in the neoadjuvant setting, IMC-A12 effectively targets the IGF-1R axis in prostate cancer patients. Metabolic differences between patients may alter the efficacy of IMC-A12 in this setting. [Table: see text]
Long-Term Clonal Evolution of Circulating Follicular Lymphoma-Like B Cells in Healthy Individuals: An Early Pathway to Lymphomagenesis.
Authors: Sandrine Roulland, Julie Agopian, Mélanie Briand, Jean-Marc Navarro, Yannick Lecluse, Pascal Gauduchon, Pierre Lebailly, Bertrand Nadel
Journal: Blood (2007)
Abandoning Care in Laminar Air Flow (LAF) Units and Routine High Dose Intravenous Immunoglobulines (IVIG) in Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) Does Not Increase Mortality and Rate of Infections.
Authors: Nathan Cantoni, Jakob Passweg, Maja Weisser, Armin Droll, Susanne Christen, Andreas Widmer, Ursula Flueckiger, Reno Frei, André Tichelli, Alois Gratwohl
Journal: Blood (2004)
418. Effective Treatment of Oligometastatic Melanoma Using Combination VSV Viroimmunotherapy and Stereotactic Radiotherapy
Authors: Kevin G. Shim, Rosa Diaz, Shane Zaidi, Miran Blanchard, Michael Grams, Timothy Kottke, Jill Thompson, Svetomir N. Markovic, Richard G. Vile
Journal: Molecular Therapy (2015)

Oligometastatic (OM) disease represents an intermediate stage of progression between fully systemic metastasized disease and localized tumor burden. Clinical data is emerging that patients with OM are potentially curable, in part because of advances in the precision of radiation therapy treatment, and in part because of advances in the efficacy of immunotherapy on low burden systemic disease. We developed a model of OM melanoma by challenging mice both locally (subcutaneous injection) and systemically (intravenous injection) with B16 melanoma cells, resulting in both local tumor burden and a small number of prominent, systemically distributed lung metastases. We used this model to investigate whether systemic viroimmunotherapy, using Vesicular Stomatitis Virus (VSV) expressing tumor associated antigens to treat low level metastatic tumor burden, could be combined with clinically relevant stereotactic body radiation therapy (SBRT) to treat advanced local disease. In this respect, mice treated with only one treatment modality (systemic VSV-TAA, or local SBRT) needed to be sacrificed reproducibly due to progression of the untreated disease (local tumor or systemic metastatic disease, respectively). In contrast, mice treated with a combination of VSV-TAA and SBRT entered long-term remission resulting in apparent cure of tumor in up to 100% of mice depending upon the experiment. Increased lymphocyte, and CD45+ leukocyte infiltration was observed in tumors following both SBRT and VSV therapy 6-10 days following therapy. Experiments to delineate the role of immune cell subsets in the successful therapy are underway. In a significant proportion of mice, systemic VSV-TAA therapy was able to control local tumor, provided it was small at the start of therapy. SBRT was rarely able to have an impact upon the treatment of metastatic disease suggesting that, in this model, radiotherapy was not the dominant immunotherapy. However, treating mice with VSV-TAA was able to stimulate a detectable anti-tumor T-cell IFN-γ memory response. We plan to further investigate the immunogenicity of VSV-TAA treatment in the context of SBRT as part of a prime-boost immunotherapy strategy for OM disease. Therefore, we have developed a successful therapeutic regime to treat oligometastic disease that combines both radiotherapy to treat local disease, and systemic viroimmunotherapy to treat low-level metastatic disease and further studies to potentiate the anti-tumor effector response in vivo are in progress.
Activation of mTOR Signaling Pathway Contributes to Tumoral Cell Survival in ALK-Positive Anaplastic Large Cell Lymphoma.
Authors: Francisco Vega, L. Jeffrey Medeiros, Coralyn Atwell, Jeong Hee Cho, Ling Tian, Francois-Xavier Claret, George Z. Rassidakis
Journal: Blood (2005)
98. Bortezomib Enhances AAV Vector Mediated Transduction But Inhibits the Secretion of Transgene Product
Authors: Yuanqing Lu, Ahmed S. Elshikha, George W. Marek, Mohammad A. Akbar, Guohua An, Mark Louis Brantly, Sihong Song
Journal: Molecular Therapy (2015)

Adeno-associated virus (rAAV) mediated gene therapy has shown promise for the treatment of alpha1 antitrypsin deficiency (AATD). Sustained alpha 1 antitrypsin (AAT) expression has been achieved in clinical trails, but the serum AAT concentrations do not reach therapeutic levels. Enhancing transduction efficiency is critical to developing a successful treatment. Since rAAV transduction may be limited by the proteasome, which degrade AAV capsids, we tested the effect of proteasome inhibitors on rAAV mediated AAT production. We treated HeLa and 293 cells with proteasome inhibitors including bortezomib and infected HeLa cells with rAAV2-GFP, rAAV2-AAT or AAV1-AAT and we Infected 293 cells with rAAV2-AAT. We measured AAT in the medium and the lysates of cells. Consistent with previous reports, bortezomib significantly enhanced AAV2 mediated GFP transduction in Hela cells. In rAAV-AAT infected cells, bortezomib treatment resulted in 9.7-13.1 fold increase in of intracellular AAT, while only modest (1.16-1.6 fold) increases of secreted AAT compared to that in cells without bortezomib. Similarly, intramuscular injection of rAAV1-AAT to C57BL6 mice treated with bortezomib also resulted in a small (~1 fold) increases in serum AAT compared with no treatment. These results indicate that bortezomib inhibited AAT protein secretion. To test the role unfolded protein response (UPR) in AAT accumulation, we measured UPR-related genes and showed that bortezomib treatment increased the mRNA levels of the protein chaperone and UPR sensor GRP78 (BiP) indicating an activation of ER stress pathways. Together, our results indicate that bortezomib can enhance rAAV transduction, but it can also inhibit the secretion of transgene product, which will limit the application of this drug for enhancing the efficiency of certain gene therapy, such as alpha 1 antitrypsin gene therapy.