tbuckley/cabot-search huggingface dataset:
Celecoxib and sulindac sulfide enhance the cytotoxic effect of standard chemotherapeutic agents and possess anti-tumor activity mediated by p21<sup>cipl/waf1</sup> expression
Authors: D. Trask, J. Bock, P. Goswami, S. Menon
Journal: Journal of Clinical Oncology (2004)

3186 Background: Standard treatment modalities for head and neck cancer remain surgery, radiation, and chemotherapy. While surgical techniques, delivery of radiation, and chemotherapy options have expanded, survival rates remain stagnant. Targeted therapy with novel anticancer molecules show future promise. However, in the interim, any agent added to improve conventional treatment, without significant side effects, is a needed addition. NSAIDs are demonstrating chemopreventative and therapeutic benefits with low side-effect profiles, however, the mechanisms underlying these effects are poorly understood. Methods: In vitro growth inhibition of celecoxib and sulindac sulfide, alone and in combination with docetaxel and VP-16, were assayed by growth curve analysis and the MTT assay. Apoptosis was measured by sub-Go DNA accumulation and the production of activated caspase-3. Cell cycle distribution was performed with flow cytometry of PI stained cells. Protein levels of p21, p53, Rb, cyclin D, COX-2, and COX-1 were determined by western analysis. In vivo tumor growth inhibition was analyzed by volume changes in flank xenograft tumors in nude mice. Results: Celecoxib and sulindac sulfide inhibit the growth of UM-SCC-1 cells in a dose dependent fashion accompanied by an increase in apoptosis. This growth inhibition correlates with a G1 blockade which is accompanied by transcriptional activation of p21cip1/waf1without induction of p53 in this wild-type p53 cell line. Celecoxib and sulindac sulfide cause additive growth inhibition when combined with VP-16 and docetaxel. Animal studies correlate with in vitro studies with regard to protein induction and growth suppression. Conclusions: Celecoxib and sulindac sulfide can be combined with standard chemotherapeutic agents to increase apoptosis in head and neck cancer cells and tumors. Growth inhibition is accompanied cell cycle arrest in G1 and induction of p21cip1/waf1in a p53-independent pathway. These pre-clinical studies form the foundation for future clinical trials. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Pharmaceuticals, Inc. Aventis Pharmaceuticals, Inc.
Abstract 1770: A role of nicotinamide phosphoribosyltransferase in growth of KRAS mutant non-small cell lung cancer
Authors: Shunsuke Okumura, Takaaki Sasaki, Yoshinobu Ohsaki
Journal: Cancer Research (2015)

Abstract Background: KRAS mutations are frequently found in non-small cell lung cancer (NSCLC). The KRAS mutations could be predictive of resistance to targeted therapy like epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) or a prognostic factor in NSCLC. No successful targeted therapy currently exists to treat patients with KRAS mutant NSCLC, and novel therapeutic strategies are needed to prolong survival in patients with KRAS mutant NSCLC. Nicotinamide phosphoribosyltransferase (nampt) is a rate-limiting enzyme in NAD+ salvage, and we previously reported that nampt is a potent therapeutic target in NSCLC. Based on the analysis result of GEO database, we found that expression of nampt is associated with RAS-MAPK signaling pathway in NSCLC, and we therefore, conducted an in vitro study to evaluate a role of nampt in growth of KRAS mutant NSCLC. Methods: We used a panel of KRAS mutant NSCLC cell lines (A427, A549, H157, H23, H1792, H2009, H358, H441, Calu6, Calu1). The cells were treated with a nampt inhibitor, FK866, and acid phosphatase (APH) assay (Thermo SCIENTIFIC) was used to evaluate cell viability of the KRAS mutant cells. Changes in expression of MAPK signaling pathway and BCL2 family proteins (antibodies from Cell Signaling and Santa Cruz) were evaluated by western blot. Apoptosis of the cells treated with FK866 was detected using an Annexin V FITC apoptosis detection kit (BD Biosciences). FACS analysis was performed using a BD FACSAria II cytometer (BD Bioscience). Autophagic proteolysis was studied by Cyto-ID autophagy detection kit (Cosmo Bio), and the expression of the fluorescent signal was visualized by a FV1000 confocal microscope (OLYMPUS JAPAN). Results: We found that the sensitivity to FK866 was different among the KRAS mutant cell lines, and for instance, A427 cells were sensitive while H157 cells were resistant. FK866 suppressed growth of KRAS mutant NSCLC and decreased expression of p-ERK expression in the cell line sensitive to FK866. We will report alteration of apoptosis and autophagy in the KRAS mutant NSCLC treated with FK866. Conclusion: Nampt could be a potent therapeutic target in KRAS mutant NSCLC. Citation Format: Shunsuke Okumura, Takaaki Sasaki, Yoshinobu Ohsaki. A role of nicotinamide phosphoribosyltransferase in growth of KRAS mutant non-small cell lung cancer. [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 1770. doi:10.1158/1538-7445.AM2015-1770
Meta-Analysis of Hodgkin Lymphoma and Asthma Genome-Wide Association Scans reveals common variants in GATA3
Authors: Yinfei Kong, Pouya Khankhanian, Daniel Himmelstein, Amie E. Hwang, Kristin A Rand, Dalin Li, David J. Van Den Berg, Arjan Diepstra, David V. Conti, Smita Bhatia, Pierre-Antoine Gourraud, Sally L. Glaser, Thomas M. Mack, Jorge Oksenberg, Kenan Onel, Anke Van Den Berg, Ruth F. Jarrett, James D. McKay, Henrik Hjalgrim, Sergio Baranzini, Frank D. Gilliland, W. James Gauderman, Wendy Cozen
Journal: Blood (2014)
223. Duration of Factor IX Expression in Macaques Following AAV8-Mediated Liver Transduction
Authors: Hiroaki Mizukami, Tsukasa Ohmori, Ryosuke Uchibori, Yasushi Saga, Masashi Urabe, Akihiro Kume, Yoichi Sakata, Keiya Ozawa
Journal: Molecular Therapy (2016)

We have been evaluating the efficacy and safety of hemophilia gene therapy using macaques, and demonstrated that liver-targeted approach with AAV8-based vector has resulted in therapeutic level of factor IX expression at the practical vector doses. Another important finding is the inhibitory effect of neutralizing antibody (NAb) against AAV capsid upon AAV vector-based gene transfer approach; none of the subjects with positive NAb showed recognizable transgene expression following IV injection of the vector. At this stage, one of the most crucial questions is the duration of this therapeutic modality. As this approach utilizes hepatocyte transduction by a non-integrating vector, the length of this therapy should depend on the lifetime of the transduced cells. During the series of experiment, we observed 5 animals for long-term outcome (longer than 3 years). All of these animals showed therapeutic levels of factor IX expression following vector injection, and the expression levels lasted throughout the observation period in all of the animals. In one animal, the expression level was kept constant within therapeutic level for more than 7 years. No adverse effect was observed in any of the animals. These findings suggest long-term efficacy and safety of this therapeutic approach, supporting application to human treatment. This study was performed in collaboration with Tsukuba Primate Research Center, National Institute for Biomedical Innovation, and The Corporation for Production and Research of Laboratory Primates, Japan.
113. Potent Therapeutic Efficacy of Neurotensin Receptor-Targeting and Extracellular Matrix-Degrading Oncolytic Adenovirus in an Orthotopic Pancreatic Tumor Model
Authors: Youjin Na, Joung-Woo Choi, Dayananda Kasala, Jinwoo Hong, Eonju Oh, Yan Li, Soo-Jung Jung, Sung Wan Kim, Chae-Ok Yun
Journal: Molecular Therapy (2016)

Pancreatic cancer is highly aggressive, malignant, and notoriously difficult to cure using conventional cancer therapies. These conventional therapies have significant limitations due to excessive extracellular matrix (ECM) of pancreatic cancer and poor cancer specificity. The excess ECM prevents infiltration of drugs into the inner layer of the solid tumor. Therefore, novel treatment modalities that can specifically target the tumor and degrade the ECM are required for effective therapy. In the present study, we used ECM-degrading and Wnt signal-disrupting oncolytic adenovirus (oAd/DCN/LRP) to achieve a desirable therapeutic outcome against pancreatic cancer. In addition, to overcome the limitations in systemic delivery of oncolytic Ad (oAd) and to specifically target pancreatic cancer, neurotensin peptide (NT)-conjugated polyethylene glycol (PEG) was chemically crosslinked to the surface of Ad, generating a systemically injectable hybrid system, oAd/DCN/LRP-PEG-NT. We tested the targeting and therapeutic efficacy of oAd/DCN/LRP-PEG-NT toward neurotensin receptor 1 (NTR)-overexpressing pancreatic cancer cells, both in vitro and in vivo. The oAd/DCN/LRP-PEG-NT elicited increased NTR-selective cancer cell killing and increased transduction efficiency when compared with a cognate control lacking NT (oAd/DCN/LRP-PEG). Furthermore, systemic administration of oAd/DCN/LRP-PEG-NT significantly decreased induction of innate and adaptive immune responses against Ad, and blood retention time was markedly prolonged by PEGylation. Moreover, NTR-targeting oAd elicited greater in vivo tumor growth suppression when compared with naked oAd, and 9.5×106-fold increased tumor-to-liver ratio. This significantly enhanced antitumor effect of oAd/DCN/LRP-PEG-NT was mediated by active viral replication and viral spreading, which was facilitated by ECM degradation and inhibition of Wnt signaling-related factors (Wnt, β-catenin, and/or vimentin) in tumor tissues. Taken together, these results demonstrate that oAd/DCN/LRP-PEG-NT has strong therapeutic potential for systemic treatment of NTR-overexpressing pancreatic cancer, due to its NTR-targeting ability, enhanced therapeutic efficacy, and safety.
A phase II study to evaluate the efficacy and safety of catumaxomab as consolidation treatment in patients with epithelial ovarian cancer in second or third complete remission.
Authors: A. M. Oaknin, L. Chiva, I. Romero, A. Romero, M. M. Essing, A. González-Martín
Journal: Journal of Clinical Oncology (2011)

TPS195 Background: Patients with epithelial ovarian cancer (OC) in 2nd or 3rd complete remission (CR) present with minimal residual disease that cannot be eliminated with standard chemotherapy and is responsible for a recurrence in almost every patient, with a median progression-free survival (PFS) of 10 months. The trifunctional antibody catumaxomab (anti-EpCAM x anti-CD3) administered as an intraperitoneal (i.p.) infusion has proven to be effective in patients with refractory tumors and recurring malignant ascites and was approved by the European Medicines Agency in April 2009. The purpose of this phase II study is to estimate the clinical benefit of consolidation treatment with catumaxomab in patients with epithelial OC in 2nd or 3rd CR. Methods: A planned number of 35 assessable patients with epithelial OC in 2nd or 3rd CR will be included and documented. The study comprises a 14-day selection period, an 11-day treatment phase, a toxicity follow-up phase of 28 days from the last dose of catumaxomab, and subsequent follow-up every 3 months until disease progression, determined by RECIST. Catumaxomab will be administered as an i.p. infusion over 3 hours at a constant rate through a fixed polyurethane silicon-coated catheter, which will be inserted under ultrasound guidance during the selection period or at the latest in the morning of the day of the first infusion. The catheter will remain in the peritoneal cavity during the entire treatment period. The primary objective is to determine the clinical benefit of catumaxomab treatment in these patients, assessed by PFS and the percentage of progression-free patients at 12, 18 and 24 months. The duration of PFS with catumaxomab will be compared individually for each patient to that observed during the previous CR. Secondary endpoints are safety, compliance, treatment-free interval and overall survival rate. In addition, translational research will be performed to correlate tumor-infiltrating lymphocytes (TILs) in the primary tumor and lymphocyte subpopulations in serum with the efficacy of catumaxomab. The trial is actively recruiting and an interim analysis of the first 6 patients enrolled is planned.
Nilotinib and Dasatinib Produce Synergistic Growth-Inhibitory Effects In Imatinib-Resistant CML Cells, Including Subclones Bearing the Multi-Resistant BCR/ABL Mutant T315I
Authors: Karoline V. Gleixner, Harald Herrmann, Irina Sadovnik, Karina Schuch, Winfried F Pickl, Christian Sillaber, Peter Valent
Journal: Blood (2010)
<i>Opisthorchis felineus</i> negatively associates with skin test reactivity in Russia—EuroPrevall‐International Cooperation study
Authors: O. S. Fedorova, J. J. Janse, L. M. Ogorodova, M. M. Fedotova, R. A. Achterberg, J. J. Verweij, M. Fernández‐Rivas, S. A. Versteeg, J. Potts, C. Minelli, R. van Ree, P. Burney, M. Yazdanbakhsh
Journal: Allergy (2016)

Abstract Background Most studies on the relationship between helminth infections and atopic disorders have been conducted in (sub)tropical developing countries where exposure to multiple parasites and lifestyle can confound the relationship. We aimed to study the relationship between infection with the fish‐borne helminth Opishorchis felineus and specific IgE, skin prick testing, and atopic symptoms in Western Siberia, with lifestyle and hygiene standards of a developed country. Methods Schoolchildren aged 7–11 years were sampled from one urban and two rural regions. Skin prick tests ( SPT ) and specific IgE ( sIgE ) against food and aeroallergens were measured, and data on allergic symptoms and on demographic and socioeconomic factors were collected by questionnaire. Diagnosis of opisthorchiasis was based on PCR performed on stool samples. Results Of the 732 children included, 34.9% had opisthorchiasis. The sensitization to any allergen when estimated by positive SPT was 12.8%, while much higher, 24.0%, when measured by sIgE . Atopic symptoms in the past year (flexural eczema and/or rhinoconjunctivitis) were reported in 12.4% of the children. SPT was positively related to flexural eczema and rhinoconjunctivitis, but not to wheezing. Opisthorchiasis showed association with lower SPT response, as well as borderline association with low IgE reactivity to any allergen. However, the effect of opisthorchiasis on SPT response was not mediated by IgE, suggesting that opisthorchiasis influences SPT response through another mechanism. Opisthorchiasis also showed borderline association with lower atopic symptoms. Conclusions There is a negative association between a chronic helminth infection and skin prick test reactivity even in a developed country.
303. Deletion of Pdx1 in Mouse Pancreatic Ducts by CRISPR-Cas9 Mediated Gene Editing
Authors: Aiping Lu, George K. Gittes, Johnny Huard, Ping Guo
Journal: Molecular Therapy (2016)

Introduction: The homeodomain transcription factor Pdx1 is crucial for pancreas formation. Pdx1-expressing cells are first observed at embryonic day 8.5 (E8.5), prior even to the earliest indication of morphogenesis, in endodermal cells designated to give rise to the pancreas. In adult mouse, Pdx1 protein is transiently expressed when pancreas is injured, such as Langerhans islets damage in alloxan induced diabetic mice, implying Pdx1 may be necessary for the neogenetic formation of β-cells from mature ducts. In order to study the role of pdx1 in the pancreatic duct for pancreatic regeneration, most investigators use the Cre-lox system to generate duct-specific Pdx1 deletions in mice. This method is able to delete Pdx1specifically from tissue or cells with or without a tamoxifen-inducible (cre-ERT2) system; however, several caveats and limitations exist with tamoxifen-induced depletion. In addition, the cre-ERT2 system may be leaky, resulting in constitutive rather than inducible activation in some cells. To overcome these flaws from the Cre-ERT2/lox system, we decided to use a novel CRISPR-Cas9 gene editing technique to delete pdx1 in pancreatic ducts. Methods: We previously used a mouse short Sox9 promoter (468 bp) to generate a recombinant adeno-associated virus (AAV) carrying a reporter GFP (AAV6-Sox9-GFP), and this recombinant virus construct was infused into the pancreatic ducts, through the common bile/pancreatic duct, to specifically tag the duct cells. In order to address pancreatic duct specific deletion of Pdx1 after alloxan ablation of beta-cells, we first to applied the CRISPR-Cas9 gene editing technique on the HEK293-CMV-GFP cell line in vitro (Figure 2) and ROSA26 LSL tomato reporter mice ex vivo (Figure 3), and then employed AAV6 mediated CRISPR-SaCas9 under the control of the mouse sox9 short promoter, coupled with paired guide RNAs (gRNAs) flanking the Pdx1 exon2 (Figure 4) through pancreatic duct infusion into the pancreas. RESULTS AND CONCLUSIONS: These CRISPR-SaCas9 and gRNAs AAV viruses were co-infused into pancreases of C57BL/6J mice 2 days after alloxan treatment. One week after AAV6-SaCas9+gRNAs infusion, it appeared that only the Pdx1 in pancreatic ductal cells were deleted. Comparatively, PBS or AAV6-CMV-GFP viral infused C57BL/6J mice and ROSA26 LSL tomato reporter mice expressed fluorescence in the entire pancreas as a result of the deleted loxP sites that removed the stop cassette, the Pdx1 is not deleted. Thus, we first report here a highly efficient and specific ablation of Pdx1 in adult mouse pancreatic ducts using the CRISPR-Cas9 technique. Figure 1. Construction of AAV CRISPR-SaCas9 and gRNA vectors. Figure 2. Deletion of ZsGeen in HEK293-CMV-GFP cells using SacCas9 and gRNA in vitro. Figure 3. Valiation of SaCas9 and gRNA in vivo deletion of loxP sites in ROSA26-LSL tomato mice pancreas. Figure 4. Deletion of Pdx1 exon2 in alloxan treated C57 pancreatic ducts.
Abstract 504: Glutamine metabolic inhibitors suppress growth and tumorigenicity in MYC and MYCN-driven pediatric malignancies
Authors: Allison Hanaford, Catherine Guerra, Charles Eberhart, Eric Raabe, Antoinette Price
Journal: Cancer Research (2015)

Abstract The MYC family of oncogenes is associated with aggressive pediatric cancers such as medulloblastoma and neuroblastoma. These transcription factors promote oncogenesis in part by altering cellular metabolism. In multiple types of cancer, high-level MYC expression drives increased glutamine metabolism. We hypothesized that MYC-driven medulloblastoma and MYCN amplified neuroblastoma would be sensitive to the glutamine metabolic inhibitors 6-diazo-5-oxo-l-norleucine (DON) and Acivicin. These drugs have previously be used in pediatric clinical trials, but never extensively clinically tested in MYC-driven malignancies. The high MYC medulloblastoma cell lines D425Med and D283Med experienced an 82% decrease in growth as measured by MTS assay when treated with Acivicin or DON (p&amp;lt;0.004). DON and Acivicin treatment also caused a 400% increase in apoptosis as measured by cleaved caspase-3 immunofluorescence (p&amp;lt;0.03). In human neural stem cells transformed with MYC, Acivicin treatment decreased proliferation by 50% as measured by BrdU incorporation (p&amp;lt;0.003) and increased apoptosis by over 100% as measured by cleaved caspase-3 immunofluoresence (p&amp;lt;0.0001). Human neural stem cells immortalized with SV40 were unaffected by Acivicin and DON treatment (p = 0.1). In mice with D283Med flank xenografts, Acivicin decreased the size of tumors by 70%. DON treatment decreased the volume of flank tumors by 94% in animals with D425Med xenografts (p = 0.001). In mice with D425Med cerebellar xenografts (p = 0.0018), DON tripled median survival from 26 to 90 days in animals with. The MYCN amplified neuroblastoma cell lines LAN5 and IMR32 were also sensitive to treatment with DON and Acivicin. DON and acivicin treatment significantly decreased proliferation as measured by BrdU incorporation (p&amp;lt;0.03) and significantly increased apoptosis as measured by cleaved caspase-3 immunofluroescence (p&amp;lt;0.003). The non-MYCN amplified neuroblastoma cell line SKNAS was resistant to treatment with both DON and Acivicin, suggesting that expression confers sensitivity to glutamine analogs. These data suggest glutamine metabolism is a therapeutic target in medulloblastoma and neuroblastoma with elevated MYC or MYCN levels, and potentially other pediatric cancer types associated with MYC oncogenes. Citation Format: Allison Hanaford, Catherine Guerra, Charles Eberhart, Eric Raabe, Antoinette Price. Glutamine metabolic inhibitors suppress growth and tumorigenicity in MYC and MYCN-driven pediatric malignancies. [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 504. doi:10.1158/1538-7445.AM2015-504
Integrated Analyses Identify a Master MicroRNA Regulatory Network for the Mesenchymal Subtype in Serous Ovarian Cancer
Authors: Da Yang, Yan Sun, Limei Hu, Hong Zheng, Ping Ji, Chad V. Pecot, Yanrui Zhao, Sheila Reynolds, Hanyin Cheng, Rajesha Rupaimoole, David Cogdell, Matti Nykter, Russell Broaddus, Cristian Rodriguez-Aguayo, Gabriel Lopez-Berestein, Jinsong Liu, Ilya Shmulevich, Anil K. Sood, Kexin Chen, Wei Zhang
Journal: Cancer Cell (2013)