tbuckley/cabot-search huggingface dataset:
Abstract 4362: Coordinated regulation of several microRNAs in lung cancer patients
Authors: Irene Ferrer, Ana Salinas, Angela Marrugal, Jon Zugazagoitia, Amancio Carnero, Luis Paz-Ares, Sonia Molina-Pinelo
Journal: Cancer Research (2017)

Abstract Background Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers. NSCLCs are mainly classified adenocarcinoma and squamous cell carcinoma. It seems more and more obvious that specific molecular analyses are necessary to elucidate the complexity of clinically relevant phenotypes which determine the lung carcinogenesis. This includes the role of microRNAs (miRNAs) in the disease, involved in the complexity of gene expression regulation. Different modulator mechanisms are involved in the biogenesis and function of miRNAs, one of them is DNA methylation. Alterations in these mechanisms may contribute to the tumor genesis and progression. The purpose of this study was to assess miRNA methylation patterns in patients with NSCLC to study the potential of coordinate regulation of miRNAs as a relevant mechanism involved in this pathogenesis. Materials and Methods DNA methylation of gene clusters was analyzed by Illumina 70 subjects. The samples were divided into two cohorts. A first cohort constituted from 47 patients who had undergone surgical resection for clinical early stage NSCLC. A second group from 23 subjects was used as health cohort. DNA was extracted using the QIAamp DNA Mini Kit. For each assay, 500 ng of DNA was treated with sodium bisulfate using EZ DNA Methylation™ Kit and cleaned with ZR-96 DNA Clean-up Kit™, before standard Illumina amplification, hybridization, and imaging steps. Methylation data were processed using the RnBeads R package. Results We identified two clusters clearly corregulated by methylation in lung cancer, involving 49 miRNAs differentially hypomethylated in tumor samples respect to control tissue. Some of these miRNAs have been implicated in several pathways in cancer. Conclusions Our results strongly imply hypomethylation of two miRNA clusters, which represent key targets in unravelling of the mechanism of lung tumorigenesis. Citation Format: Irene Ferrer, Ana Salinas, Angela Marrugal, Jon Zugazagoitia, Amancio Carnero, Luis Paz-Ares, Sonia Molina-Pinelo. Coordinated regulation of several microRNAs in lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4362. doi:10.1158/1538-7445.AM2017-4362
Abstract 5146: Increasing penetration of anticancer drugs through sortilin receptor-mediated cancer therapy: A new targeted and personalized Approach in the treatment of ovarian cancer
Authors: Michel Demeule, Jean-Christophe Curie, Alain Larocque, Cyndia Charfi, Richard Béliveau, Claude Vezeau, Borhane Annabi
Journal: Cancer Research (2017)

Abstract The development of personalized therapies against ovarian cancer remains highly challenging in current modern oncology. One way to achieve greater selectivity and better anticancer drug delivery into cancer cells is to conjugate cytotoxic agents to specific peptide ligands that will selectively target receptors abundantly and/or exclusively expressed on these cells. Increased expression of Sortilin, a scavenging receptor, has been clinically observed in several human cancers including breast, prostate, colon, pancreas, skin, and pituitary. In particular, Sortilin has also been reported to be overexpressed in ovarian cancers as compared to non-malignant ovarian tissue. In light of this, we developed a peptide conjugation platform using a new Sortilin receptor-mediated vectorization strategy to increase cell targeting selectivity and cell delivery efficacy of anticancer agents. As a proof-of-concept, Doxorubicin was conjugated to peptide sequences, termed Katana peptides (KA). In vitro, significantly increased Sortilin mediated intracellular delivery of the Doxorubicin-Katana peptide conjugate (DoxKA) was observed in SKOV3 and ES-2 ovarian cancer cell line models, with conserved efficient Doxorubicin cytotoxic mechanism. Uptake of DoxKA in ES-2 ovarian cancer cells was reduced when Sortilin expression was specifically silenced by using siRNA or upon competition with the Sortilin ligands neurotensin and progranulin. In addition, DoxKA was found to bypass the P-glycoprotein (P-gp) efflux pump since, in contrast to Doxorubicin uptake in MDCK-MDR1 cells overexpressing the P-gp efflux pump, the uptake of DoxKA was unaffected by the P-gp inhibitor Cyclosporin A. In vivo, DoxKA was better tolerated and caused a more potent inhibition of human ovarian tumor xenografts growth than did Doxorubicin alone. These results provide strong evidence for the potential of this drug development platform in the generation of novel personalized therapeutics with specific targeting of SORT1-positive cancer cells. Citation Format: Michel Demeule, Jean-Christophe Curie, Alain Larocque, Cyndia Charfi, Richard Béliveau, Claude Vezeau, Borhane Annabi. Increasing penetration of anticancer drugs through sortilin receptor-mediated cancer therapy: A new targeted and personalized Approach in the treatment of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5146. doi:10.1158/1538-7445.AM2017-5146
Abstract 4820: Developing a xenograft human tumor model in immunocompetent mice
Authors: Matthew T. Basel, Sanjeev Narayanan, Chanran Ganta, Tej B. Shrestha, Marla Pyle, Stefan H. Bossmann, Deryl L. Troyer
Journal: Cancer Research (2017)

Abstract Animal models are essential to preclinical cancer research and are used clinically to determine optimal treatment regimens, but current xenograft models are limited in their utility, especially due to the lack of a competent immune system. Here we demonstrate that a xenograft tumor model can be developed in immunocompetent mice by tolerizing murine fetuses to human tumor cells. A375 human melanoma cells were injected into day E14 fetuses and, after birth, mice were challenged again with A375 cells to determine their ability to develop tumors. Intravenous injections of A375 cells after tolerization resulted in metastatic-like lung tumors, which were verified to be human in origin by immunohistochemistry and PCR. The development of lung neoplasms was dependent on fetal tolerization; non-tolerized mice did not develop tumors after injection. Interestingly, subcutaneous injected cells did not form tumors, but this was shown to be due to an innate, non-adaptive immune response and did not create lasting rejection of tumor cells. This procedure was repeated with several different tumor lines to show the universal nature of the method: BxPC3 (human pancreatic cancer), M21 (human melanoma), HeLa (human cervical cancer), and MDA231 (human breast carcinoma). Citation Format: Matthew T. Basel, Sanjeev Narayanan, Chanran Ganta, Tej B. Shrestha, Marla Pyle, Stefan H. Bossmann, Deryl L. Troyer. Developing a xenograft human tumor model in immunocompetent mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4820. doi:10.1158/1538-7445.AM2017-4820
Quality and Safety in Health Care, Part XXIX
Authors: Jay A. Harolds
Journal: Clinical Nuclear Medicine (2017)

The American College of Cardiology, the Society of Thoracic Surgeons, and other organizations cooperated to form the Transcatheter Valve Therapy Registry. This registry studies information on the outcome of valve therapy device placement with a transcatheter approach. The companies that manufacture these devices can use the registry to meet the post-product sale surveillance requirements of the US Food and Drug Administration. There will also be linkage to the registry information from the Society of Thoracic Surgeons Adult Cardiac Surgery Database, which has information on open cardiac valve surgery.
Abstract 934: EGFR induces ILF3 and G9a expressions to maintain Oct4-mediated stemness property in lung cancer
Authors: Chun-Chia Cheng, Jungshan Chang, Huan-Chau Lin, Ai-Sheng Ho, Ken-Hong Lim, Chun-Chao Chang, Yi-Fang Chang, Cheng-Wen Wu
Journal: Cancer Research (2017)

Abstract Cancer stem cells survive and lead to tumor recurrence in tumor therapeutic treatments. Lung cancer cells highly express epidermal growth factor receptor (EGFR), which is critical for tumor progression. We hypothesized that EGFR may play a pivotal role in the induction of cancer stemness cells (CSCs). The aim of this study attempted to investigate the molecular mechanism of EGFR-mediated cancer stemness, and to discover the potent therapeutic agents. A high expression level of cancer stemness markers, ALDH1, CD133, Oct4, and Nanog was observed in tumorspheres derived from HCC827. External EGF further elevated the expression of Oct4 in HCC827 cells. Moreover, chemical inhibition and genetic knockdown of EGFR reduced the Oct4 expression and also tumorsphere formation. We found that inhibitors targeting to EGFR (afatinib), ILF3 (YM155), and G9a (UNC0642) are potential to reduce the formations of tumorspheres. The results revealed that EGFR triggered the formation of tumorspheres through elevating the activations of G9a-mediated stemness genes. In addition, YM155 effectively inhibited tumor growth and formation of tumorspheres as an anti-lung cancer agent blocking the EGFR-G9a cell initiating program pathway. This study demonstrated that EGFR participated in maintain of cancer stemness property through expressing ILF3 and G9a expressions. YM155 inhibited the EGFR-G9a stemness pathway, and reduced the formation of tumorspheres as a potent anti-lung cancer agent. Citation Format: Chun-Chia Cheng, Jungshan Chang, Huan-Chau Lin, Ai-Sheng Ho, Ken-Hong Lim, Chun-Chao Chang, Yi-Fang Chang, Cheng-Wen Wu. EGFR induces ILF3 and G9a expressions to maintain Oct4-mediated stemness property in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 934. doi:10.1158/1538-7445.AM2017-934
Abstract 3730: Early metabolic response to tumor-treating fields in patients with recurrent glioblastoma
Authors: Sandeep Mittal, Geoffrey R. Barger, Edit Bosnyák, Varun B. Shah, Csaba Juhász
Journal: Cancer Research (2017)

Abstract PURPOSE. Tumor-Treating Fields (TTFields) is an FDA-approved treatment approach for patients with both newly-diagnosed and recurrent glioblastoma. The main purpose of the present study was to explore if amino acid positron emission tomography (PET) is able to detect an early, objective metabolic tumor response during the first months of TTFields therapy. METHODS. Patients with MRI signs of recurrent glioblastoma eligible for TTFields along with maintenance temozolomide were recruited for PET scanning with alpha[C-11]-methyl-L-tryptophan (AMT) at baseline (before start of TTFields application) and up to 3 months later. Serial MRIs were also performed in 1-2 months intervals. AMT accumulation in the MRI-detected tumor mass was measured by standardized uptake values (SUVs), and PET-based tumor volumes were also calculated. Interval changes of these PET variables were compared to changes in areas of MRI enhancement. RESULTS. Out of 7 recruited patients, 5 showed appropriate compliance (&amp;gt;75%) with the device and underwent follow-up PET. Four of the 5 patients showed a clear metabolic response during TTF treatment on PET imaging. Two patients, who received TTFields treatment only (in addition to maintenance temozolomide), showed 25% and 100% decrease of PET-based tumor volumes, respectively. MRI was stable (patient #1) or showed increasing contrast enhancement (#2) during the same period. In this latter patient, TTFields was continued with bevacizumab treatment, leading to decreased contrast enhancement and further decrease of AMT uptake on a second follow-up PET. In two other patients (#3 and #4), TTFields were combined with bevacizumab rescue treatment. Patient #3 showed a markedly decreased tumoral AMT uptake and metabolic volume along with stable MRI enhancement. Patient #4 showed interval decrease of tryptophan PET uptake 2 months after initiation of TTFields therapy. Finally, patient #5 showed an interval expansion of the PET-based tumor volume along with MRI progression during a 2-month follow-up despite TTFields combined with bevacizumab and carboplatin. CONCLUSIONS. This is the first study to demonstrate an objective metabolic response of recurrent glioblastoma within 1.5-3 months after initiation of TTFields. The data suggest that amino acid PET can identify early responders to TTFields therapy. Citation Format: Sandeep Mittal, Geoffrey R. Barger, Edit Bosnyák, Varun B. Shah, Csaba Juhász. Early metabolic response to tumor-treating fields in patients with recurrent glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3730. doi:10.1158/1538-7445.AM2017-3730
Abstract 5240: Induction of molecular endpoints by reactive oxygen species in human lung cells predicted by physical- chemical properties of engineered nanoparticles
Authors: Jeffrey A. Ross, Garret B. Nelson, Carlton Jones, Sheau-Fung Thai
Journal: Cancer Research (2017)

Abstract A series of six titanium dioxide and two cerium oxide engineered nanomaterials were assessed for their ability to induce cytotoxicity, reactive oxygen species (ROS), and various types of DNA and protein damage in human respiratory BEAS-2B cells exposed in vitro for 72 hours at several concentrations. Although only limited cytotoxicity was observed at concentrations up to 300 µg/ml for all of the nanomaterials, significant increases in 8-oxo-deoxyguanosine, lipid peroxidation mediated protein adducts, and endogenous DNA adducts measured by 32P-postlabeling were detected at concentrations as low as 30 µg/ml, suggesting that molecular changes associated with ROS induction may provide a better means of assessing the low-dose hazards posed by nanomaterials. To identify molecular properties predictive of the ability of nanoparticles to induce ROS sequelae, a least absolute shrinkage and selection operator multiple regression approach has been used to identify relationships between assay outcomes and nanoparticle physical/chemical properties, including particle size, surface area, zeta potential, and elemental analysis. For several of the assay endpoints examined, concentrations of trace metals in the nanoparticles appear to be better predictors of assay outcomes than physical properties. This is an abstract of a proposed presentation and does not necessarily reflect EPA policy. Citation Format: Jeffrey A. Ross, Garret B. Nelson, Carlton Jones, Sheau-Fung Thai. Induction of molecular endpoints by reactive oxygen species in human lung cells predicted by physical- chemical properties of engineered nanoparticles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5240. doi:10.1158/1538-7445.AM2017-5240
Abstract 21: Regulation of proliferation and invasion through the inhibition of IGF signaling pathway on Epstein-Barr virus associated gastric cancer
Authors: Inhye Jeong, Hoi Young Lee, Jae Kyung Roh, Tae Soo Kim, Suk Kyeong Lee, Woo-Ick Jang, Hyun Cheol Chung, Sun Young Rha
Journal: Cancer Research (2017)

Abstract Epstein-Barr virus associated gastric cancer (EBVaGC) is one subtype of four molecular classifications by TCGA group. Specifically, EBV related viral RNAs, microRNAs and proteins regulate cancer progression phenomena like aggressiveness, motility, invasion and metastasis. Nonetheless, understanding the mechanisms of viral growth dependency beyond malignant EBV transformation are still deficient. Finding the EBV dependent pathway with significant biological role and the clinically appropriated drug is needed for EBVaGC in this regard. We investigated new therapeutic target and its role of regulating in proliferation and invasion using EBVaGC cell line model. First, we determined proliferation both of AGS and EBV infected AGS (AGS-EBV) cell lines during 7 days by proliferation assay. For the test of BI836845 (IGF ligand neutralizing antibody, Boehringer Ingelheim, German) efficacy, CCK-8 assay was performed. mRNA expression levels of IGF-1R, IGF-1, IGFBP-3 and IGFBP-6 which is the key regulator of IGF-signaling were measured by RT-PCR. Also, protein expression levels of IGF associated and downstream factors were confirmed by Western blotting. Lastly, invasiveness of cells was detected by invasion assay. As a result, AGS-EBV showed the slower proliferation rate compared to AGS, but the sensitivity to BI836845 was significantly increased in a dose-dependent manner (p&amp;lt;0.001). Interestingly, baseline IGFBP-3 mRNA expression of was enhanced in AGS-EBV compared with AGS. In addition, BI836845 treated group showed up-regulated IGFBP-3 mRNA level in AGS and down-regulated IGFBP-3 mRNA level in AGS-EBV. When BI836845 treated to AGS-EBV, phospho-Akt level was highly inhibited. Moreover, invasiveness of AGS-EBV was elevated about 2 fold more than AGS. Treatment of BI836845 in AGS-EBV represented significant decrease the invasiveness (p=0.08). In conclusion, AGS-EBV seems to modulate their proliferation and invasion through the IGF signaling pathway. Inhibition of IGF signaling pathway would be the potential therapeutic strategy for EBV associated gastric cancer. Citation Format: Inhye Jeong, Hoi Young Lee, Jae Kyung Roh, Tae Soo Kim, Suk Kyeong Lee, Woo-Ick Jang, Hyun Cheol Chung, Sun Young Rha. Regulation of proliferation and invasion through the inhibition of IGF signaling pathway on Epstein-Barr virus associated gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 21. doi:10.1158/1538-7445.AM2017-21
Abstract 4056: A modulator of multidrug resistance protein 1 selectively depletes glutathione and synergizes with L-buthionine sulfoximine to sensitize MRP1-expressing cancer cells to chemotherapy
Authors: Christine C. Gana, Kimberley Hanssen, Denise M. Yu, Claudia Flemming, Murray Norris, Michelle Haber, Jamie Fletcher
Journal: Cancer Research (2017)

Abstract Multidrug resistance protein 1 (MRP1) is frequently overexpressed in tumors where it effluxes chemotherapeutic agents, protecting tumor cells from chemotherapy. This is clearly illustrated in the pediatric solid tumor neuroblastoma, where MRP1 expression is highly prognostic of clinical outcome (1,2) and contributes to chemoresistance in mouse models (3). MRP1 also effluxes low levels of glutathione (GSH), a crucial intracellular antioxidant necessary to avoid damage from the reactive oxygen species induced by radiotherapy and chemotherapy and an important component of both Phase II and Phase III drug metabolism. Depletion of GSH in cancer cells would be of therapeutic value, however the GSH synthesis inhibitor L-buthionine sulfoximine (BSO) has only limited selectivity for tumor over normal cells. We have identified a novel MRP1 inhibitor, 7-methyl-5-phenyl-2-[(4-phenyl-1-piperazinyl)carbonyl]pyrazolo[1,5-a]pyrimidine, that blocks MRP1-mediated drug efflux while greatly enhancing MRP1- mediated GSH efflux and are investigating the utility of this dual-function inhibitor for the treatment of MRP1-overexpressing cancers. Methods: Cells expressing high levels of MRP1 were treated with MRP1 drug substrates in combination with MRP1 inhibitors. Viability was assessed by short-term cytotoxicity or clonogenic assays and GSH levels determined by glutathione recycling assay. Results: Our MRP1 modulator depleted intracellular GSH in an MRP1-dependent manner and sensitized MRP1-expressing human neuroblastoma, lung and ovarian cancer cell to chemotherapeutics. This effect was highly synergistic with BSO, both in depleting GSH (CI&amp;lt;0.36, p&amp;lt;0.05) and abolishing colony formation (CI&amp;lt;0.01, p&amp;lt;0.05). Conclusion: Our MRP1 modulator blocks MRP1- mediated drug efflux while greatly enhancing MRP1- mediated GSH efflux in MRP1 expressing cells, potentially providing an increased therapeutic window for chemotherapeutics in MRP1- overexpressing cancers. Synergy with BSO could widen the range of drugs and cancers that this could be beneficial for. References 1. Haber, M., et al., (2006) J.Clin Oncol 24, 1546-1553 2. Norris, M. D., et al., (1996) New Engl J Med 334, 231-238 3. Burkhart, C. A., et al., (2009) Cancer Res 69, 6573-6580 Citation Format: Christine C. Gana, Kimberley Hanssen, Denise M. Yu, Claudia Flemming, Murray Norris, Michelle Haber, Jamie Fletcher. A modulator of multidrug resistance protein 1 selectively depletes glutathione and synergizes with L-buthionine sulfoximine to sensitize MRP1-expressing cancer cells to chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4056. doi:10.1158/1538-7445.AM2017-4056
Abstract 3674: Local irradiation promotes antitumor immunity and abscopal effect of antigen-specific immunotherapy by enhancing dendritic cell maturation
Authors: Ming-Cheng Chang, Jason Chia-Hsien Cheng, Ying-Cheng Chiang
Journal: Cancer Research (2017)

Abstract Background: Ionizing radiation therapy (RT) is a well-established method to eradicate locally advanced tumors. Whether or no local RT can enhance the potency of an antigen-specific DNA vaccine and the possible underlying mechanism were evaluated. Materials and Methods: The number of E7-specific CD8+ cytotoxic T cell precursors and anti-E7 Abs from Tumor-bearing mice treated with local RT (6Gy twice per week) and the CTGF/E7 DNA vaccine were evaluated. Abscopal effects were also monitored. HMGB-1and DC maturation from local irradiation were analyzed by flow cytometry. The ratio of effector-to-suppressor cells in the tumor microenvironment was also investigated. Results: Tumor-bearing mice treated with local RT (6Gy twice per week) and the CTGF/E7 DNA vaccine exhibited a dramatic increase in the number of E7-specific CD8+ cytotoxic T cell precursors, higher titers of anti-E7 Abs, a significant reduction of tumor size, and longer survival. The combination of local RT and the CTGF/E7 vaccine also elicited abscopal effects on non-irradiated local subcutaneous and distant pulmonary metastatic tumors. Local irradiation can induce the expression of HMGB-1 in apoptotic tumor cells and stimulate DC maturation, which results in inducing antigen-specific immune responses. In addition, local irradiation, although inducing Treg cells, can eventually increase a higher ratio of effector-to-suppressor cells in the tumor microenvironment. Conclusions: Local irradiation can enhance the antigen-specific immunity and antitumor effects on local and distant metastatic tumors generated by an antigen-specific DNA vaccine. Irradiation combined with antigen-specific immunotherapy is a potential new strategy for cancer therapy. Citation Format: Ming-Cheng Chang, Jason Chia-Hsien Cheng, Ying-Cheng Chiang. Local irradiation promotes antitumor immunity and abscopal effect of antigen-specific immunotherapy by enhancing dendritic cell maturation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3674. doi:10.1158/1538-7445.AM2017-3674