bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3083A: C6-ceramide nanoliposomes sensitize paclitaxel resistant ovarian cancer cells to chemotherapy treatment
Authors: Llaneza Danielle C. , Deering Tye G. , Sherwood Samantha G. , Cornelison John R. , Kester Mark , Landen Charles N. 
Published: July 2017

Abstract
Ovarian cancer is the fifth leading cause of cancer deaths among women, and the majority of women are diagnosed at advanced stages resulting in poorer outcomes and survival rates. One of the driving forces behind these outcomes is the development of chemoresistance, and subsequent proliferation and invasion of tumor cells. In a patient-derived xenograft model of ovarian cancer, we identified the sphingosine pathway as significantly enriched in tumors after treatment with conventional chemotherapy. In order to target the sphingosine pathway, we investigated the potential effects of combining paclitaxel with C6-ceramide nanoliposomes in paclitaxel-resistant ovarian cancer cell lines, HeyA8-MDR and SKOV3-TR. Ceramide has been shown to be a key player in several processes important for tumor suppression including apoptosis, autophagy, and cell cycle arrest. We administered paclitaxel and C6-ceramide to HeyA8-MDR and SKOV3-TR cell lines in vitro and measured cell viability and expression of apoptotic and autophagic proteins. Results showed that in both cell lines, C6-ceramide significantly decreases the IC50 dose of paclitaxel, compared to control ghost nanoliposome treated cells. The IC50 of paclitaxel decreased in HeyA8-MDR cells from 400nM to 150nM, and in SKOV3-TR cells from 1000nM to 450nM. Western blot analyses indicate that combination treatment increases expression of apoptotic (cleaved caspase-3) factors in HeyA8-MDR cells, and autophagic (LC3) factors in SKOV3-TR cells, over single agent treatment or control. Paclitaxel is known to increase expression of apoptotic factors while decreasing expression of autophagic factors. Ceramide may increase both apoptotic and autophagic factors. In an orthotopic mouse model with the HeyA8-MDR line, combination treatment of paclitaxel and C6-ceramide resulted in significantly decreased tumor burden (1.38g +/- 0.74), compared to control ghost (p = 0.022, 2.81g +/- 1.57), C6-ceramide alone (p = 0.078, 2.50g +/- 1.58), and paclitaxel alone (p = 0.005, 2.48g +/- 0.75) groups. The combination of C6-ceramide and paclitaxel may prove useful in elucidating and targeting underlying chemoresistance mechanisms in ovarian cancer.
Citation Format: Danielle C. Llaneza, Tye G. Deering, Samantha G. Sherwood, John R. Cornelison, Mark Kester, Charles N. Landen. C6-ceramide nanoliposomes sensitize paclitaxel resistant ovarian cancer cells to chemotherapy treatment [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 3083A. doi:10.1158/1538-7445.AM2017-3083A
Abstract 3089: Combining MEK and HDAC inhibitors as a therapeutic strategy to promote differentiation of colorectal cancer
Authors: Jenkins Laura J. , Luk Ian Y. , Tse Janson W. , Mooi Jennifer , Dhillon Amardeep S. , Mariadason John M. 
Published: July 2017

Abstract
The five-year survival rate for patients with metastatic colorectal cancer is less than 15%, necessitating an urgent need to develop novel therapeutic strategies for this disease. Loss of differentiation is associated with worse overall survival in colorectal cancer, suggesting that strategies to re-induce differentiation may provide clinical benefit. Differentiation therapy is effective in the treatment of acute promyelocytic leukemia but whether this approach can be efficacious in treating colorectal cancer is unknown. Inhibitors of the MAPK signaling pathway including the MEK inhibitor Trametinib can induce markers of differentiation in colorectal cancer cells. Trametinib also induces expression of Cdx-2, a known driver of colonic cell differentiation. Similarly, histone deacetylase inhibitors (HDACi) induce markers of differentiation in multiple tumor cell lines, including colon cancer cells. The aim of this study was to assess the potential therapeutic benefit of combining MEK (Trametinib) and HDAC (Panobinostat) inhibitors to further promote differentiation in colorectal cancer cells, and to elucidate the mechanistic basis for this effect. Combination treatment of HT29 and T84 cells with Trametinib and Panobinostat significantly enhanced mRNA and protein expression of the differentiation markers Cadherin 17 (CDH17) and Keratin 20 (KRT20), compared to either agent alone. Trametinib also induced expression of Cdx-2, an effect that was enhanced upon combination treatment with Panobinostat. Notably, Cdx-2 knockdown attenuated CDH17 and KRT20 induction by the combination, establishing a direct role for Cdx-2 in differentiation induction by the Trametinib/Panobinostat combination. Concomitant with inducing differentiation, the drug combination also invoked more apoptosis than either agent alone. To validate these findings in vivo, HT29 cells grown as xenografts were treated with Trametinib and Panobinostat alone and in combination. Mice treated with the combination had significantly smaller tumours than mice treated with vehicle or either agent alone. Consistent with the in vitro findings, immunostaining of the tumour xenografts demonstrated a strong increase in CDH17, KRT20 and Cdx2 expression upon treatment with the drug combination. Collectively, this study highlights a drug combination strategy to re-induce differentiation for the treatment of colorectal cancers.
Citation Format: Laura J. Jenkins, Ian Y. Luk, Janson W. Tse, Jennifer Mooi, Amardeep S. Dhillon, John M. Mariadason. Combining MEK and HDAC inhibitors as a therapeutic strategy to promote differentiation of colorectal 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 3089. doi:10.1158/1538-7445.AM2017-3089
Abstract 3099: pH-regulated hydrophilicity/hydrophobicity-, surface charge-reversible and redox sensitive nanogels for anticancer drug delivery
Authors: Yang Hao , Wang Qin , Li Fuying , Zhu Yanhong , Gan Lu , Yang Xiangliang 
Published: July 2017

Abstract
Long circulation in blood, enhanced tumor accumulation and penetration, efficient cellular internalization and intracellular drug release are major challenges in the development of ideal anticancer drug delivery systems. Although several strategies have been reported to improve therapeutic efficacy, they mainly meet one or a few features which can not circumvent all the barriers. Here the stimuli-responsive zwitterionic nanogels were developed to overcome the sequential physiological barriers in cancer chemotherapy. The nanogels were constructed via a simple precipitation polymerization method by using temperature-sensitive monomer N-isopropylacrylamide (NIPAM) pH-responsive monomer methylallyl amine (MAA) and betaine-based zwitterionic monomer sulfobetaine methacrylate (SBMA) with in vivo anti-protein adsorption property as comonomers, and disulfide bonds-containing N, N'-bis(acryloyl) cystamine (BAC) as crosslinker. Volume phase transition temperature (VPTT) and surface charge of the prepared nanogels were precisely controlled by altering the feeding molar ratio of these comonomers. Remarkably, The nanogels possess ultra-pH sensitive hydrophilicity/hydrophobicity reversible property, in which the nanogels were hydrophilic in the blood (pH 7.4, 37 °C) for prolonged circulation, while they were rapidly switched to hydrophobic with similar size and surface charge at acidic tumor pH, resulting in enhanced tumor accumulation and penetration and strong internalization by normal cancer cells and CSCs. For efficient lysosomal escape and intracellular drug release, the nanogels were positively charged at lysosome pH, which allowed them to be transported into the cytosol where the loaded cargo DOX was released from the nanogels with the introduction of intracellular high GSH concentration to exert cytotoxicity. This study indicated that pH-dependent hydrophilicity/hydrophobicity-, surface charge-reversible and redox sensitive nanogels might be used as potential carriers for anticancer drugs, which provided a foundation for designing an effective drug delivery system for cancer therapy.
Note: This abstract was not presented at the meeting.
Citation Format: Hao Yang, Qin Wang, Fuying Li, Yanhong Zhu, Lu Gan, Xiangliang Yang. pH-regulated hydrophilicity/hydrophobicity-, surface charge-reversible and redox sensitive nanogels for anticancer drug delivery [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 3099. doi:10.1158/1538-7445.AM2017-3099
Abstract 3101: Hyperthermia at the single-cell level for disseminated cancer disease with immuno-magnetic nanoparticles
Authors: Kagawa Tetsuya , Kishimoto Hiroyuki , Ohara Toshiaki , Tazawa Hiroshi , Kagawa Shunsuke , Nagasaka Takeshi , Nohara Satoshi , Kato Ichiro , Sandhu Adarsh , Aono Hiromichi , Fujiwara Toshiyoshi 
Published: July 2017

Abstract
Hyperthermia using magnetic nanoparticles and alternating magnetic field is promising for cancer therapy. In most cases, the usefulness of this magnetic nanoparticle-based hyperthermia has been shown by applying magnetic nanoparticles to tumor tissue such as a subcutaneous tumor with direct injection technique; however, if the magnetic nanoparticles can be cancer cell-specifically delivered at the cellular level, the magnetic field hyperthermia would have the potential to treat various sorts of disseminated cancer diseases. The aim of this study is to prove this concept. Maghemite nanoparticles (MNPs) were conjugated with the anti-HER2 antibody (Tmab) for cancer targeting, and the Tmab-MNPs were applied to the co-culture flask containing both HER2-expressing breast cancer AU565 cells and normal fibroblast FEF3 cells. Thirty minutes later from the Tmab-MNPs administration, the medium was removed and the cells were washed to remove excess Tmab-MNPs. Prussian blue iron staining and immunostaining for Tmab showed co-localization of the maghemite nanoparticles and Tmab only on the cancer cells, which suggested that MNPs conjugation with Tmab was successful and that cancer specific delivery of MNPs at the cellular level was achieved in vitro. Moreover, application of alternating current magnetic field at 280 kHz for 1 hour caused apoptotic-like cell death only to cancer cells without any cell damage to normal fibroblast FEF3 cells. Intracellular hyperthermia using cancer-specific antibody-modified magnetic nanoparticles have the potential to be applied to the treatment of disseminated cancer diseases.
Citation Format: Tetsuya Kagawa, Hiroyuki Kishimoto, Toshiaki Ohara, Hiroshi Tazawa, Shunsuke Kagawa, Takeshi Nagasaka, Satoshi Nohara, Ichiro Kato, Adarsh Sandhu, Hiromichi Aono, Toshiyoshi Fujiwara. Hyperthermia at the single-cell level for disseminated cancer disease with immuno-magnetic 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 3101. doi:10.1158/1538-7445.AM2017-3101
Abstract 3105: Targeting microRNAs in brain tumors with oligonucleotide nanoparticle conjugates
Authors: Grafals Nilmary , Quiñones Blanca I. , Vivas Pablo E. , Barletta Gabriel 
Published: July 2017

Abstract
Glioblastoma Multiforme (GBM) is the deadliest type of primary brain tumor being responsible for more than 14,000 deaths annually. The survival rate of GBM patients from time of diagnosis is 5 months if left untreated and 15 months with standard care of treatment. Despite great research efforts in the last 30 years, GBM survival rate has only increased by 2%. This is mostly due to high recurrence, treatment resistance, and the existence of the blood brain barrier (BBB) which restricts drug delivery to the tumor tissue. Therefore, the development of novel therapeutic modalities able to cross the BBB is urgently needed. MicroRNAs (miRNAs) are small (18-22 nt.) non-coding RNAs that regulate gene expression at the post-transcriptional level by binding to the 3’UTR of target mRNAs. Several dysregulated miRNAs have been reported in all tumor types, including GBM. Targeting oncogenic miRNAs with oligonucleotide miRNA inhibitors (OMIs) in vitro has shown therapeutic potential. However, in vivo administration requires the development of nanocariers capable of increasing the stability of OMIs in circulation and improving their delivery to target tissues. In addition, nanocarriers that can overcome the BBB are needed. The most studied and promising nanocarriers are gold nanoparticles (AuNP) and liposomes. While AuNPs have bioimaging and microscopy advantages, liposomes are clinically preferred. Therefore, we propose encapsulating OMIs-AuNPs to BBB targeted liposomes. In this study we present the characterization of miRNA inhibitors conjugated to AuNP. Briefly, 15 nm AuNP were functionalized to OMIs by two different techniques: Salt aging functionalization method and PEG and surfactant assisted conjugation method. Afterwards, both nanoconjugates were analyzed for particle size, zeta potential and loading capacity. The PEG and surfactant assisted functionalization proved to be superior in all of the analysis, resulting in 30 nm OMIs-AuNPs with a zeta potential of -8 mV and a loading capacity ratio of 64 oligonucleotides per AuNP. Further characterization studies such as cell internalization and cytotoxicity are under evaluation.
Citation Format: Nilmary Grafals, Blanca I. Quiñones, Pablo E. Vivas, Gabriel Barletta. Targeting microRNAs in brain tumors with oligonucleotide nanoparticle conjugates [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 3105. doi:10.1158/1538-7445.AM2017-3105
Abstract 3107: Targeting nanotherapeutics to the invasive glioblastoma margin via the cell surface receptor Fn14
Authors: Wadajkar Aniket S. , Dancy Jimena G. , Connolly Nina P. , Winkles Jeffrey A. , Woodworth Graeme F. , Kim Anthony J. 
Published: July 2017

Abstract
The most common and deadly form of primary brain cancer, glioblastoma (GBM), is characterized by significant intratumoral heterogeneity, high vascularity, and infiltrative growth. Delivering effective and sustained treatments to the invading GBM cells without worsening damage to the adjacent brain is a major challenge. We aim to develop an innovative, local delivery approach that couples chemotherapy-loaded brain penetrating biodegradable nanoparticles with tumor cell-targeting capabilities and convection enhanced delivery (CED). We formulated sub-100 nm sized, close to neutrally charged, poly(lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) nanoparticles with ~5% w/w carmustine (BCNU) payload coated with a fibroblast growth factor-inducible 14 (Fn14) antibody to specifically target Fn14-positive brain-invading tumor cells. We observed that PLGA surface modification using non-adhesive PEG allowed nanoparticles to rapidly move through brain tissue in ex vivo rat brain slices, potentially increasing the distribution of delivered therapeutics. We showed that Fn14-targeted nanoparticles were able to selectively bind to recombinant Fn14 but not to brain extracellular matrix proteins in surface plasmon resonance assays, as well as diffuse within brain tissue in multiple particle tracking assays. In addition, when administered intracranially, Fn14-targeted nanoparticles showed improved brain tumor retention in C57BL/6 mice bearing orthotopic KR158B tumors compared to non-targeted nanoparticles. We propose that targeting treatments to invading cancer cells using non-adhesive nanoparticles will limit non-specific interactions within brain and tumor tissue and thereby allow specific interactions at target structures and increase the BCNU therapeutic index. To test this hypothesis, we plan to determine the therapeutic efficacy of Fn14-targeted and non-targeted, non-adhesive nanoparticles, capable of releasing BCNU over a 3 week period, by intracranial CED injections in C57BL/6 mice bearing orthotopic KR158B invasive tumors.
Citation Format: Aniket S. Wadajkar, Jimena G. Dancy, Nina P. Connolly, Jeffrey A. Winkles, Graeme F. Woodworth, Anthony J. Kim. Targeting nanotherapeutics to the invasive glioblastoma margin via the cell surface receptor Fn14 [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 3107. doi:10.1158/1538-7445.AM2017-3107
Abstract 3112: Roles of asialoglycoprotein receptor 2 in gastric cancer progression
Authors: Tanaka Haruyoshi 
Published: July 2017

Abstract
Background
Hepatic metastasis and relapse contribute to the high incidence of gastric cancer (GC)-related fatalities, and represent a frequent and crucial problem for oncologists. Knowledge of the unique molecular attributes to hepatic metastasis will improve our understanding of the biology of metastatic GC and facilitate development of specific biomarkers and appropriate targeted therapies, leading to efficacious personalized treatment.
Methods
Transcriptome and bioinformatics analyses were conduct to identify a candidate molecule that specifically mediate hepatic recurrences of GC. Small interfering RNA (siRNA) experiments to determine the effect of knockdown on phenotype. Expression levels of the candidate molecule was determined in the gastric tissues of 200 patients with GC.
Results
Asialoglycoprotein receptor 2 (ASGR2), a membrane trafficking protein, was identified as a candidate biomarker specific to hepatic metastasis. Transcription levels of ASGR2 were differential among GC cell lines and increased compared to a control nontumorigenic epithelial cell line. Inhibiting ASGR2 expression decreased the invasion and migration abilities of GC cells. Increased expression of ASGR2 mRNA in GC tissues was significantly associated with lymphatic involvement, vessel invasion, advanced stage and hepatic metastasis. In patient subgroup of stage II GC, those with increased ASGR2 expression had significantly shorter overall and disease-free survival than those without.
Conclusions
ASGR2 may represent a biomarker for hepatic metastasis of GC and as a target for therapy.
Citation Format: Haruyoshi Tanaka. Roles of asialoglycoprotein receptor 2 in gastric cancer progression [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 3112. doi:10.1158/1538-7445.AM2017-3112
Abstract 3113: Knockdown of cell division cycle-associated 8 (CDCA8) suppresses hepatocellular carcinoma growth via the upregulation of tumor suppressor ATF3
Authors: Jeon Tae-Won , Ko Min Ji , Seo Yu-Ri , Baik In Hye , Hwang Ilseon , Ryoo Hun-Mo , Kim Jin Young , Park Keon Uk , Lee Yun-Han 
Published: July 2017

Abstract
Background: Hepatocellular carcinoma (HCC) is the third most lethal cancer worldwide which remains a major challenge due to poor prognosis and limited treatment options. Cell division cycle associated 8 (CDCA8) is known as a component of a chromosomal passenger complex required for stability of the bipolar mitotic spindle and it is commonly overexpressed in human HCC. However, the functional role of CDCA8 in HCC progression remains to be clarified. In this study, we hypothesized if targeting of CDCA8 with small interfering (si) RNA could alter the course of HCC progression. We also investigated the molecular mechanism that mediates HCC cell death caused by CDCA8 silencing.
Methods: Human HCC cell lines, Huh1 and Huh7, were transfected with CDCA8 siRNA and tested for growth inhibition and apoptotic induction using MTS, FACS and microscopic analysis. To obtain insights into the molecular changes in response to CDCA8 knockdown, global changes in gene expression were examined using RNA sequencing.
Results: siRNA silencing of CDCA8 inhibited HCC cell growth and long-term colony formation by blocking cell cycle progression and by inducing apoptotic cell death. RNA sequencing data showed that, representatively, the anti-proliferative effects were driven by a subset of molecular alterations including the upregulation of tumor suppressive ATF3 and GADD34 genes and the downregulation of BGLAP, a key regulator of cell growth and invasiveness. Subsequent Western blot analysis affirmed that CDCA8 silencing induces the increase in the levels of ATF3 and GADD34 and the decrease in phosphorylated Akt in both Huh1 and Huh7 cells. Also, the same condition decreased the levels of PARP-1 and pro-caspase 3, accelerating apoptosis. Of importance, silencing of CDCA8 expression effectively suppressed HCC tumor growth in a murine xenograft model.
Conclusion: These findings suggest that targeting CDCA8 could be an attractive option for molecular therapy of HCC.
Citation Format: Tae-Won Jeon, Min Ji Ko, Yu-Ri Seo, In Hye Baik, Ilseon Hwang, Hun-Mo Ryoo, Jin Young Kim, Keon Uk Park, Yun-Han Lee. Knockdown of cell division cycle-associated 8 (CDCA8) suppresses hepatocellular carcinoma growth via the upregulation of tumor suppressor ATF3 [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 3113. doi:10.1158/1538-7445.AM2017-3113