bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5614: Legumain protease substrate modified TAT-liposome cargo: an efficient tool for targeting malignant diseases.
Authors: Liu Ze , Xiong Min , Liao Debbie , Lv Dan , Reisfeld Ralph A. , Wrasidlo Wolfgang , Chen Si , Stupack Dwayne G. , Sun Peiqing , Tan Xiaoyue , Xiang Rong 
Published: August 2014

Abstract
Tumor targeting specificity and efficacy of the internalization of macro-biomolecular drugs have emerged as two major obstacles hampering the application of liposome-based delivery system against tumor. Trans-activating transcriptional activator (TAT) is a member of the cell-penetrating peptides which enhance the penetration of various macro-biomolecular cargos. In this study, we developed a modified TAT-Liposome cargo in which the activation of TAT peptide was blocked by Legumain protease substrate Ala-Ala-Asn-(AAN). Firstly, we confirmed the extremely high level of Legumain expression in a variety of solid tumors, as well as its specific effect on recognition and digestion of AAN. Then we conjugated AAN with the TAT peptide and constructed the modified liposome (AAN-TAT-Lipo) cargo. Flow-cytometry assay showed the internalization of AAN-TAT-Lipo was significantly higher than that of AAN-Lipo in 4T1 cells which expressed active Legumain. In vivo, the concentration of Dox encapsulated in AAN-TAT-Lipo was significantly higher in the tumor sites and lower in normal tissues compared with Free-Dox, AAN-Lipo-Dox and TAT-Lipo-Dox groups after administration in mouse model of orthotopic breast cancer. Luciferase assay showed that the AAN-TAT-Lipo-Dox dramatically inhibited tumor growth compared with other groups. TUNEL staining demonstrated that the apoptotic cells in tumor sites were significantly increased in the group of AAN-TAT-Lipo-Dox, compared with other groups. Whereas, the apoptotic cells in the heart, liver, spleen and kidney were decreased in the group of AAN-TAT-Lipo-Dox. Taken together, the modified TAT-lipo cargo via blocking TAT peptide activation with a Legumain specific substrate, AAN, is proven effective for improving the efficacy of internalization, and reducing the systemic toxicity of the tumor targeting delivery system as well.
Citation Format: Ze Liu, Min Xiong, Debbie Liao, Dan Lv, Ralph A. Reisfeld, Wolfgang Wrasidlo, Si Chen, Dwayne G. Stupack, Peiqing Sun, Xiaoyue Tan, Rong Xiang. Legumain protease substrate modified TAT-liposome cargo: an efficient tool for targeting malignant diseases. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5614. doi:10.1158/1538-7445.AM2013-5614
Abstract 5634: Increased co-amplification of HER2 and STARD3 in a cell line model of acquired lapatinib resistance.
Authors: McDermott Martina , Anderson Lee , Shields Liam , O'Brien Neil , Prendergast Allison , Kennedy Susan , Gallagher William , Zagozdzon Radoslaw , Byrne Annette , Crown John , Slamon Dennis , O'Donovan Norma 
Published: August 2014

Abstract
Resistance to lapatinib, a tyrosine kinase inhibitor of HER2, is a significant clinical problem and to date the mechanisms of acquired lapatinib resistance remain largely unknown. In order to study acquired lapatinib resistance we established an in vitro cell line model through continuous culture of HCC1954 cells with 1 μM lapatinib. After 6 months the resulting HCC1954-L cells where significantly less sensitive to lapatinib with an IC50 of 2.6 ± 0.3 μM compared to aged-matched parental cells (IC50 0.42 ± 0.02 M; p = 0.004). In addition, lapatinib treatment had no significant effect on the growth of HCC1954-L xenograft tumors in mice, indicating the utility of HCC1954-L cells as an in vivo model of acquired lapatinib resistance.
Array CGH analysis was performed on the sensitive and resistant cell lines. Chromosomal aberrations were detected in 15 regions in the HCC1954-L cells, including increased amplification of the region of chr17q12 known to contain HER2 and STARD3. Immunoblotting was performed to assess whether the increased amplification corresponded with increased expression of the proteins. HCC1954-L cells exhibited a small but significant increase (1.2 fold) in HER2 protein expression (p=0.02) compared to parental cells. Increased gene amplification of HER2 was also confirmed by FISH analysis. While STARD3 protein expression was undetectable in in parental HCC1954 cells, HCC1954-L cells expressed high levels of STARD3 protein. Knockdown of STARD3 using siRNA resulted in a 20% decrease in cell growth compared to scrambled control treated cells, suggesting that STARD3 amplification and expression plays a role in the proliferation of HCC1954-L cells.
In summary, we have developed a robust model of acquired lapatinib resistance which exhibits increased amplification and expression of HER2 and STARD3.
Citation Format: Martina McDermott, Lee Anderson, Liam Shields, Neil O'Brien, Allison Prendergast, Susan Kennedy, William Gallagher, Radoslaw Zagozdzon, Annette Byrne, John Crown, Dennis Slamon, Norma O'Donovan. Increased co-amplification of HER2 and STARD3 in a cell line model of acquired lapatinib resistance. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5634. doi:10.1158/1538-7445.AM2013-5634
Abstract 5645: Angiogenic activity leads failure of antitumor activity of cixutumumab, an anti-Insulin like growth factor receptor monoclonal antibody.
Authors: Lee Ji-Sun , Kang Ju-Hee , Boo Hye-Jin , Myers Jeffrey N. , Johnson Faye M. , Glisson Bonnie S. , Oh Seoung-Hyun , Lee Ho-Young 
Published: August 2014

Abstract
The type 1 insulin-like growth factor receptor (IGF-1R) signaling is dysregulated in many cancers, thus being a target of cancer therapy. Several preclinical trials have reported the efficacy of IGF-1R targeted therapies, mostly using tyrosine kinase inhibitors or monoclonal antibodies (mAbs); however many of clinical trials have shown limited therapeutic efficacy. In this study, we investigated the resistance mechanism to IGF-1R mAb-based therapies using cixutumumab, a fully humanized mAb against IGF-1R. We tested the efficacy of cixutumumab using OSC19 and 686LN head and neck squamous cell carcinoma (HNSCC) and MDA-MB-231 breast cancer orthotopic and H1299 non-small cell lung cancer (NSCLC) xenograft tumor models. We observed that cixutumumab treatment induced either no change or increased tumor growth and decreased the survival duration of the animals bearing those tumors. Treatment with cixutumumab upregulated migration and invasion of HNSCC and NSCLC cells without any effects on cell proliferation. We further examined the effects of cixutumumab on tumor angiogenesis and found that conditioned media from cancer cells treated with cixutumumab increased tube formation and migration of human umbilical endothelial cells (HUVECs). The angiogenic activity of cixutumumab was also confirmed by matrigel plug assay with HNSCC cell lines. Collectively, these data suggest that cixutumumab-induced angiogenesis-stimulating activities and migration and invasion potential of cancer cells are major factors of resistance to IGF-1R mAbs. These data further suggest that inhibitors of angiogenesis are useful strategy to overcome the resistance against the IGF-1R mAb-based therapy.
Citation Format: Ji-Sun Lee, Ju-Hee Kang, Hye-Jin Boo, Jeffrey N. Myers, Faye M. Johnson, Bonnie S. Glisson, Seoung-Hyun Oh, Ho-Young Lee. Angiogenic activity leads failure of antitumor activity of cixutumumab, an anti-Insulin like growth factor receptor monoclonal antibody. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5645. doi:10.1158/1538-7445.AM2013-5645
Abstract 5661: Nanoparticle based combinatorial siRNA therapy against human hepatocellular carcinoma (HCC) .
Authors: Decaens Thomas , Factor Valentina M. , Kulic Iva , Andersen Jesper B. , Seo Daekwan , Lee Yun-Han , Judge Adam D. , Conner Elizabeth A. , MacLachlan Ian , Thorgeirsson Snorri S. 
Published: August 2014

Abstract
Background: We have previously demonstrated the therapeutic effect of lipid nanoparticles (LNP) loaded with single siRNA targeting CSN5 and WEE1 against human HCC in mouse models.
Aim: To test the benefit of a combinatorial versus single siRNA therapy in mouse models of human HCC and to identify molecular mechanism(s) involved in therapeutic response by extensive microarray analyses.
Materials and Methods: LNP formulations of chemically modified siRNAs targeting CSN5 and WEE1 were produced by Tekmira® Pharmaceuticals. SCID-beige mice were used for subcutaneous (Hep3B) and intra-hepatic (Huh7-luciferase) tumor transplantation. Mice with established tumors were treated intravenously with 4 mg/kg single agent siRNA or 2 mg/kg + 2 mg/kg siCSN5:siWEE1 siRNA co-encapsulated in the same LNP. Tumors were assayed following 1 to 9 injected doses. Tumor progression in the Huh7 orthotopic model was monitored by bioluminescence imaging and metastases were evaluated at endpoint.
Results: Significant target silencing was observed in tumors after single or repeat administration with no antagonism between siRNAs occurring in the CSN5:WEE1 combination. We observed significant inhibition of tumor growth and metastases in mice treated with active siRNAs compared to LNP containing a non-targeting control sequence. Potency was not lost with siCSN5:siWEE1 LNP, where the concentration of each siRNA is halved in combination, relative to the most efficacious single agent. Data from preliminary microarray analyses demonstrate a strong transcriptome difference between each treatment group.
Conclusion: We demonstrate a clear efficacy of a LNP based combinatorial siRNA therapy in human mouse models of HCC. Overall this therapy led to a significant decrease of tumor size induced by mRNA inhibition
Citation Format: Thomas Decaens, Valentina M. Factor, Iva Kulic, Jesper B. Andersen, Daekwan Seo, Yun-Han Lee, Adam D. Judge, Elizabeth A. Conner, Ian MacLachlan, Snorri S. Thorgeirsson. Nanoparticle based combinatorial siRNA therapy against human hepatocellular carcinoma (HCC) . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5661. doi:10.1158/1538-7445.AM2013-5661
Abstract 5663: In vitro radiosensitization of human cervical cancer HeLa cells with iron oxide- titanium dioxide core-shell nanoparticles conjugated with 3,4-Dihydroxyphenylacetic acid (DOPAC).
Authors: Mirzoeva Salida , Wanzer Beau M. , Paunesku Tatjana , Woloschak Gayle E. 
Published: August 2014

Abstract
Cervical cancer is resistant to current surgical, chemo- and radiotherapy interventions and represents a virtually incurable tumor. In this study, we explored titanium dioxide core-shell nanocomposites conjugated with DOPAC (DOPAC-NCs) as radiosensitizers. Radioresistant human carcinoma cervical HeLa cell cultures were treated with or without of increasing concentrations of DOPAC-NCs (5-20 nM) prior to irradiation. One hour later, cells were irradiated with a single dose of gamma radiation (5 Gy, 10 Gy, or 15 Gy). Seventy-two hours following radiation treatment, cell proliferation/viability was assessed by MTS assay. Sham-irradiated cells were served as a control. We have found that treatment of HeLa cells with DOPAC-NCs affected the survival of irradiated cells in a dose-dependent manner. Our data demonstrate that cell survival of cells irradiated with 15 Gy and pre-treated with the highest concentration of DOPAC-NCs was as low as 23.7% compared to survival of cells that were not treated with DOPAC-NCs prior to irradiation. In opposite, without radiation, treatment with DOPAC-NCs had no effect on cell viability/proliferation.
These findings provide in vitro evidence that DOPAC-NCs may be developed and employed as radiosensitizers in cervical cancer radiation therapy.
Citation Format: Salida Mirzoeva, Beau M. Wanzer, Tatjana Paunesku, Gayle E. Woloschak. In vitro radiosensitization of human cervical cancer HeLa cells with iron oxide- titanium dioxide core-shell nanoparticles conjugated with 3,4-Dihydroxyphenylacetic acid (DOPAC). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5663. doi:10.1158/1538-7445.AM2013-5663
Abstract 5668: An experimental study of folic acid coupled nano-paclitaxel for targeted treatment of ovarian cancer.
Authors: Li Hongxia 
Published: August 2014

Abstract
To study the effect of folic acid coupled nano-paclitaxel in vivo and in vitro targeted treatment of ovarian cancer and preliminarily elucidate its therapeutical mechanism. Methods: The folic acid coupled nano-paclitaxel drug were prepared by the co-incubation method; The folic acid receptor-positive ovarian cancer cell lines were screened by immunohistochemical staining method; the targeting effect of the drug on SKOV3 cells were assessed qualitatively by fluorescence microscopy and quantitatively by flow cytometry (FCM). The killing effect of the drug on SKOV3 cells and SKOV3/TAX cells were monitored in vitro by plotting cell growth curve, the MTT method, FCM measurement, and electron microscopy; Tumor-burdened nude mice were administered with the drug by intraperitoneal and iv injection, the amounts of tumors were compared. The tumor killing effect of the drug in treating celiac metastases were examined qualitatively by electron microscopy and quantitatively by FCM. Results: (1) The particle size and encapsulation efficiency of folic acid coupled nano-paclitaxel drugs were (140.5±10.3)nm and 97% respectively; (2) Both SKOV3 cells and SKOV3/TAX cells were folic acid receptor positive; (3) Folic acid coupled nano-paclitaxel drugs demonstrated targeted killing effect on SKOV3 cells by the mediation of the folic acid receptor. The intracellular drug concentration gradually increases along with the incubation time. (4)The effects of folic acid coupled nano-paclitaxel drugs on SKOV3 cells and SKOV3/TAX cells were significantly better than the nano-paclitaxel, but the effects was similar when the concentrations were 0.2 and 2 μg/ml. The resistance index of SKOV3 / TAX cells was decreased in the course of treatment; (5) The cell apoptosis rates of the three groups after treatment were 84.63% in abdominal group,35.23% in veinal group,and 10.12% in control group respectively (p &lt; 0.01). The apoptotic necrosis in tumor issues of abdominal group was quite obviously. But the tumor-burdened quantities in three groups were 3.38±1.77, 4.50±2.20, and 3.86±1.95 respectively. there were no statistical significance (P &gt; 0.05). Conclusions: Folic acid coupled nano-paclitaxel drugs have better therapeutical effects in treating both drug-sensitive and drug-resistant ovarian cancer lines. The drugs administered through intraperitoneal injection showed better results than via iv injection.
Citation Format: Hongxia Li. An experimental study of folic acid coupled nano-paclitaxel for targeted treatment of ovarian cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5668. doi:10.1158/1538-7445.AM2013-5668
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 5678: Design of GRP78 inhibitors as novel therapeutics for breast cancer.
Authors: Ramkumar Kavya , Debnath Bikash , Lee Amy S. , Neamati Nouri 
Published: August 2014

Abstract
Cancer cells exploit cellular stress response mechanisms, such as the unfolded protein response, to survive through cytotoxic treatments. A key mediator of the unfolded protein response, the 78kDa glucose regulated protein (GRP78) chaperone, has frequently been found to be overexpressed in breast cancer. In addition to providing a growth advantage to cancer cells, GRP78 induction leads to drug resistance. Suppressing GRP78 levels using siRNA has been shown to slow cancer cell progression and overcome drug resistance. Another approach to inactivating GRP78 is by inhibiting its ATPase activity. Currently, there are only few selective GRP78 inhibitors in development despite ample evidence of its critical role in cancer cell survival and drug resistance. Here, we report a novel class of small-molecule inhibitors of GRP78 ATPase activity. We designed a focused library of compounds based on a structure-based docking approach and screened for inhibition of GRP78 ATPase activity. Based of the initial hit, we further optimized several analogues with more potent activity and selectivity for GRP78 inhibition (IC50 &lt;5μM). The lead compound, KR-240, induced CHOP significantly under conditions of ER stress and activated the pro-apoptotic arm of the unfolded protein response. KR-240 showed moderate cytotoxicity against a panel of breast cancer cell lines and increased sensitivity to chemotherapeutic agents, further supporting the role for GRP78 in cancer survival and drug resistance. Overall, our results indicate that our novel GRP78 inhibitor, KR-240 has the potential for further development as an anticancer agent.
Citation Format: Kavya Ramkumar, Bikash Debnath, Amy S. Lee, Nouri Neamati. Design of GRP78 inhibitors as novel therapeutics for breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5678. doi:10.1158/1538-7445.AM2013-5678
Abstract 572: Proline-rich acidic protein 1 (PRAP1), a novel mitotic arrest deficient 1 (MAD1) interacting partner, suppresses mitotic checkpoint signaling in hepatocellular carcinoma.
Authors: Sze Karen MF , Chu Glanice K. , Mak Queenie HY , Ng Irene OL 
Published: August 2014

Abstract
DNA aneuploidy or chromosomal instability is commonly observed in major types of human cancers, and one of the causes for chromosomal instability is defective mitotic checkpoint signaling in cells. Loss of mitotic checkpoint contributes to chromosomal instability, leading to carcinogenesis. The mitotic checkpoint monitors the status of kinetochore-microtubule attachment and delays the onset of anaphase until all kinetochores have been attached with microtubules. Mitotic arrest deficient 1 (MAD1) is key component in mitotic checkpoint signaling. We previously identified a novel isoform of MAD1, which we named MAD1β (Sze et al. Cancer Res 2008;68:9194-9201). In this study, using yeast-two hybrid screening, we have identified a novel MAD1 interacting partner, proline-rich acidic protein 1 (PRAP1). The function of PRAP1 is largely unknown. Hence, we investigated its role in mitotic checkpoint signaling in hepatocellular carcinoma (HCC). We demonstrated the physical interaction between PRAP1, MAD1 and MAD1β in yeast-two hybrid screening and with co-immunoprecipitation assay. Both MAD1 and MAD1β proteins were co-immunoprecipitated with PRAP1. Moreover, we stably expressed PRAP1 in two HCC cell lines, BEL-7402 and SMMC-7721, which have competent mitotic checkpoints. We observed that stable expression of PRAP1 induced impairment in mitotic checkpoint (P &lt; 0.01). After treatment with either colcemid or nocodazole, the PRAP1-stably expressing BEL-7402 and SMMC-7721 cells showed significantly lower mitotic indices as compared with the corresponding vector control cells. Ectopic expression of PRAP1 also resulted in chromosome bridge formation (P&lt; 0.01) and aberrant chromosome numbers (P &lt; 0.001) in these cell lines. All these cellular changes contributed to chromosomal instability. Interestingly, ectopic expression PRAP1 led to significant underexpression of MAD1 but not MAD1β in HCC cells. Taken altogether, our data indicate that PRAP1 is an interacting partner of MAD1 and may have functions of degrading MAD1 and in turn suppressing mitotic checkpoint signaling in HCC.
(This study was partly funded by a Hong Kong Research Grants Council GRF grant [HKU 772608])
Citation Format: Karen MF Sze, Glanice K. Chu, Queenie HY Mak, Irene OL Ng. Proline-rich acidic protein 1 (PRAP1), a novel mitotic arrest deficient 1 (MAD1) interacting partner, suppresses mitotic checkpoint signaling in hepatocellular carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 572. doi:10.1158/1538-7445.AM2013-572
Abstract 577: DNA replication origin of human alphoid centromere regions .
Authors: Erliandri Indri , Fu Haiqing , Kim Jung-Hyun , Aladjem Mirit , Earnshaw William , Nagaraja Ramaiah , Schlessinger David , Larionov Vladimir 
Published: August 2014

Abstract
The human centromere DNA consist of 171 bp AT-rich-alpha satellite DNA that tandemly arranged into higher order repeat units that is diverged at each centromere, extend from 200kb to 4MB. As the chromosomal site that regulates accurate chromosome segregation, maintaining the correct and coordinated DNA replication prior to cell division is critical. This process should ensure that whole genetic information transferred to daughter cell faithfully. Irregularities on replication process are leading to the mitosis defect and apoptosis. Flanking regions of alpha-satellite DNA arrays are organized in heterochromatin domains that are co-localized with other types of centromeric repeats, i.e. satellite II and gamma-satellite DNA. Previous studies indicate that centromeric DNA replicates in the middle to late S-phase. However little is known what determines activities and positions of replicators on chromatin domains. In this work, we addressed the mechanism of replication on the centromere and other repeat sequences on pericentromeric regions using two different approaches: i) origin mapping using nascent-strand DNA and ii) DNA-protein interaction using chromatin-immunoprecipitation (ChIP) assay. Our results detect active origin of replication within alpha-satellite DNA monomers of centromere, as well as on gamma-satellite repeats. In contrast, satellite II repeats representing centromere-adjacent heterochromatin do not exhibit a significant activity as origin of replication. The accumulation of modified-Histone proteins indicated dynamic activity of DNA arrays. Moreover, DNA replication proteins are formed complex with centromere proteins, presented direct evident on DNA replication activity on centromere. In summary, data indicated position of replicator within alphoid centromere and other large tandem repeat arrays on pericentromeric region with condense chromatin structure, thus suggested role of epigenetic modifications on DNA arrays propagation.
Citation Format: Indri Erliandri, Haiqing Fu, Jung-Hyun Kim, Mirit Aladjem, William Earnshaw, Ramaiah Nagaraja, David Schlessinger, Vladimir Larionov. DNA replication origin of human alphoid centromere regions . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 577. doi:10.1158/1538-7445.AM2013-577