bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2594: Ciclopirox inhibits lymphatic endothelial cell tube formation by suppressing VEGFR-3-mediated ERK signaling pathway
Authors: Luo Yan , Huang Shile 
Published: June 2012

Abstract
Ciclopirox olamine (CPX), an off-patent antifungal agent used to treat mycoses of skin and nails, has recently been demonstrated to be a potential anticancer agent. However, the underlying mechanism is not well understood. Here for the first time we show that CPX inhibited lymphangiogenesis in an in vitro model (tube formation). This effect was in part associated with inhibition of vascular endothelial growth factor receptor 3 (VEGFR-3) expression, as overexpression of VEGFR-3 conferred partial resistance to CPX inhibitory effect on tube formation in lymphatic endothelial cells (LECs), whereas downregulation of VEGFR-3 mimicked the effect of CPX, blocking the tube formation. Further study revealed that CPX did not alter mRNA level, but inhibited protein synthesis and promoted protein degradation of VEGFR-3. In addition, we found that CPX inhibited phosphorylation of the extracellular signal-related kinase 1/2 (ERK1/2), a downstream effector of VEGFR-3. Overexpression of VEGFR-3 attenuated CPX inhibition of ERK1/2 phosphorylation, whereas downregulation of VEGFR-3 inhibited extracellular signal-related kinase 1/2 (ERK1/2) phosphorylation in LECs. Ectopic expression of constitutively active mitogen -activated protein kinase kinase 1 (MKK1) resulted in activation of ERK1/2, and partially prevented CPX inhibition of LEC tube formation. The results suggest that CPX inhibits LEC tube formation at least in part through inhibiting VEGFR-3-mediated ERK signaling pathway.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2594. doi:10.1158/1538-7445.AM2011-2594
Abstract 2615: Antitumor activity of a dual PI3K and HDAC inhibitor in hematologic cancer models
Authors: Bao Rudi , Wang Dagong , Qu Hui , Yin Ling , Xu Guang-Xin , DellaRocca Steven , Borek Mylissa , Atoyan Ruzanna , Forrester Jeffrey , Samson Maria , Wang Jing , Zhai Hai-Xaio , Chan Mendy , Lai Cheng-Jung , Cai Xiong , Qian Changgeng 
Published: June 2012

Abstract
Recent evidence indicates that PI3K-Akt-mTOR signaling plays a crucial role in the development and progression of hematologic cancers. Therefore, inhibition of this pathway using isotype-selective or pan-PI3K inhibitors has recently been investigated extensively in hematologic malignancies. However, compensatory/feedback mechanisms in cancer cells may present a major challenge for these PI3K inhibitors. On the other hand, HDAC inhibitors, such as vorinostat and romidepsin, have been approved as a monotherapy for CTCL. Their efficacy as single agent or in combination with other approved therapeutics is being evaluated in multiple clinical trials for other types of hematologic cancers, including DLBCL, Hodgkin lymphoma, AML, ALL, CLL, and multiple myeloma. Based on the observation that synergic effects can be achieved by inhibition of both HDAC and PI3K in cancer cells as reported previously, we developed small-molecule compounds that are able to simultaneously inhibit both PI3K and HDAC. One of the lead compounds exhibits potent inhibition of all PI3K class I subtypes as well as HDAC. In cell growth inhibition assays, this compound displays potent activity in hematologic cancer cell lines, including leukemia, lymphoma, and myeloma. Besides PI3K-Akt-mTOR pathway suppression, this compound is able to up-regulate tumor suppressors p53 and p21 and simultaneously inhibit compensatory Ras-Raf-MEK signaling in cancer cells via epigenetic modifications by HDAC inhibition. In vivo experiments demonstrate this compound is orally bio-available with a long half-life in tumor tissues from xenograft models. Efficacy studies demonstrate this compound is able to inhibit tumor growth or induce tumor regression in animals implanted with various hematologic cancer cell lines. Furthermore, this compound induces apoptosis and inhibits cancer cell proliferation in these tumor xenografts. Favorable safety profile has been observed in early preclinical studies. Based on these results, this compound warrants further investigation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2615. doi:10.1158/1538-7445.AM2011-2615
Abstract 2646: N-ethylmaleimide modulates gemcitabine effect on ribonucleotide reductase M1 subunit (RRM1)
Authors: Chen Zhengming , Bepler Gerold 
Published: June 2012

Abstract
Ribonucleotide Reductase M1 (RRM1) is the regulatory subunit of the holoenzyme that catalyzes the conversion of ribonucleotides (NTP) to 2’-deoxyribonucleotides (dNTP) in mammalian cells. Its function is indispensible in cell proliferation and DNA repair. It is also a crucial marker of therapeutic efficacy in various cancers. This study investigated how the alkylating agent N-ethylmaleimide (NEM) interacts with the antimetabolite gemcitabine in inhibiting its target protein RRM1.
Lung cancer cell lines and the human embryonic kidney cell line (HEK293) were used for transfection, immunoprecipitation, and proliferation assays. Site-directed mutagenesis was used to create point mutations. The protein ID and modification sites were identified by LC/MS/MS. Flow cytometry was used for sorting and plating cells. Mouse xenografts were used for in vivo validation.
When cells were treated with gemcitabine and the alkylating agent NEM, a novel 110kD band, along with the 90kD native RRM1 band, was recognized in immunoblots. This 110kD band was identified as RRM1 by LC/MS/MS. It is specific to gemcitabine/NEM, among 11 chemotherapy drugs and 3 alkylators tested. It can also be detected in the mouse xenografts treated with gemcitabine. We mutated 7 residues that are essential for the RRM1 activity to alanine. Among these mutants, C218A, C429A, and E431A did not show any 110kD band, while C444A, N427A, C787A and C790A showed diminished 110kD, suggesting the 110kD RRM1 is involved in functionality. This was further confirmed by proliferation assays with gemcitabine and NEM in wild type and mutant cells.
In conclusion, the alkylator NEM specifically modulates the gemcitabine-RRM1 interaction and understanding the mechanism may lead to improved efficacy of and reduced resistance to gemcitabine.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2646. doi:10.1158/1538-7445.AM2011-2646
Abstract 2683: Identification of tumor antigens in neu transgenic mice as diagnostic targets for the early detection of human breast cancer
Authors: Mao Jianning , Ladd Jon , Wu Mei , Gad Ekram , Lu Hailing , Hanash Samir , Disis Mary 
Published: June 2012

Abstract
Tumor antigens, expressed early in disease, which can induce specific antibody response could serve as biomarkers for early detection of human breast cancer. However, the ability to obtain sera from women prior to the development of breast cancer is limited, which makes it difficult to identify early antigens directly from breast cancer patients. Transgenic mouse models have been proved to demonstrate similar antigen repertoire to breast cancer patients. Therefore, we propose to identify early tumor antigens in neu transgenic mice and use them as diagnostic targets for early detection of human breast cancer. We have collected serial sera from neu transgenic mice, sera collected before the animals develop palpable tumor “pre-diagnostic sera”. With serological analysis of recombinant cDNA expression libraries (SEREX) approach, we were able to identify nine tumor antigens from pre-diagnostic sera, Rpl5, TNFaip3/A20, Pdhx, Otud6b, Stk39, Zfp238, Dnajc10, Lgals8 and Vps35. These antigens demonstrated detectable IgG antibody response prior to tumor development in neu transgenic mice. IgM is the first antibody to be produced during a humoral immune response, so we questioned whether including antigen specific IgM with IgG responses could achieve a better diagnostic performance. Firstly, we analyzed receiver-operating-characteristic (ROC) curves of these antigens by IgG and IgM ELISA analysis in neu transgenic mice and 26 FVB control mice. By combining IgG and IgM ELISA, we were able to achieve a higher AUC: Otud6b and Stk39 show an AUC of 0.882, and adding Lgals8 IgG ELISA to this panel can achieve an AUC of 0.924 in discriminating cases from control mice. We documented that these autoantibodies are also detectable in the serum of women with breast cancer and then screened a panel of sera derived from the Women's Health Initiative cohort (samples obtained 6-18 months prior to the development of breast cancer) and case matched controls. We evaluated serum for the presence of IgG and IgM specific autoantibodies to Pdhx, Otud6b, and Stk39. With both IgG and IgM ELISA analysis, a panel combining the three antigens demonstrates an AUC of 0.633 in patients diagnosed within 5 month and an AUC of 0.688 in patients diagnosed within 5-18 month of the blood draw. In summary, we conclude that tumor antigens identified in neu transgenic mouse model can be used for early detection and diagnosis of breast cancer in women. The combination of antigen specific IgG and IgM antibodies may enhance the sensitivity of the assay for early detection.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2683. doi:10.1158/1538-7445.AM2011-2683
Abstract 2684: Immunosensitization of apoptosis-resistant MART-1 negative human melanomas by bortezomib
Authors: Jazirehi Ali R. , Economou James S. 
Published: June 2012

Abstract
Adoptive cell transfer (ACT) of ex-vivo engineered autologous lymphocytes encoding high-affinity MART-1+/ HLA A*0210+-specific T-cell receptor α/β (TCRα/β) (F5 CTL) mediates dramatic, but partial, clinical responses in lymphodepleted metastatic melanoma patients. Various mechanisms have been postulated for the limited clinical responses. Selective outgrowth of antigen (MART-1)-loss variants is one potential mechanism of immune-resistance. Our first hypothesis is that development of MART-1-loss variants is due to MART-1 down-modulation upon encountering F5 CTLs. We also hypothesized aberrant apoptotic signaling may contribute to immune-resistance. To test these hypotheses, we established an in vitro model of resistant (R) lines from sensitive parental (P) lines under F5 CTL-selective pressure. Unlike P lines, F5 CTLs failed to recognize and kill R lines. Moreover, R lines exhibited hyper-activation of NF-κB anti-apoptotic signaling pathway and over-expression of NF-κB-dependent resistant-factors. Specific pharmacological inhibition of NF-κB and silencing of resistant-factors (siRNA) were required, but insufficient, to restore sensitivity of R lines. MART-1 peptide pulsing restored recognition (cytokine release) but not killing of R lines by F5 CTLs. However, bortezomib blocked NF-κB activity, reduced expression of resistant-factors, restored MART-1 expression, and immuno-sensitized R lines. Moreover, MART-1 specific CTLs from metastatic melanoma patients were unable to kill the R lines, whereas bortezomib sensitized the R lines to MART-specific CD8 cells. These novel results suggest that bortezomib interferes with both deregulated signaling pathway and restores recognition of poorly-immunogenic resistant-variants by melanoma-reactive CTLs, thus, imposes a pro-apoptotic/MART-1+ phenotype to R cells and reverses their acquired-resistance. Results also imply that immune-resistance is multi-faceted; development of MHC-/Ag-loss variants and perturbed apoptotic signaling pathways are both important contributing factors. Combining targeted therapy with F5 CTL overrides resistance, which may improve clinical responses.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2684. doi:10.1158/1538-7445.AM2011-2684
Abstract 2686: Anti-tumor effects of a folate-immunoglobulin conjugate are enhanced by cytokine treatment in vitro and in vivo
Authors: Jaime-Ramirez Cristina , Kondadasula SriVidya , Jones Natalie B. , Mani Aruna , Roda Julie , Karpa Volodymyr , Lu Yanhui , Li Hong , Zhang Xiaoli , Jarjoura David , Lee Robert J. , Carson William E. 
Published: June 2012

Abstract
Folate conjugation is a means of selectively targeting therapeutics to folate receptor (FR)-expressing cancer cells. A novel folate-bound immunoglobulin (F-IgG) was tested for its ability to target natural killer (NK) cells to folate-receptor expressing cancer cells in the presence or absence of NK-activating cytokines.
FR expression by the KB and HeLa cell lines was confirmed by immunoblot analysis (IB) and flow cytometry. Binding of F-IgG to NK cell Fc receptors led to increased phosphorylation of the epidermal growth factor related kinase (ERK) as measured by IB. Lysis of FR+ KB tumor cells by NK cells was increased 8-fold following treatment with F-IgG as compared to C-IgG (p&lt;0.0001 across E:T ratios from 6.25:1 to 50:1). NK cell lysis of F-IgG- coated KB target cells was significantly enhanced following treatment of NK cells with IL-2, IL-12, IL-15 and IL-21 (all at 10ng/mL). NK cell production of IFN-γ, RANTES and MIP-1α was significantly enhanced by IL-12 in response to F-IgG-coated KB target cells as compared to control-treated cells (p&lt;0.005; IFN-γ-2100 vs. 1000pg/mL, RANTES-800 vs. 150pg/mL, MIP-1α 1800 vs. 500pg/mL, respectively). Studies using the L1210JF murine leukemia model confirmed the anti-tumor activity of F-IgG and the ability of NK-activating cytokines to significantly enhance its effects. NK cell depletion in tumor-bearing mice demonstrated that the anti-tumor effects of IL-12 and F-IgG are dependent on NK cells.
These studies indicate that F-IgG induces an immune response by NK cells against FR-positive cancer cell lines and that cytokine treatment has a synergistic effect on this response both in vitro and in vivo. Thus F-IgG has a potential to be used as a therapeutic antibody for the treatment of FR-positive cancers in combination with immune modulatory cytokines.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2686. doi:10.1158/1538-7445.AM2011-2686
Abstract 2700: Effects of anticancer drugs on the viability and the function of peripheral blood mononuclear cells
Authors: Sakai Hiromi , Kokura Satoshi , Ishikawa Takeshi , Okajima Manabu , Matsuyama Tatsuzou , Matsumoto Tsuguhiro , Funaki Jun , Adachi Satoko , Matsuura Yuko , Konishi Hideyuki , Naito Yuji , Yoshikawa Toshikazu 
Published: June 2012

Abstract
[Background/Purpose] Cytotoxic chemotherapy is generally considered immunesuppressive because of its toxicity for dividing cells in the bone marrow. However, recent experimental studies support the notion that certain cytotoxic anticancer agents may actually exhibit immune modulatory activities. Effects of anticancer drugs on adoptive transferred cells remain unclear. Therefore, the purpose of this study was to evaluate the effects of anticancer drugs on the viability and the function of peripheral blood mononuclear cells (PBMCs).
[Method] 5-FU, CPT-11, CDDP and GEM were assessed in the present experiment. PBMCs were treated with each drug for 2hrs, and then cell viability was determined by trypan blue staining and WST-8 assay. For assessment of effects of each drug on proliferation and cytokine producing ability of PBMCs, PBMCs were stimulated with PHA for 48 hrs, following the treatment with each anticancer drug for 2hrs. Proliferation potency of PBMCs was measured using BrdU cell proliferation assay and the producing ability of various cytokines from PBMCs was measured using ELISA. The percentages of IFN-γ-expressing cells and regulatory T cells (Tregs) in GEM-treated PBMCs were measured using flow cytometric assay.
[Results] The anticancer drugs did not affect the cell viability of PBMCs. While 5FU and CPT-11 did not influence proliferation potency, CDDP and GEM inhibited it in concentration-dependent manner. Treatment with GEM enhanced the production of IFN-γ from PBMCs and decreased the number of Tregs induced by PHA. Flow cytometric assay revealed that GEM treatment increased the number of IFN-γ-producing cells in CD4 cells, but GEM did not affect in CD8 cells.
[Conclusions] The anticancer drugs did not affect the cell viability of PBMCs in the present experiment. We have found that GEM may be a practical strategy for the enhancement of IFN-γ production from CD4 cells and reduction of Tregs. Thus, GEM should be evaluated in conjunction with a variety of immunotherapy approaches.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2700. doi:10.1158/1538-7445.AM2011-2700
Abstract 2713: Association of HBV/inflammation and stemness expression in HBV-related HCC recurrence
Authors: Chang Te-Sheng , Lee Kam-Fai , Lin Hsin-Yi , Tung Shui-Yi , Kuo Liang-Mou , Jen Xin-Wei , Huang Yen-Hua 
Published: June 2012

Abstract
Hepatocellular carcinoma associated with chronic HBV hepatitis (HBV-HCC) tends to have a poorer prognosis. Inflammation is a common and strong participant in the development of HBV-HCC. However, the mechanism of HBV/inflammation-induced hepatocarcinogenesis still remains largely unknown. Here we demonstrate the potential synergistic role of HBV and proinflammatory cytokines in stemness expression which might associate with HBV-HCC recurrence. In this study, human HCC cell lines including HBV- HCC cells (HepG2.2.15, PLC5, Hep3B, and HA22T), and non-HBV HCC cells (HepG2 and Huh 7) were cultivated with inflammation condition medium (inflam-CM). Inflam-CM significantly increased the expression levels of pluripotent transcription factors (Oct-4, Sox2, and Nanog) and the percentage of side population cells in HBV-HCC but less or not in non-HBV HCC. Furthermore, flow-cytometry and epifluorescence analysis showed that inflam-CM markedly increased the GFP+ cell population in Oct-4 promoter-GFP-HepG2.2.15 cells but not in Oct-4 promoter-GFP-HepG2 cells, supporting the synergistic effect of proinflammatory cytokines and HBV in Oct-4 expression. To test the role of stemness expression in HCC prognosis, HA-Oct-4-HepG2 (HepG2 cells over-expressing HA-Oct-4) were used for drug sensitivity and migration/invasion assay. HA-Oct-4 HepG2 cells showed higher drug resistance and migration/invasion ability comparing with HepG2 cells. The responsible proinflammatory cytokines were to be identified using specific neutralizing antibodies and/or signaling inhibitors. The clinical impact was further analyzed using human HCC frozen tissues and tissue blocks which were collected under IRB approval. Real-time quantitative PCR analysis of HCC frozen tissues (N = 102) revealed a significant difference between HBV-HCC and HCV-HCC for the expression of Oct-4 (p=0.0089), Nanog (p=0.0021) and disease-free interval (DFI) (p&lt;0.001). Immunohistochemical staining of HCC tissue blocks (N = 33) further confirmed the strong correlation between stemness expression (Oct-4 and Nanog) and short DFI. In summary, proinflammatory cytokines and HBV may work collaboratively to activate the stemness expression which results in early HBV-HCC recurrence. This finding characterizes a potential target for adjuvant therapy against HBV-HCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2713. doi:10.1158/1538-7445.AM2011-2713
Abstract 2718: Longer duration of preceding high-risk HPV infection is associated with an increase of chromosomal aberrations in high-grade cervical intraepithelial neoplasia
Authors: Steenbergen Renske D.M , Bierkens Mariska , Wilting Saskia M. , van Wieringen Wessel N. , van de Wiel Mark A. , Ylstra Bauke , Meijer Chris JLM , Snijders Peter J. 
Published: June 2012

Abstract
High-grade cervical intraepithelial neoplastic (CIN2/3) lesions represent a heterogeneous disease both with respect to clinical behaviour and chromosomal aberrations detected. We hypothesized that the extent of chromosomal aberrations reflects the duration of their existence. To test this hypothesis, chromosomal profiles were determined of CIN3 lesions of women with a known 5 year history of high-risk human papillomavirus virus (hrHPV) infection, in which duration of prior hrHPV infection was considered a proxy for duration of CIN3 lesion existence. Eight women had a &lt;5 year preceding hrHPV infection (CIN3&lt;5yrPHI) and 24 had a PHI lasting ≥5 years (CIN3≥5yrPHI). For comparison, 6 CIN3 lesions adjacent to squamous cell carcinomas (CIN3-SCC), their corresponding SCCs, and 6 CIN1 lesions were included. Unsupervised hierarchical clustering analysis of the chromosomal profiles revealed two clusters. One was characterized by relatively quiet genomic profiles including all CIN1, 75% of CIN3&lt;5yrPHI and 37.5% of CIN3≥5yrPHI. Samples in the second cluster, displaying multiple aberrations, included 62.5% CIN3≥5yrPHI and all except one CIN3-SCC and all SCCs. The number of genomic aberrations increased according to lesion grade and also with longer duration of PHI. The increase in aberrations in CIN3≥5yrPHI compared to &lt;5yrPHI was highly significant (p=0.002), suggesting that CIN3≥5yrPHI represent more severe lesions. In conclusion, a longer duration of preceding hrHPV infection is associated with an increased number of chromosomal aberrations. Hence, CIN3 lesions with a longer duration of existence are more prone to have an increased short-term risk of cervical cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2718. doi:10.1158/1538-7445.AM2011-2718