bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 35: Genome-wide molecular profiling of peri-tumoral neocortex revealed genes possibly responsible for tumor-induced epilepsy
Authors: Li Xiaojin , Xu Jun , Fan Xuemo , Niesen Charles E. , Wang Charles 
Published: June 2012

Abstract
Epilepsy is a common cause of morbidity affecting approximately one third of patients with primary brain tumors. The molecular mechanism underlying the tumor induced epileptogenesis is poorly understood. Since the alteration in the peritumoral microenvironments is believed to play a significant role in inducing the epileptic state, we hypothesize that the change in gene expression of neighboring astrocytes and neurons may contribute to the increased neuronal excitability. To identify the genes possibly responsible for tumor induced epilepsy, a genome-wide gene expression profiling was conducted using Affymetrix HG U133 plus 2.0 arrays and RNAs derived from 1-5 year old formalin-fixed paraffin embedded (FFPE) peritumoral cortex from 5-paired (seizure vs. non-seizure) low grade brain tumor patients. RNAs were extracted from 3-5 microdisections of FFPE tissue blocks using Qiagen RNeasy FFPE kit and cDNA were synthesized and amplified using NuGen's WT-Ovation FFPE RNA amplification system and FL-Ovation cDNA biotin module. Our results showed that although FFPE derived RNAs were significant fragmented with a peak of 100-200 bases, gene detection rate was found to be significant high (up to 49.8%) with excellent 3’/5’ ratios (GAPDH, 1-3.4). The rate of gene detection is depending on the archive time of tissue blocks (correlation coefficient = -0.71, P&lt; 0.05). We identified 345 differentially expressed genes (DEGs, 2-fold plus P &lt; 0.05). Principal Component Analysis (PCA) based on both global genes and 345 DEGs showed that epilepsy samples were clustered together tightly (except one sample) and were clearly separated from the non-epilepsy samples. Gene Ontology (GO) analysis on 345 DEGs revealed several important functional groups of genes including signal transduction (20.6%), metal ion binding (18.2%), cation binding (17.9%), receptor activity (10.8%) and receptor binding (4.0%). Other significant DEGs include transcription factors, glutamate receptors and intercellular matrix proteins. Pathway analysis showed these 345 DEGs were mainly involved in focal adhesion (12 genes), ECM-receptor interaction (11 genes) and cell communication (9 genes) pathways. In conclusion, our study showed that (1) archival FFPE brain tissue is an excellent resource for genomic studying; and (2) the altered gene expression in the peri-tumoral neurons implicate multiple cellular pathways in the induction of the epileptic state. Identification of genes responsible for brain tumor-induced epilepsy may lead to novel and better management of epilepsy in brain tumor patients.
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 35. doi:10.1158/1538-7445.AM2011-35
Abstract 3500: Histone deacetylator (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA) sensitizes squamous carcinoma cells of lung to pemetrexed
Authors: Kim Soyeon , Kim Tae Min , Lee Se-Hoon , Kim Dong-Wan , Heo Dae Seog 
Published: June 2012

Abstract
Objectives: The multitargeted antifolate pemetrexed is approved as a first-line or second-line treatment of nonsquamous nonsmall cell lung cancer. The expression of the thymidylate synthase (TS) gene may mediate resistance to pemetrexed. In this study, we investigated whether the pemetrexed in combination with SAHA enhances the cytotoxicity of squamous carcinoma cells of lung.
Methods: Squamous carcinoma cells of lung (NCI-H157, HCC-95 and HCC-1588) were exposed to 10-3M to 10-7M of pemetrexed with various HDAC inhibitors and their cytotoxicities were analyzed using the colorimetric assay. Cell cycle and apoptosis analyses were evaluated by flow cytometry. The mRNA and cellular protein levels were detected by RT-PCR and western blot assay.
Results: After NCI-H157 was exposed to SAHA, TS mRNA and protein expression levels were strongly suppressed by time and dose-dependent manner, respectively. Additionally, although pemetrexed activated phosphorylation of AMPK-α, secondary target (AICAR) of pemetrexed, co-treatment of pemetrexed and SAHA decreased phosphorylation of AMPK-α and mTOR pathway. NCI-H157, HCC-95, and HCC-1588 treated with sequential SAHA (24h) followed by SAHA plus pemetrexed (72h) represented more synergistic cytotoxicities than those treated with simultaneous 96h exposure combination (p&lt;0.05). This sequential treatment was significantly associated with TS inhibition as well as apoptosis of squamous carcinoma cells. While pemetrexed increased expressions of p21, PARP, and cleaved caspase 3 and reduced expression of bcl-2, the combination of pemetrexed and SAHA additionally increased the pro-apoptotic molecules. Sequential treatment of SAHA followed by pemetrexed resulted in 10-fold and 1.6-fold higher sub-G1 portions than control and pemetrexed alone groups, respectively in NCI-H157 cell. In particular, the sequential administration produced more apoptotic index as compared to pemetrexed alone in NCI-H157 cell (27% vs 8%).
Conclusion: Our results demonstrate SAHA reduces TS expression and sequential treatment with pemetrexed has a synergistic cytotoxicity in squamous cell carcinoma of lung.
Sequential treatment of SAHA and pemetrexed might be a new strategy to overcome pemetrexed resistance in patients with squamous cell carcinoma of lung.
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 3500. doi:10.1158/1538-7445.AM2011-3500
Abstract 3515: Combined effects of leptomycin B and doxorubicin on lung cancer
Authors: Lu Chuanwen , Cobos Everardo , Gao Weimin 
Published: June 2012

Abstract
To develop novel molecularly targeted therapy has become an important focus of research efforts in lung cancer treatment. Our previous study has shown leptomycin B (LMB), by blocking chromosome maintenance region 1 (CRM1), significantly inhibits cell proliferation in lung cancer cells in a p53-dependent manner. These results suggest the potential use of LMB as a new therapeutic regimen for lung cancer treatment. On the other hand, doxorubicin (DOX) is one of the most effective anticancer agents, which induces p53 activation and nuclear accumulation. The objective of this study is to determine the combinative cytotoxic and molecular effects of LMB and DOX on lung adenocarcinoma cell line, A549. Cells were treated with DOX alone, pre-treatment of DOX/LMB and subsequent treatment of LMB/DOX, or DOX and LMB simultaneously. Cell viability was measured by the MTT assay. The inhibitory effects of DOX on A549 were dose and time-dependent (P&lt;0.001). The 50% inhibitory concentrations (IC50s) of DOX at 24, 48, and 72 h were 60.0, 2.2, and 1.7 µM, respectively. The pre-treatment of 0.5 µM DOX for 24 h significantly improved the cytotoxic effects of LMB on A549 cells at 48 h (P&lt;0.05). The resulting IC50 of LMB was decreased more than 2 fold after pre-treatment of DOX (4.4 nM) as compared to that of LMB alone (10.6 nM). However, the pre-treatment of LMB and the simultaneous treatment of DOX and LMB did not change the cytotoxic effects of either treatment of LMB or DOX. p21 and survivin are well-known p53 downstream genes that play important roles in cell cycle arrest and/or apoptosis. The protein expression levels of these two genes were further analyzed by western blots. Our results showed that the protein expression level of p21 was significantly increased while the protein expression level of survivin was significantly decreased in A549 cells treated with either pre-treatment of DOX and LMB or LMB alone in comparison with those of controls. Furthermore, these changes were more pronounced in pre-treatment of DOX and LMB group as compared to those of LMB alone group. Taken together, our data suggest that the combined therapy using an initial DOX treatment (through activating p53) and subsequent LMB treatment (through blocking the CRM1 function to accumulate activated p53 in the cellular nucleus), that lead to the activation of p53 downstream transcripted genes for cell cycle arrest and apoptosis, might be more effective as a new therapeutic strategy for lung cancer treatment.
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 3515. doi:10.1158/1538-7445.AM2011-3515
Abstract 3521: Alleviation of cancer chemotherapeutic agent-induced toxicity by the synthetic panaxytriol analogues of Panax Ginseng
Authors: Chou Ting-Chao , Dong Huajin , Zhang Xiuguo , Lei Xiaoguang , Danishefsky Samuel J. 
Published: June 2012

Abstract
Therapeutic index (TI) of cancer therapeutic agent is the ratio of maximal tolerated dose (MTD) and the optimal therapeutic dose (OTD). “Reduction in toxicity” and/or “increasing efficacy” by augmentation or synergy will invariably lead to improved TI and patient's well-being during therapy. We found a series of polyacetylene small molecules that is promising just to do that. Through total synthesis, we designed the panaxytriol (PXT) analogs of panax ginseng C.A. Meyer, such as PXTA, PXTAI, PXTAEI and its isomers that are biologically more active than their parent natural ingredient, PXT. At sub-toxic doses, the PXT-compounds, as a single entity (e.g., not an extract, mixture or preparation), are found to process the following intriguing pharmacological properties that have potential applications in cancer chemotherapy or radiation therapy. They are: (i) Exhibited moderate anti-tumor effect in the absence of any toxicity, and slightly augment or synergize anti-tumor effect of taxol or epothilones, in xenograft tumor bearing nude mice; (ii) Significantly or markedly reduced cancer therapeutic agent-induced toxicity such as body-weight losses (e.g., by Taxol, iso-oxazole fludelone, iso-oxazole dehydelone, 5-FU, cyclophosphamide), lethality (e.g., high dose 5-FU) and neurotoxicity (e.g., peripheral neuropathy induced by Taxol); (iii) Showed moderate anti-inflammatory effect in foot-paw-carrangreenan assays in CD-1 mice; (iv) Improved the hematological parameters following high dose 5-FU; (v) The alleviation of body-weight loss also manifested by the oral administration; (vi) Reduced the radiation-induced body-weight loss in CD-1 mice; (vii) Reduced the lethality of radiation; and (viii) Induced the cancer preventive phase II enzyme, quinone reductase (NQ01). PXT-analogs also stimulated human PBMC proliferation in a biphasic and delayed manner in vitro and stimulated splenocyte proliferation of CD-1 mice in delayed manner, suggesting the immuno-enhancing effect. In conclusion, our results demonstrate that co-administration of PXT-based agent with a range of cancer chemotherapeutic agents or radiation therapy will decrease various therapy-associated toxicities and thus increase the therapeutic index. These findings indicate a promising improvement for the cancer chemotherapeutic or radiation therapeutic strategies.
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 3521. doi:10.1158/1538-7445.AM2011-3521
Abstract 3536: Caulobacter crescentus as new intravesical treatment for bladder cancer
Authors: Gust Kilian M. , Lange Dirk , Nomellini John F. , Smit John , So Alan I. 
Published: June 2012

Abstract
Introduction and Objectives: The standard of care for high risk non-muscle invasive bladder cancer is the intravesical instillation of Bacillus Calmette-Guérin (BCG), an attenuated strain of the pathogen Mycobacterium bovis, associated with significant side effects often ending treatment prematurely. Using nonpathogenic bacterial strains with anti-tumor activity would thus be beneficial. Caulobacter crescentus is a gram-negative, non-pathogenic fresh water bacterium that does not replicate in a mammalian host and therefore qualifies for having a good bio-safety profile. Caulobacter crescentus has previously been shown to have anti-tumor activity in a model of mammary carcinoma. The aim of this study was to evaluate the anti-tumor activity of intravesical administered Caulobacter cresecentus in an immuno-competent animal model for bladder cancer.
Materials and Methods: In vitro, the mouse bladder tumor cell line MBT-2, derived from C3H/He mice, was treated with increasing concentrations of Caulobacter crescentus (C.cresc.). Microscopy and growth assays were performed. In vivo, the same cell line, previously lenti-viral transduced with a luciferase gene (MBT-2 luc), was instilled in the bladder of 6 week old, female C3H/He mice (3×106 cells/50ul). Bioluminescent imaging was performed to determine tumor burden on day 5 and mice were randomized to treatment groups. Intravesical treatments (109 C.cresc. in 50ul of H2O or H2O as control) were performed on days 6, 8, 11 and 15 and tumor growth was examined by bioluminescence after i.p. injection of luciferin. Mice were euthanized on day 20 and mouse bladders processed for histology and immuno-histochemistry.
Results: In vivo, intravesical treatment of MBT-2 luc tumor bearing C3H/He mice showed a significant inhibition of tumor growth compared to the control group, while no side-effects due to the intravesical C.cresc. application were observed.
Additionally performed in vitro experiments revealed that incubation of MBT-2 cells with C.cresc. resulted in a concentration dependent growth inhibition.
Conclusions: These preliminary results support the safety and efficacy of Caulobacter crescentus as a novel intravesical treatment for bladder cancer. Further investigation is needed to reveal the exact mechanism of action and to distinguish, if a direct anti-tumor effect of C.cresc. or the host immune-response is the driving component of the anti-tumor effect.
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 3536. doi:10.1158/1538-7445.AM2011-3536
Abstract 3538: In vivo combination studies of PM01183 with alkylating, antimetabolites, DNA-topoisomerase inhibitors and tubulin binding agents
Authors: Guillén Ma José , Cataluña Oscar , Palomares Mandy , Lopez Raquel , Cuevas Carmen , Aviles Pablo M. 
Published: June 2012

Abstract
PM01183 is a new synthetic tetrahydroisoquinoline alkaloid that binds to selected DNA sequences and promotes apoptosis by inducing double-strand breaks at nanomolar concentrations. PM01183 displays significant antitumor activity in several murine models of human cancer. PM01183 is currently in phase I/II clinical development for cancer treatment. Nonclinical combination studies are increasingly relevant during the development of any anticancer compound. As such, PM01183 was assayed in combination (two-drugs) with representatives of alkylating agents (dacarbazine, temozolomide and cisplatin), antimetabolites (5-FU and gemcitabine), DNA-topoisomerase inhibitors (irinotecan and doxorubicin) and tubulin binding agents (paclitaxel and vinorelbine). Different models were used depending on the combination explored: STS (HT1080) for dacarbazine; glioma (U-87 MG) for temozolomide; gastric (HGC-27) for cisplatin and 5-FU; pancreas (SW1990) for gemcitabine; colon (HT-29) and NSCLC (H460) for irinotecan; and ovarian (A2780) for doxorubicin, paclitaxel and vinorelbine. Athymic nu/nu mice bearing tumors (ca. 150 mm3) were randomly allocated to 13 treatment groups: i) placebo; ii) PM01183 at 4 different dose levels, namely MTD (0.180 mg/kg), 0.75MTD, 0.5MTD and 0.25MTD; iii) Compound to be combined, at 4 different dose levels MTD, 0.75MTD, 0.5MTD and 0.25MTD; and, iv) PM01183 plus the combined compound, administered with the combination at (1+1), (0.75+0.75), (0.50+0.50) and (0.25+0.25) of MTD ratios. The antitumor activity was followed by T/C, (change in tumor volume for each treated -T- and placebo -C- groups during placebo-treated survival period). Then, the fraction affected (Fa) by the treatment was calculated (1-T/C) and, the combination index (CI) by the CI-isobol method determined. Synergism (CI ≤ 1 at Fa &gt; 0.8) was recorded when PM01183 was combined with dacarbazine (HT1080), cisplatin (HGC-27), 5-fluororacil (HGC-27), gemcitabine (SW1990), irinotecan (H460), doxorubicin (A2780), paclitaxel (A2780) and vinorelbine (A2780).
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 3538. doi:10.1158/1538-7445.AM2011-3538
Abstract 3542: A novel Hedgehog pathway inhibitor in combination with chemotherapy in mesothelioma cell lines
Authors: Lui Natalie , Li Hui , Do Hanh , Sheng Qing , Jablons David , He Biao 
Published: June 2012

Abstract
We tested a novel Hedgehog pathway inhibitor in combination with chemotherapy to determine if there are synergistic effects in mesothelioma cell lines. The Hedgehog signaling pathway has been shown to be activated in many types of cancer. Our laboratory developed a novel Hedgehog pathway inhibitor that has promising characteristics. Several mesothelioma cell lines were treated with this new compound in combination with two standard chemotherapeutic agents, pemetrexed and cisplatin. The cells were seeded in 96-well plates on day 1 and then treated with a matrix of drug dosages on day 2. Cell viability was measured on day 5 using the CellTiter-Glo Luminescent Cell Viability Assay (Promega). The dose-effect relationship was plotted for each drug alone to determine the IC50, the inhibitory concentration at which cell viability was 50%. The IC50 of our Hedgehog inhibitor ranged from 1uM to 10uM for various cell lines. The dose-effect relationship in the combination studies was analyzed using Calcusyn (Biosoft). A combination index less than 0.9, indicating synergy, was found at several dose combinations in multiple cell lines. In summary, a novel Hedgehog pathway inhibitor in combination with chemotherapy showed synergy in multiple mesothelioma cell lines, showing high potential for this new compound to improve standard chemotherapeutic regimens and allow treatment at lower doses with fewer side effects.
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 3542. doi:10.1158/1538-7445.AM2011-3542
Abstract 3545: Autophagy inhibition as a therapeutic strategy in cancer
Authors: Chen Ning , Price Sandy , Karantza Vassiliki 
Published: June 2012

Abstract
Autophagy is an evolutionarily conserved process involving degradation of cellular components in lysosomes to maintain protein and organelle quality control, and temporarily sustain cell viability in response to stressful stimuli. Several studies have demonstrated the dual role of autophagy in tumorigenesis as both a tumor suppressor and a protector of cancer cell survival under stress. It is well recognized that anticancer therapies, such as chemotherapy and irradiation (RT), induce autophagy as a pro-survival response, likely resulting in therapeutic resistance. Therefore, concurrent autophagy inhibition as a chemo- and RT-sensitizer has generated great interest in cancer therapy. We generated Beclin1+/+ and Beclin1+/- immortalized mouse mammary epithelial cells (iMMECs) stably expressing the apoptosis inhibitor BCL-2 and the autophagy marker EGFP-LC3 to investigate how acute autophagy inhibition and chronic autophagy deregulation impact tumor sensitivity to anticancer drugs commonly used against breast cancer. We also used human cancer cell lines, including MCF-7, PANC-1, MIA PaCa-2 and HCT-116 cells, to explore whether pharmacologic autophagy inhibition or genetic knockdown of autophagy regulators exhibits a synergistic anticancer effect with newer antineoplastic drugs, such as mTOR inhibitors (CCI-779 and RAD001) and novel antimicrotubule agents (ixabepilone). Treatment efficacy was evaluated by clonogenic survival and cytotoxicity assays in 2D- and 3D-epithelial cell culture in vitro and by tumor responsiveness assays in mice in vivo. Autophagy inhibition sensitized Beclin1+/+ apoptosis-defective iMMECs to doxorubicin, but not to paclitaxel, and had an even greater impact on autophagy-deficient cells. Moreover, autophagy inhibition via choloroquine or Beclin1 knockdown enhanced the treatment efficacy of mTOR inhibitors on MCF-7, PANC-1, MIA PaCa-2 and HCT116 cells in vitro and in xenograft tumors in nude mice in vivo. These studies provide insight into how autophagy functional status in tumors impacts treatment responsiveness and into how to best incorporate pharmacologic autophagy modulation in the decision tree for cancer treatment.
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 3545. doi:10.1158/1538-7445.AM2011-3545
Abstract 3546: Cucurbitacin B as a direct mTOR inhibitor synergizes with methotrexate for treatment of human osteosarcoma
Authors: Lee Dhong Hyun Tony , Thoennissen Nils , Goff Catherine , Iwanski Gabriela , Doan Ngan , Said Jonathan , Koeffler H. Phillip 
Published: June 2012

Abstract
The mammalian target of rapamycin (mTOR) pathway is one of the most important oncogenic pathways in cancer, and the upregulation of the mTOR pathway is frequently observed in human osteosarcoma (OS). In this study, we demonstrated for the first time that cucurbitacin B, a plant-derived tetracyclic triterpenoid, is a direct mTOR inhibitor in OS using drug affinity responsive target stability (DARTS) analysis. Binding of cucurbitacin B to mTOR resulted in the inhibition of mTOR phosphorylation in MG-63 and SAOS-2 human OS cells in vitro, which was further confirmed by the inhibition of ribosomal S6 protein kinase (S6K) and eukaryotic translation initiation factor 4E binding protein 1 (4EBP1). This finding led us to hypothesize the possible use of cucurbitacin B as a single agent as well as in combination with methotrexate (MTX) for OS treatment. Cucurbitacin B in combination with MTX synergistically inhibited OS cell growth in vitro such that combination index (CI) &lt; 0.9. Murine xenografts treated with either low-dose cucurbitacin B (LD-CuB, 0.5 mg/kg body weight) or low-dose MTX (LD-MTX, 150 mg/kg) alone failed to decrease tumor size. However, combined therapy at identical concentrations inhibited tumor growth by 62% vs LD-CuB and 81% vs LD-MTX (p&lt;0.001). The effect persisted even at a two-thirds decrease (50 mg/kg) in the MTX dose. In conclusion, cucurbitacin B is a direct inhibitor of mTOR, and the combined use of cucurbitacin B with MTX showed promising antiproliferative activity against human OS. The use of this combination should be explored further in clinical studies.
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 3546. doi:10.1158/1538-7445.AM2011-3546