bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 530: Contribution of fibroblasts isolated from primary lung cancers and normal lung tissue to tumor growth
Authors: Andriani Francesca , Bertolini Giulia , Caserini Roberto , Bursomanno Sara , Gasparini Patrizia , Pastorino Ugo , Sozzi Gabriella , Roz Luca 
Published: June 2012

Abstract
Fibroblasts isolated from cancer specimens have been shown to possess pro-tumorigenic properties, often associated with traits reminiscent of myofibroblasts found at sites of wound healing, but little is known about the mediators of the interaction between fibroblasts and cancer cells especially in lung cancer.
To evaluate the contribution of fibroblasts to lung cancer development we established 60 fibroblast cultures from cancerous and normal lung tissue from primary lung cancer patients, including 18 pairs of normal (NF) and cancer-associated fibroblasts (CAF) from the same patient. The mesenchymal nature of the cultures was confirmed by expression of surface markers CD90, CD166, CD105 and CD73 and negativity for epithelial and hematopoietic markers (ESA and CD45). Further immunophenotyping with markers specific for fibroblasts subpopulations (FSP, vimentin, alpha-SMA, FAP) identified frequent expression of activation markers, with up to 50% of alpha-SMA+ cells. Interestingly activation properties were identified also in cultures derived from normal lung tissue.
Co-mingling of fibroblasts (NF or CAF) with A549 lung cancer cells generally resulted in increased tumor size after injection in nude mice and 2/4 of the CAF cultures tested also increased tumor take when cancer cells were injected at low doses. Human cells were identified by HLA staining in the stroma of tumors grown after co-injection confirming the contribution of the mixed fibroblasts to tumor development. Furthermore medium conditioned by fibroblasts promoted growth of lung cancer cells or immortalized bronchial epithelial cells. All the cultures tested displayed a normal karyotype suggesting that the functional properties of fibroblasts are likely to be the result of epigenetic changes.These results indicate that lung fibroblasts might play a central role in the growth and progression of lung neoplasia. Consistently with their activated phenotype also cultures from normal lung tissue of heavy smokers displayed pro-tumorigenic activity, indicating that the microenvironment of lungs heavily exposed to damage from carcinogenic substances might already be predisposed to foster the growth of transformed epithelial cells. The full dissection of this complex picture might reveal mediators of the cross-talk between stroma and cancer cells and provide novel therapeutic targets.
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 530. doi:10.1158/1538-7445.AM2011-530
Abstract 5329: Degradable multimodal nanoparticles with fluorescence and magnetic resonance contrast
Authors: Papineni Rao V. , McLaughlin William , Vizard Douglas , Reddy Ram 
Published: June 2012

Abstract
Molecular Imaging is making rapid strides as a tool in understanding and the cure of cancer. Like no panacea, here again a need of multimodality exists, where more than one modality is becoming a necessity to cogently decipher the role or action of the biomolecule in the pathology or cure. Here, we developed a multimodal nanoparticle (NP) that can be simultaneously be imaged by optical, and magnetic resonance Imaging (MRI) modalities. In combination, the two modalities compensate each other's deficiencies in the spatial resolution, sensitivity, and the depth detection. Encapsulation of MR contrast and amine functionalization was performed in a one pot synthesis by microemulsion technique with supra magnetic iron oxide (SPIO). The hydrodynamic radii of nanoparticle and zeta potential were measured using Nicomp 380 zls particle sizer. 9L gliosarcoma tumor bearing rat model was administered with the SPIO nanoparticles and validated using 7 tesla MRI scanner. PEGylated SPIO nanoparticles after conjugation with water soluble, near-infrared (NIR) tricarbocyanine, cyclic enamine-functionalized dye, were injected intratumorally and monitored noninvasively using near-IR fluorescence imager. Steady retention in the tumor as compared to the free near-infrared (NIR) dye injected into the control mice indicates the dye-colloidal particle dwell characteristics and suitability for targeted diagnostics. In summary, we have described the development of a simple and efficient dynamic Imaging multimodal nanoparticle to be used for NIRF and MR Imaging.
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 5329. doi:10.1158/1538-7445.AM2011-5329
Abstract 5333: Relationship of osteosarcoma surface marker expression to human mesenchymal stem cells undergoing osteoblastic differentiation
Authors: Park Amy Y. , Tarim John , Bratman Russell E. , Gorlick Richard 
Published: June 2012

Abstract
Osteosarcoma (OS) is the most common primary malignant bone tumor in children and young adults, but it is unknown at what point, in the pathway of differentiation between a human mesenchymal stem cell (hMSC) and a mature osteoblast (OB), OS originates. Identifying the cell of origin is crucial in understanding the molecular pathogenesis of OS. These studies are hampered by the fact that the various steps in the differentiation of human MSC into its more differentiated progenitors are poorly characterized.
In this study, hMSCs were derived from the freshly obtained bone marrow of patients as well as purchased through ATCC. Flow cytometry was used to detect the surface expression phenotype of MSC markers, where CD34 and CD45 were negative and CD44, CD73, CD90, and CD105 were positive. The hMSCs were characterized and all demonstrated multilineage differentiation capacity into adipocytes, chondroblasts, and osteoblasts, which was confirmed by Oil Red O, Alcian Blue, and Alizarin Red S stains, respectively. Osteoblasts were further characterized by measuring osteocalcin protein levels using ELISA. RNA was extracted from hMSCs and OB derived from the same patient and gene expression measured by microarray on the Affymetrix Gene 1.0 ST array. A list of differentially expressed genes was generated, which were narrowed to only include surface markers. Antibodies corresponding to surface markers were used for ELISA and flow cytometry on hMSCs and OBs, to confirm the change in gene expression with differentiation. Further studies will include flow cytometry to define intermediate stages in the differentiation pathway from hMSCs to OBs and their capacity to differentiate into the various mesenchymal lineages.
It has been possible to derive hMSC with pluripotent differentiation capacity from patient bone marrows. These will be utilized to define the patterns of differentiation and ultimately relate to osteosarcoma to help define its progenitor cell. It is hoped that a clearer understanding of the progenitor cell of OS will help find prognostic factors and molecular therapeutic targets.
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 5333. doi:10.1158/1538-7445.AM2011-5333
Abstract 5338: A repressive EWS-FLI1 subsignature is the result of FOXO1 suppression and nuclear exclusion
Authors: Niedan Stephan , Kauer Maximilian , Jug Gunhild , Walker Robert L. , Meltzer Paul S. , Kovar Heinrich 
Published: June 2012

Abstract
The EWS-FLI1 chimeric protein, characteristic of Ewing′s sarcoma (ESFT), constitutes the prototype of an aberrant oncogenic ETS transcription factor. The mechanisms of transcriptional regulation leading to ETS-driven tumorigenesis are poorly understood. In-silico analysis of time-resolved expression data revealed enrichment of ETS binding motifs in EWS-FLI1 activated target promoters, while EWS-FLI1 repressed promoters showed most prominently enrichment of recognition motifs for forkhead box (FOX) proteins. Several FOX genes were found to be bound by EWS-FLI1 in ChIP-seq and transcriptionally affected by EWS-FLI1 knockdown. We therefore hypothesized that EWS-FLI1 exerts an important part of its repressive activity via inhibition of FOX proteins. Upon silencing of EWS-FLI1, both FOXO1 and FOXO3 proteins were strongly induced in ESFT cells consistent with this hypothesis, but only FOXO1 translocated to the nucleus. However, in the presence of EWS-FLI1, ectopic FOXO1 was found excluded from the nucleus as consequence of phosphorylation. Nuclear translocation was restored by either inhibition of CDK2, a directly EWS-FLI1 activated kinase, augmented by chemical inhibition of PI3K, or by mutation of CDK2 phosphorylation sites. These results suggest an important role for CDK2 in FOXO1 repression by EWS-FLI1. To test the contribution of FOXO1 to the EWS-FLI1 repressive signature on the ESFT transcriptome, the overlap between genes activated by EWS-FLI1 knockdown and genes activated by ectopically expressed, nuclear directed FOXO1 was determined and compared to the effects of EWS-FLI1 knockdown under concomitant FOXO1 silencing. A significant overlap between FOXO1 activated and EWS-FLI1 repressed genes was identified (P&lt;10e-20, hypergeometric test). Taken together, these data confirm our hypothesis that a repressive subsignature of EWS-FLI1 regulated genes is due to suppression of FOXO1. Functional restoration of nuclear FOXO1 expression in ESFT cells resulted in impaired proliferation and significantly reduced soft agar colony formation ability suggesting that FOXO1 plays an important role in ESFT oncogenesis.
This study was supported by grant 22328-B09 from the Austrian Science Fund FWF.
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 5338. doi:10.1158/1538-7445.AM2011-5338
Abstract 5375: Reestablishing cell cycle control in breast cancers through therapeutic CDK4/6 inhibition
Authors: Dean Jeffry L. , Thangavel Chellappagounder , McClendon A. Kathleen , Ertel Adam , Knudsen Erik S. 
Published: June 2012

Abstract
One hallmark of cancer is the deregulation of cell cycle machinery, which ultimately serves to promote aberrant proliferation that fuels tumorigenesis and progression. Particularly, the cyclin D1/Rb/E2F axis plays a crucial role in the development of disease by serving to connect aberrant mitogenic signaling with cell cycle transcriptional programs. In this context, the role of estrogen receptor (ER) in breast cancers has been previously described to exert influence upstream of this axis. While first-line strategies targeting ER activity are prevalent and initially effective in the majority of ER-positive breast cancers, acquired resistance and therapeutic failure remain a major clinical challenge. Current analyses have revealed that cell cycle progression is effectively uncoupled from the activity and functional state of ER in these models. As a gene expression signature of cyclin D/Rb/E2F-dysfunction was found to be associated with luminal B breast cancers (which are known to exhibit a relatively poor response to endocrine therapy), the prevalence of ER dysfunction occurring upstream of cyclin D1 suggests that targeting CDK 4/6 activity may be effective. To this end, we examined the therapeutic response to a CDK 4/6 inhibitor (PD-0332991) in human breast cancer cell lines and demonstrated a highly-specific role for Rb in mediating this response, which was dependent on transcriptional repression manifest through E2F activity. These analyses additionally demonstrated that the chronic loss of Rb can promote evolution to a CDK4/6-independent state and near complete resistance to PD-0332991. In addition to these studies, model systems of ER-positive breast cancers with differential susceptibility to endocrine therapy were employed to define common nodes for new therapeutic interventions. These collective findings suggest that suppression of cyclin D-supported kinase activity and restoration of Rb-mediated transcriptional repression could represent a viable therapeutic option in tumors that fail to respond to hormone-based therapies. Consistent with this hypothesis, CDK4/6 inhibiton was effective at suppressing the proliferation of all hormone refractory models analyzed. Combined, these findings underscore the clinical utility of mediating aberrant cell cycle progression through down-stream cytostatic therapies in treating tumors that have experienced failure of first line and endocrine-based therapy, and provide rationale for incorporation of CDK 4/6 inhibition into current existing therapeutic regimens.
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 5375. doi:10.1158/1538-7445.AM2011-5375
Abstract 5379: Ciclopirox induces autophagy through reactive oxygen species-mediated inhibition of mTOR signaling pathway
Authors: Zhou Hongyu , Huang Shile 
Published: June 2012

Abstract
Ciclopirox olamine (CPX), a synthetic antifungal agent clinically used to treat mycoses of the skin and nails, has been recently found to inhibit tumor growth in mouse model of leukemia and breast cancer MDA-MB231. The mammalian target of rapamycin (mTOR), an evolutionarily conserved serine/threonine kinase, is known as a negative regulator of autophagy. Herein, we found that CPX substantially increased GFP-LC3 dots and expression of LC3-II, a hallmark of autophagy, suggesting that CPX induced autophagy. Meanwhile, we discovered that CPX inhibited mTOR signaling in different cancer cell lines, as evidenced by reduced phosphorylation of the downstream targets of mTOR, p70 S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1). Recently, it has been demonstrated that autophagy can be induced by reactive oxygen species (ROS). Interestingly, we further found that CPX treatment dose-dependently induced ROS generation. Pretreatment with N-acetyl-L-cysteine (NAC) suppressed CPX-induced ROS and the conversion of LC3I to LC3II, suggesting that CPX-induced autophagy is mediated by ROS generation. Moreover, the inhibition of phosphorylation of S6K1 and 4E-BP1 by CPX were partially rescued by NAC pretreatment as well. These data suggest that CPX-induced autophagy may be attributed to induction of ROS and subsequent inhibition of mTOR signaling.
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 5379. doi:10.1158/1538-7445.AM2011-5379
Abstract 5384: Amonafide demonstrates a clearly differentiated chemoresistance and chemosensitivity profile when compared to classical TopoII inhibitors
Authors: Green Colin F. , Chau MyDoanh , Christensen Jennifer , Ajami Alfred 
Published: June 2012

Abstract
Background: Amonafide is a novel DNA intercalator that induces apoptosis by mechanisms involving Topo II. Previous pharmacogenomic studies have shown differences between amonafide and classical TopoII inhibitors. Here data from publicly available gene expression studies have been analyzed to determine the chemoresistance and chemosensitivity profiles of amonafide compared to other agents.
Methods: Data were mined from the Stanford, MIT-Broad and NCI databases. A subset of genes associated with drug efflux, chemo-sensitivity & -resistance was selected from the array data. Effects on gene expression were assessed by determining Pearson correlation coefficients (PCC) for gene-drug pairs.
Results: For drug efflux genes & 15 genes associated with cell regulation, amonafide, and 5-azacytidine (azaC) had a positive correlation between expression & cytotoxicity; doxorubicin (Dox), and daunorubicin (Dnr) showed a negative correlation; cytarabine (araC) was unaffected. The chemo-sensitivity and -resistance profiles were determined by identifying the 15 genes with the highest correlation for each of the 5 drugs vs the other 4. Amonafide & aza-C differed clearly from araC, Dnr & Dox. Genes conferring chemosensitivity to amonafide had a negative correlation for araC, Dnr, and Dox. Genes with a positive correlation for araC, Dnr, and Dox, had a negative correlation with amonafide & azaC. A similar pattern of differences was seen for chemoresistance.

Conclusions: Amonafide is a unique chemical entity whose cytotoxicity is not affected by multi-drug resistance expression. Amonafide may evade many of the pharmacogenomic drivers confering resistance to ara-C and anthracyclines. It should therefore retain greater efficacy in combination with araC and as an alternative to anthracyclines, especially in the treatment of myeloid leukemias.
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 5384. doi:10.1158/1538-7445.AM2011-5384
Abstract 5396: LPS mimotopes: A novel class of TLR4 agonist
Authors: Shanmugam Arulkumaran , Rajoria Shilpi , George Andrea , Mittelman Abraham , Tiwari Raj K. , Suriano Robert 
Published: June 2012

Abstract
Adjuvant driven inflammation is crucial to mounting an antigen specific immune response and is initiated by the activation of toll like receptor (TLR) proteins. Currently, aluminum based adjuvants remain the only FDA approved adjuvants for vaccines. In an effort to develop a new class of adjuvants, TLR agonists, would be natural candidates. LPS, a major structural component of gram negative bacteria cell walls, has been well studied for its property to induce the systemic inflammation observed in septic shock. The objective of the present study was to identify peptide mimics of LPS that could activate TLR-4 and induce an inflammatory condition congenial to an adaptive immune response and in contrast to LPS not induce septic shock. To this end we used phage display peptide library to identify and isolate LPS peptide mimics. The activity of LPS-TLR-4 interaction was assessed by NF-κB translocation analyses in HEK-BLUE™-4 cells, a cell culture model that expresses only TLR-4. NF-κB nuclear translocation and inflammatory cytokine production was assayed by using the murine macrophage cell line RAW264.7. Increasing the NF-κB nuclear translocation is reflected by IκB-degradation within the cytoplasm. As expected, the concentration of cytoplasmic NF-κB was also decreased, which further attests to the shuttling of NF-κB within the nucleus. Similar results pertaining to increased nuclear localization of NF-κB with simultaneous decrease of cytoplasmic IκB-α and NF-κB were observed with HEK-BLUE™-4 cells. Thus, the results observed in this study suggest that the LPS peptide mimics identified act as adjuvants by virtue of their interaction with TLR-4 and thus serve as novel candidates to be considered as a new class of TLR-4 agonist adjuvants.
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 5396. doi:10.1158/1538-7445.AM2011-5396
Abstract 5397: Human mesenchymal stem cell-based cell carrier for tumor-homing delivery of replicating retrovirus vectors in glioblastoma models
Authors: Hiraoka Kei , Inagaki Akihito , Logg Christopher R. , Kamijima Shuichi , Hui Kam Man , Marini Frank C. , Kasahara Noriyuki 
Published: June 2012

Abstract
In previous studies, we have demonstrated that replicating murine leukemia virus (RMLV)-based vectors can achieve highly efficient in vivo delivery of prodrug activating genes in glioblastoma models, with infection restricted to actively dividing tumor cells without spread to extratumoral sites, resulting in significantly prolonged survival upon prodrug administration; this approach is now being tested in a multi-center clinical trial.
RMLV vectors can eventually spread to almost all actively dividing GBM cells over time. We are seeking to further improve the efficiency of this novel therapeutic strategy by engineering human mesenchymal stem cells (MSC) to function as RMLV vector producer cells (MSC-VPC). Primary MSC have been shown to actively migrate through tumor masses beyond the immediate injection site and track to diffusely infiltrating tumor foci. In the present study, we developed optimized methods for engineering MSC-VPC, and we then further examined tumor transduction efficiency of MSC-mediated RMLV delivery, and how this delivery method might affect vector replication kinetics in vivo.
First, we evaluated the vector productivity of MSC-VPC in U87 human glioblastoma cells in vitro. Primary human MSCs were infected with RMLV vector AC3-GFP, expressing the GFP marker gene. These MSC were then re-plated at very low density onto a monolayer of naïve U87 glioma cells, and fluorescence was monitored over time. Under the fluorescent microscope, progressive spread of the RMLV vector released from the MSCs could be confirmed, as indicated by increasing GFP(+) U87 cells over time. Next, we tested MSC-VPC in intracranial U87 tumor models in vivo. Five days after intracranial tumor cell implantation, 1E3 transduction units (TU) of AC3-GFP vector or 5E3 MSC-VPC (∼20% pretransduced with AC3-GFP) were stereotactically injected at the tumor site. Tumors were harvested and digested on day 9 for FACS analysis to detect GFP expression. While the highest percentage of GFP(+) cells was 28.6% in the vector supernatant-treated group, up to 45% transduction efficiency was achieved in the MSC-VPC group. These results suggest the use of MSCs as tumor-homing carriers may be provide more efficient delivery of RMLV vectors in human glioma models.
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 5397. doi:10.1158/1538-7445.AM2011-5397