bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B19: Cigarette smoke promotes human airway epithelial migration through temporal coordination of p120-catenin-dependent and -independent pathways
Authors: Zhang Lili , Gallup Marianne , Zlock Lorna , Finkbeiner Walter E. , McNamara Nancy A. 
Published: June 2012

Abstract
Background: Cigarette smoking has been linked to almost all major types of cancer. Emerging evidence suggests that smoking initiates transformed cell growth and migration by disrupting cell-cell interactions in the polarized mucosal epithelium. Together with other adherens junction proteins, p120-catenin (p120ctn) maintains cell-cell adhesion through its direct interaction with E-cadherin. Mislocalization and/or loss of p120ctn have been reported in all lung cancer subtypes and are related to poor prognosis. Our purpose was to investigate the initiating (intact p120ctn) and late (loss of 120ctn) events of smoke-promoted lung carcinogenesis using primary human bronchial epithelial (HBE) cells.
Methods: Wide-type and p120ctn-knockdown HBE cells exposed to cigarette smoke-conditioned medium were used to mimic the early and late progressive stages of lung cancer. Signaling cascades and cell migration under the two conditions were investigated.
Results: Src and Jnk activation by smoke were delayed in p120ctn-knockdown cells and inhibition of migration through the chemical blockade of EGFR, Src, and/or Jnk was dependent on p120ctn. In contrast, chemical inhibition of signaling via Akt (cell survival) or Erk (cell proliferation) was sufficient to block smoke-induced migration independent of p120ctn. Also independent of p120ctn was smoke's effect on the RhoGTPase, Rac1. Rac1 knockdown abolished dephosphorylation of actin binding protein, cofilin, in the presence and absence of p120ctn, indicating its essential role in smoke-induced cell migration.
Conclusions: These studies provide unprecedented insight regarding the multiple and interdependent molecular strategies employed by smoke to escape tightly regulated cellular processes such as cell migration, proliferation, and survival.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B19.
Abstract B45: Embryogenesis meets tumorigenesis: Nodal/activin signaling drives self-renewal and invasiveness of pancreatic cancer stem cells
Authors: Lonardo Enza , Hermann Patrick C. , Mueller Maria-Theresa , Miranda-Lorenzo Irene , Heeschen Christopher 
Published: June 2012

Abstract
Nodal and activin belong to the TGF-β superfamily and are important regulators of embryonic stem cell fate. Here we investigated whether Nodal and/or Activin regulate self-renewal and invasiveness of pancreatic cancer stem cells. While their expression was hardly detectable in differentiated pancreatic cancer cells, cancer stem cells demonstrate a drastic upregulation for Nodal and, to a lesser extent, Activin while TGF-β remained unchanged. Pancreatic stellate cells as the putative microenvironment for cancer stem cells produce very high amounts of Activin, and, to a lesser extent, Nodal. Knockdown and pharmacological inhibition of their common receptor Alk4/7 both significantly, but reversibly reduced cancer stem cell self-renewal / invasiveness and cancer stem cells subsequently became sensitive to gemcitabine. Importantly, while orthotopically engrafted primary human cancer cell suspensions were highly responsive to Nodal/Activin inhibition plus gemcitabine, engrafted primary human pancreatic cancer tissue xenografts containing massive stroma did not slow down tumor progression. Intriguingly, the addition of a stroma-targeting sonic hedgehog pathway inhibitor resulted in enhanced delivery of the Nodal/Activin inhibitor and gemcitabine, respectively, and translated into long-term disease stabilization. Therefore, modulation of the Alk4/7 pathway, if combined with hedgehog pathway inhibition and gemcitabine, provides a novel therapeutic strategy for targeted elimination of cancer stem cells in order to overcome their resistance towards gemcitabine.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B45.
Abstract B56: Organelle targeted photodynamic therapy
Authors: Dhar Shanta 
Published: June 2012

Abstract
The success of a cancer treatment is directly related to its ability to selectively kill cancer cells. Photodynamic therapy (PDT) with a photosensitizer (PS) that targets mitochondria causes a prompt release of cytochrome c into the cytoplasm and activation of caspases-9 and -3, among other caspases, that are responsible for initiating cell degradation. Photofrin is the FDA approved drug for PDT. Mitochondria have repeatedly been implicated as primary targets of porphyrin mediated PDT. However, a systematic study to direct the PDT drugs towards their cellular target, mitochondria of the cancer cell, is not yet fully explored. Phthalocyanins (Pc) are a class of compounds, which are known to successfully address the drawbacks exhibited by the porphyrin-based compounds. PDT, using the second-generation Pc, causes mitochondrial damage and induces apoptosis. However, the Pc molecules are hydrophobic and must be encapsulated within a liposomal formulation for successful delivery. Given that most effective PDT drug candidates act on the mitochondria of cancer cells and their hydrophobicity require suitable delivery vehicles for their intracellular accumulation, we hypothesize that the construction of engineered targeted drug delivery systems to direct PDT drugs to the mitochondria of the cancer cells would allow an effective phototherapeutic action. This would result in a higher local concentration of singlet oxygen in the mitochondria of cancer cells. In order to study this hypothesis, we have initiated the synthesis of a series of mitochondria targeting polymers to study nanoparticle (NP) assisted targeted delivery and anticancer properties of metallo phthalocyanins. The synthesis and biological activity of these constructs will be discussed.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B56.
Abstract C23: Epigenetic regulation of miRNAs and influence on malignancy in Ewing tumors
Authors: Richter Guenther H.S. , Plehm Stephanie , Burdach Stefan 
Published: June 2012

Abstract
Although microRNAs (miRNA) were shown to be involved in cancer progression of many tumor entities, little is known about the role of non-coding RNAs in Ewing Tumor (ET) pathogenesis. The highly malignant ET comprise the second most common type of bone associated cancers in children and are characterized by oncogenic ews/ets translocations. We previously observed the histone methyltransferase Enhancer of Zeste, Drosophila, Homolog 2 (EZH2) to be regulated by EWS-FLI1 and highly increased in ET.
Here we demonstrate that EZH2 occupies promotor regions of putative tumor suppressor miRNAs and differentiation associated miRNAs in ET. We show that EZH2 mediates silencincig of miRNA expression via histone modification as well as DNA methylation and that these miRNAs are reactivated upon EZH2 knock down or treatment with inhibitors histone deacetylation and DNA methylation. In addition, we show that the well-known oncogenic miRNA221 is highly expressed in ET and processed in the presence of Argonaute (AGO) protein 2. Using RNA interference we observed that AGO1 and AGO2 mediated processes affect cellular invasiveness and anchorage-independent proliferation in vitro and influence ET growth and metastasis in immunodeficient Rag2−/−γC−/− mice, confirming an involvement of non-coding RNAs in ET pathogenesis.
Taken together, these data illuminate the hitherto unknown epigenetic regulation of miRNA expression by EZH2 in ET and a general involvement of noncoding RNA in ET-pathogenesis, opening the avenue for new therapeutic modalities i.e. the implementation of miRNA therapeutics.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C23.
Abstract C38: Berberine/cisplatin-based radiotherapy for cervical cancer: The new and effective method to treat cervical cancer
Authors: Komal Komal , Naseem Akhtar , Deshwal Vishal Kumar , Sharma Alpana 
Published: June 2012

Abstract
Background: Cervical cancer is the most common cancer in Indian females. The present treatment regime for cervical cancer is radiotherapy based on DNA crosslinking agent like cisplatin which is associated with various side effects. Berberine, a chemopreventive agent, is a natural compound extracted from Berberidaceae family that allows suppression and retardation of carcinogenesis and effectively inhibits inflammation. The objective of this study was to compare the cisplatin-based radiosensitization with a berberine/cisplatin-induced radiosensitization.
Methods: HeLa, SiHa, and Ca Ski cells were cultured in DMEM medium supplemented in 10% FBS in a humidified atmosphere of 95% air and 5% CO2 at 37°C and were treated with 75 μM berberine/10 μg cisplatin and 10 μg cisplatin alone for 24 hrs followed by 2 Gy radiation dose from radiation source. Cells which were not sensitized with berberine/cisplatin were also treated with variable radiation doses. Apoptosis was measured by flow cytometery, protein expression was assessed using Western blotting, and caspase activity was measured using synthetic substrates.
Results: Treatment of cervical cancer cells with berberine/cisplatin combination dose followed by radiation resulted in increased apoptosis in comparison to cisplatin sensitization and exposure to radiation. The combination of berberine/cisplatin resulted in increased expression of proapoptotic Bax, p73 and downregulation of antiapoptotic Bcl XI, inflammatory Cox 2, cyclin D1 and effective reduction in activity of telomerase in comparison to cisplatin-based radiotherapy. The combination dose also resulted in increased activation of caspase-9 and -3.
Conclusion: The present study indicates that berberine has the potential to make cervical cancer therapies more effective and safer with minimization of side effects which are associated with generation of excessive reactive oxygen species in present cisplatin-based therapy regime.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C38.
Abstract C56: Characterization of PinX1 as a coregulator of steroid hormone receptors
Authors: Noriega Yamilet , Rivas Miguel , Langley Elizabeth 
Published: June 2012

Abstract
Introduction: Deregulated expression of transcriptional coactivators and corepressors has been implicated in tamoxifen (TAM) resistance, especially in ER+ breast cancer patients. The AF-1 transcriptional activation domain in the N-terminus of ER has been implicated in the tissue specific agonistic effects of TAM. Thus, using the yeast two-hybrid system with the N-terminal region of ERα, we located the PINX1 gene which encodes for a telomerase inhibitor.
Objective: In this work, we characterized PinX1 as a coregulator of ERα.
Methods and Results: Using GST pull-down assays, we confirmed the direct interaction between PinX1 and the N-terminus of ERα, showing no interaction with the C-terminus either in the presence or absence of estradiol (E2). Transcriptional activation assays using luciferase reporter genes show that PinX1 is capable of increasing ERα transcriptional activity in breast cancer cell lines, at low concentrations, but increasing PinX1 exhibits a negative effect on the transcriptional activity of ERα in these cell lines. However, Pinx1 repressed AF-1 transcriptional activity, as well as AF-2 activity in the presence of E2. ChIP assays verified that the interaction between ERα and Pinx1 occurs on E2 regulated promoters after 2h of incubation with E2. Furthermore, PinX1 inhibits E2 induced proliferation of MCF7 cells, while inhibition of PinX1 by siRNA increases E2 induced proliferation. These results suggest a role for PinX1 as a correpresor of ERα. PinX1 also interacts with the androgen and progesterone receptors. However, we demonstrate that PinX1 is a coactivator of these receptors by luciferase assays, as well as increasing DHT induced proliferation of prostate cancer cell lines. Enhanced expression of PinX1 also deregulates the expression of a number of genes that have a role in cell growth and proliferation in breast cancer cell lines.
Conclusions: Our data support a dual role for PinX1 as a correpresor of ERα and a coactivator of AR and PR. Additionally, it may be involved in functions regulating cell growth and proliferation in both breast and prostate cancer cell lines.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C56.
Abstract IA1: Building molecules to guide anticancer therapy
Authors: Olson Emilia S. , Tsien Roger Y. , Savariar Elamprakash N. , Crisp Jessica L. , Jiang Tao , Aguilera Todd A. , Whitney Mike A. , Steinbach Paul , Ellies Lesley G. , Nguyen Quyen T. 
Published: June 2012

Abstract
For clinical imaging, we need synthetic molecules with novel amplifying mechanisms for homing to diseased tissues. Activatable cell penetrating peptides (ACPPs) are polycationic cell penetrating peptides (CPPs) whose cellular uptake is minimized by a polyanionic inhibitory domain and then restored upon proteolysis of the peptide linker connecting the polyanionic and polycationic domains. Local activity of proteases able to cut the linker causes amplified retention in tissues and uptake into cells. ACPPs on dendrimers labeled with Cy5 and Gd-DOTA enable whole body magnetic resonance imaging (Olson et al (2010) PNAS 107: 4311–4316) followed by fluorescenceguided surgery. Such fluorescence guidance improves tumor-free survival in two animal models (Nguyen et al (2010) PNAS 107: 4317–4322). Contrast for tumor over normal tissues is amplified and accelerated when the polyanionic domain includes an acceptor of fluorescence resonance energy transfer (FRET), because loss of FRET (monitored either by multispectral emission or donor excited-state lifetime) instantly signals proteolysis without waiting for uncleaved substrate to wash out of normal tissues. Thrombin-cleavable ACPPs accumulate in atherosclerotic plaques, and their labeling intensity seems to correlate with progression towards rupture. Separately, we have developed fluorescent peptides that light up peripheral nerves to show surgeons where not to cut (Whitney et al (2011) Nature Biotech. 29: 352–356). Thus we believe that basic tumor biology and molecular design can help improve early detection and surgical resection, not just chemotherapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr IA1.
Abstract IA16: Technologies for detecting and analyzing proteins in living cells
Authors: Tina Alice Y. 
Published: June 2012

Abstract
Two technologies will be described: (1) a generic way to label specific recombinant proteins inside living cells with any chemical probe, and (2) a way to map the proteomic composition of subcellular compartments of living, intact cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr IA16.
Abstract IA20: DNA methylation and nucleosome repositioning in cancer
Authors: Jones Peter A. 
Published: June 2012

Abstract
Epigenetic processes are reinforced by interactions between covalent chromatin marks such as DNA methylation, histone modifications, and variants. These marks ultimately specify the locations of nucleosomes particularly with respect to transcriptional start sites and in regulatory regions. Understanding how the epigenome functions therefore requires a coordinated approach so that the mechanisms by which the chemical modifications interact with nucleosomal remodeling machines are achieved to ensure epigenetic inheritance and control of gene expression. We have developed a new methodology to simultaneously map nucleosomal positioning and DNA methylation on individual molecules of DNA. We used this nucleosomal mapping technology to ascertain alterations in nucleosomal positioning during the abnormal silencing of genes by promoter hypermethylation. These experiments show that the methylation of CpG islands at the transcriptional start sites of key tumor suppressor genes results in the stable placement of nucleosomes at the transcription start site. Inhibition of DNA methylation by 5-azanucleoside treatment results in an immediate inhibition of DNA methylation and a sequence of downstream events which ultimately result in the eviction of the nucleosomes from the transcription start site and the activation of gene expression. Interestingly this process requires the insertion of the histone variant H2AZ downstream and upstream of the transcriptional start site for full gene activation to occur. Thus inhibition of DNA methylation by these drugs which are used to treat myelodysplastic syndrome results not only in the removal of DNA methylation but in the resetting of chromatin to an active state. Genes activated in this way often undergo resilencing when the drug is removed so that understanding the precise nature of these alterations is essential in the design of the next generation of epigenetic therapies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr IA20.
Abstract IA25: Using old mouse models to identify new cancer drug targets
Authors: Hemann Michael T. 
Published: June 2012

Abstract
Effective cancer therapy, using surgery, radiotherapy, or chemotherapy results in the absence of macroscopic disease either at the site of the primary tumor or common distal sites of disease dissemination. Despite this initial tumor clearance, many patients will eventually relapse. Thus, small cohorts of tumor cells can survive in cryptic anatomical loci following therapy. These surviving cancer cells represent minimal residual disease (MRD). While cell-intrinsic processes are known to play decisive roles in chemotherapeutic response and drug resistance, relatively little is known about the impact of the tumor microenvironment on the persistence of MRD. Using a preclinical model of B cell lymphoma, we have been able to show that paracrine release of prosurvival cytokines protects subsets of lymphoma cells from cell death induced by genotoxic chemotherapy. Thus, while genotoxic damage can eradicate systemic disease, it can also, paradoxically, elicit prosurvival signaling in select anatomical sites. To further examine the role of the tumor microenvironment on therapeutic response, we have adapted large-scale loss of function genetic screen approaches for use in models of B cell malignancy in vivo. Specifically, we have made use of comprehensive shRNA libraries to target the genome in an unbiased manner. By introducing large shRNA pools into leukemia cells and transplanting modified cells into syngeneic recipients, we could identify up to 9,000 unique hairpins in individual mice, suggesting that library diversity can be maintained in this setting, and that genome-scale shRNA libraries can be screened in vivo. Genes identified using this approach represent central mediators of leukemia cell survival and potential cancer drug targets.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr IA25.
Abstract IA26: Finding mechanisms of cancer drug resistance through functional genetic screens
Authors: Bernards Rene 
Published: June 2012

Abstract
Unresponsiveness to therapy remains a significant problem in the treatment of cancer, also with the new classes of cancer drugs. In my laboratory, we use functional genetic approaches to identify biomarkers that can predict responsiveness to targeted cancer therapeutics; drugs that specifically inhibit molecules or pathways that are often activated in cancer. Nevertheless, it remains poorly explained why a significant number of tumors do not respond to these therapies. We aim to elucidate the molecular pathways that contribute to unresponsiveness to targeted cancer therapeutics using a functional genetic approach. This will yield biomarkers that may be useful to predict how individual patients will respond to these drugs. Furthermore, this work may allow the development of drugs that act in synergy with the established drug to prevent or overcome drug resistance.
To identify biomarkers that control tumor cell responsiveness to cancer therapeutics, we use multiple complementary approaches. First, we use genome wide loss-of-function genetic screens (with shRNA interference libraries) in cancer cells that are sensitive to the drug-of-interest to search for genes whose down-regulation confers resistance to the drug-of-interest (resistance screens). In addition, we use single well siRNA screens with a low dose of the drug to screen for genes whose inhibition enhances the toxicity of the cancer drug (sensitizer screens). As a third approach, we use gain of function genetic screens in which we search for genes whose over-expression modulates drug responsiveness. Once we have identified candidate drug response biomarkers in relevant cell line models, we ask if the expression of these genes is correlated with clinical response to the drug-of-interest. For this, we use tumor samples of cancer patients treated with the drug in question and whose response to therapy is documented.
In a fourth and distinct approach we perform high throughput sequencing of the “kinome” (some 600 genes) or whole exome of tumor samples to identify connections between cancer genotype and drug responses.
Examples of these four approaches to identify mechanisms of resistance to different cancer drugs will be presented.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr IA26.