bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 5633: Co-targeting the IGF1R pathway and compensatory signaling enhances cytotoxicity in head and neck cancer.
Authors: Axelrod Mark J. , Gioeli Daniel , Sharlow Elizabeth R. , Conaway Mark C. , Mendez Rolando E. , Khalil Ashraf , Taniguchi Linnea , Petricoin Emmanual F. , Leimgruber Stephanie , Weber Michael J. , Jameson Mark J.
Published: August 2014

The 5-year survival rate for patients with cancer of the Head and Neck (HNC) has not significantly improved over the past decade. Clearly, new therapeutic targets and strategies for employing existing targeted and cytotoxic therapies are needed. Studies have shown both expression and phosphorylation of the insulin-like growth factor 1 receptor (IGF1R) in both head and neck cancer cell lines and patient tumor samples. We found that small molecule inhibitors targeting IGF1R, when used as a single agent, caused varying degrees of cytotoxicity in HNC cell lines. In order to determine whether the variable biological response to IGF1R inhibition was caused by differences in the effects of the IGF1R inhibitors on the cell signaling networks of the HNC cell lines, we performed reverse phase proteomic array analysis on a panel of HNC cell lines treated with IGF1R inhibitors. Preliminary results suggest that treatment with IGF1R inhibitors caused increased expression and/or phosphorylation of a number of proteins in the array. We hypothesize that these alterations represent compensatory signaling pathways that provide resistance to cytotoxicity upon treatment with IGF1R inhibitors. In order to identify possible mechanisms of compensation for the loss of IGF1R pathway signaling, we screened a panel of small molecule inhibitors of the IGF1R/PI3K/AKT signaling pathway against a panel of inhibitors of proteins important in HNC cell signaling Preliminary results indicate that the inhibition of epigenetic modifying proteins as well as members of canonical cell signaling pathways in combination with inhibition of IGF1R signaling leads to a synergistic increase in cytotoxicity. This suggests that compensatory mechanisms exist in HNC that serve to blunt the cytotoxic effect of inhibition of IGF1R. Co-targeting IGF1R and members of these compensatory pathways may be a viable therapeutic strategy.

Citation Format: Mark J. Axelrod, Daniel Gioeli, Elizabeth R. Sharlow, Mark C. Conaway, Rolando E. Mendez, Ashraf Khalil, Linnea Taniguchi, Emmanual F. Petricoin, Stephanie Leimgruber, Michael J. Weber, Mark J. Jameson. Co-targeting the IGF1R pathway and compensatory signaling enhances cytotoxicity in head and neck cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5633. doi:10.1158/1538-7445.AM2013-5633
Abstract 693: Inhibitory effect of the CDK4/6 inhibitor, PD 0332991, is enhanced by mTOR inhibition in Non-Small Cell Lung Cancer (NSCLC).
Authors: Gopalan Priya K. , Gordillo-Villegas Andres , Zajac-Kaye Maria , Kaye Frederic J.
Published: August 2014

The p16 protein plays a critical role in the regulation of the retinoblastoma (RB) pathway, which inhibits cell growth through cell cycle regulation. The p16 gene, CDKN2a, is inactivated in 70% of NSCLC tumors, resulting in unregulated activation of CDK 4/6, and consequently increased cell cycling. The drug PD 0332991 (PD) is a highly specific inhibitor of CDK4/6. Western blots of p16-deficient NSCLC cell lines have confirmed a decrease in phosphorylated RB with PD-treated cells compared to untreated cells. We have observed a 34% decrease in viability by an MTS assay, and a 30% increase in cell senescence by a β-galactosidase assay in PD-treated p16-deficient cell lines compared to untreated cells. Based on these data, we are currently conducting a single-arm phase II clinical trial of single-agent PD 0332991 in patients with advanced NSCLC who have failed at least one prior chemotherapy regimen. We hypothesized that a combination of PD with other targeted therapies, acting on the same and intersecting pathways, would result in increased tumor cell death. Using MTS viability assays, we tested PD with and without other inhibitors in p16-deficient NSCLC cell lines. These inhibitors were: 1) the demethylating agent, decitabine, since the p16 gene, CDKN2a, is most often inactivated by hypermethylation (PD 66.1%, decitabine 49.7%, combination 80.2% viability); 2) the MEK inhibitor, AZD 6244, based on a report of a potential synthetic lethal interaction between K-Ras and CDK4 (PD 66.1%, AZD 6244 90.1%, combination 72.0% viability); 3) the CDK1/2/9 inhibitor, AZD 5438, since CDK 1 and 2 are thought to play a role in resistance to CDK 4/6 inhibition (PD 66.1%, AZD 5438 76.3%, combination 96.6% viability), and 4) the mTOR inhibitor, everolimus, since the mTOR pathway can upregulate cyclin D1, which complexes with CDK4/6 in the RB pathway (PD 67.3%, everolimus 65.1%, combination 46.4% viability, p<0.02 for PD compared to combination). Based on our studies, we saw that the combination of PD and everolimus significantly decreased cell viability. Western blots of p16-deficient NSCLC cell lines showed a further decrease in phosphorylated RB with the combination compared with PD alone. These data are promising, and we will be further determining the mechanism of inhibition of this combination. This study provides the groundwork for a future clinical trial of everolimus and PD 0332991 in combination in NSCLC patients with p16-deficient tumors.

Citation Format: Priya K. Gopalan, Andres Gordillo-Villegas, Maria Zajac-Kaye, Frederic J. Kaye. Inhibitory effect of the CDK4/6 inhibitor, PD 0332991, is enhanced by mTOR inhibition in Non-Small Cell Lung Cancer (NSCLC). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 693. doi:10.1158/1538-7445.AM2013-693
Abstract 709: Mitosis interference of cancer cells by NovoTTF-100A causes decreased cellular viability.
Authors: Lee Sze Xian , Wong Eric T. , Swanson Kenneth D.
Published: August 2014

Cancer cell death from traditional cytotoxic chemotherapy and radiation is a result of triggering cell cycle checkpoint with p53 playing a prominent role in orchestrating this effect. Unlike these traditional approaches, the NovoTTF-100A device, which has been approved for the treatment of recurrent glioblastomas, kills tumor cells by a novel mechanism that interferes with the proper progression through mitosis. As is the case with earlier therapeutic interventions, only a subset of patients shows significant response to TTFields treatment. Our research reveals that the tumor-treating fields (TTFields) affects processes proximal to the metaphase-to-anaphase transition, leading to cell cycle arrest in anaphase and eventual cell death. Tissue culture cells exposed to the TTFields during mitosis exhibit a variety of outcomes, including cell arrest in anaphase, cytokinesis with cytokinetic furrow regression, and slippage out of mitosis without division. Time-lapse movies of cells stained with the DNA stain DRAQ5 and exposed to the TTFields revealed membrane blebbing and oscillation, as well as failed segregation of sister chromatids from the metaphase plate, both of which were initiated near the time of metaphase-to-anaphase transition. Immunoflourescence of cells after short-term treatment with TTFields during mitosis showed disordered separation of chromosomes from metaphase plates accompanied by lagging chromosomes, dispersion of chromosomes from the metaphase plate, chromosomes de-condensation in the absence of cytokinesis, and daughter cells with asymmetric chromosomal segregation. Flow cytometry also revealed the presence of cells with abnormal DNA content in cultures treated with TTFields. In contrast to the p53 mutant cell lines, MDA-MB-231 and HCT 116, U87 cells with wild-type p53 exhibit increased Annexin V binding, Caspase activation and increased markers of endoplasmic reticulum (ER) stress after brief exposure during mitosis. This suggests the TTFields induced cellular damage is able to trigger p53-dependent cell death in cells that escape killing during M-phase. These data show that the effects of TTFields on cellular damage during M-phase and provide evidence for the notion that the differential responses to treatment seen in patients may be rooted in the underlying genetic alterations in their tumors.

Citation Format: Sze Xian Lee, Eric T. Wong, Kenneth D. Swanson. Mitosis interference of cancer cells by NovoTTF-100A causes decreased cellular viability. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 709. doi:10.1158/1538-7445.AM2013-709
Abstract 749: Characterization of p54nrb/NonO promoter in NSCLC.
Authors: Lin Sheng-Yi , Lai Yi-Hua , Chen Hsuan-Yu , Chen Huei-Wen , Yu Sung-Liang , Hong Tse-Ming , Chang Gee-Chen , Chen Jeremy J.W.
Published: August 2014

p54nrb/NonO is a multiple function nuclear protein. It has been implicated in numerous processes within the nucleus including transcriptional regulation, DNA unwinding, nuclear RNA processing, DNA double-strand break repair and tumorigenesis. In vivo, p54nrb usually forms a heterodimer with its partner PSF as a RNA splicing factor, but its roles in tumor progress is unknown. In recent years, p54nrb has been report in bladder cancer and prostate cancer that different expression of p54nrb between normal tissue and tumor tissue. p54nrb is upregulated in bladder cancer and prostate cancer. However, the mechanism about transcriptional regulation of p54nrb is still unknown. In this study, we characterize p54nrb function in non-small cell lung cancer cell (NSCLC) line and the transcriptional regulation of p54nrb promoter. First we find p54nrb transcription start site and use PCR technology to clone -1671/+1261 (2952 bp) p54nrb promoter. Then we analyzed p54nrb promoter region by deletion of p54nrb promoter 5’ end and luciferase report assay. The results of luciferase assay demonstrated that there is an important regulation region in p54nrb promoter +311/+414 fragment. And deletion of p54nrb promoter +109/+203 region can cause a part of luciferase activity decreasing. Furthermore, we used programe to predict what kind of transcription factor binding site on these two p54nrb promoter region. And we found three CCAAT box and AP-1, AP2α, Sp1, PEA3, NF-1, YY1 binding site. To investigate which transcription factors involve in transcriptional regulation of p54nrb. We observed the change of p54nrb after overexpressed AP-1, AP2α and Sp1 in CL1-0, CL1-5 and A549 cell line, and the protein level and mRNA level of p54nrb didn't change after overexpressed AP-1, AP2α and Sp1.

Citation Format: Sheng-Yi Lin, Yi-Hua Lai, Hsuan-Yu Chen, Huei-Wen Chen, Sung-Liang Yu, Tse-Ming Hong, Gee-Chen Chang, Jeremy J.W. Chen. Characterization of p54nrb/NonO promoter in NSCLC. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 749. doi:10.1158/1538-7445.AM2013-749

Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 896: miR-198 silencing is a mechanism of gemcitabine resistance in human pancreatic adenocarcinoma.
Authors: Ogunwobi Olorunseun O. , Li Jian , Zhao Xiangxuan , Trevino Jose , George Thomas , Liu Chen
Published: August 2014

Pancreatic adenocarcinoma (PAC) is a very aggressive disease with extremely high mortality rate. Chemotherapy with gemcitabine (G) is a standard of care for advanced disease, but chemotherapy resistance is commonly noted. Human PAC is characterized by overexpression of the proto-oncogene c-met. Increased activation of c-met has been reported in G-resistant PAC cells. Also, aberrant expression of microRNAs (miRNAs) has been linked to cancer progression. Furthermore, a recent study showed that miR-198 regulates c-met expression by binding to the 3′-untranslated region of c-met mRNA. However, the role of miR-198 in chemotherapy resistance in PAC has not previously been studied. Consequently, in this study we used the G-sensitive and G-resistant subclones of the L3.6pl human PAC cell line to examine the role of miR-198 in G-resistant PAC. We observed that the G-resistant subclone had increased expression of c-met (using qPCR and western blotting) and phosphorylated c-met (using western blotting), but not hepatocyte growth factor (HGF). Furthermore, using qPCR we observed significant silencing of miR-198 expression in the G-resistant subclone in comparison to the G-sensitive subclone (P < 0.01). To determine the functional significance of miR-198 silencing in G resistance, we silenced miR-198 expression in the G-sensitive subclone by transfection of a specific oligonucleotide inhibitor of miR-198. We observed that miR-198 silencing resulted in increased expression of c-met and phosphorylated c-met. Further, miR-198 silencing on its own increased total RNA concentration significantly by 146% (P < 0.05) and cell viability by 14.3% (P < 0.05; using MTT assay), both suggestive of a proliferative effect. However, significant effects on apoptosis were undetectable (using Hoechst nuclear staining). Furthermore, miR-198 silencing significantly abrogated G-induced apoptosis (P < 0.05) and G-induced reduction of cell viability (P < 0.05). We conclude that G-resistant human PAC cells have silencing of miR-198. Moreover, miR-198 silencing in PAC cells induces increased expression and phosphorylation of c-met, increased cell proliferation and abrogation of G-induced apoptosis and induction of proliferation. Therefore, miR-198 silencing is a mechanism of G-resistance in PAC. Furthermore, therapeutic strategies to enhance miR-198 expression may be beneficial in PAC.

Citation Format: Olorunseun O. Ogunwobi, Jian Li, Xiangxuan Zhao, Jose Trevino, Thomas George, Chen Liu. miR-198 silencing is a mechanism of gemcitabine resistance in human pancreatic adenocarcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 896. doi:10.1158/1538-7445.AM2013-896
Abstract LB-90: DUPA-99mTc localizes to prostate cancer in men with locally advanced and metastatic disease.
Authors: Gardner Thomas A. , Fletcher James W. , Ko Song-Chu , Low Philip S. , Ratliff Timothy L.
Published: August 2014

Objectives: Currently, the absence of an effective prostate cancer targeted imaging agent limits the ability to correctly clinically stage prostate cancer. The conjugation of a high affinity PSMA-targeting ligand, 2-[3-(1, 3-dicarboxy propyl)-ureido] pentanedioic acid (DUPA) to technetium 99m (99mTc) has generated a new prostate cancer imaging agent termed DUPA-99mTc. The objective of this phase 0 clinical trial was to confirm the preclinical data demonstrating high affinity localization to human prostate cancer cells and tissues.

Methods: Nine men with advanced and metastatic prostate cancer confirmed by CT scan and/or bone scan were enrolled in the Phase 0 trial to investigate both the biologic efficacy and toxicity of the DUPA-99mTc agent. Dosimetry studies of images, blood and urine at 5 and 20 mCi doses were obtained at baseline, 5 min, 1, 2, 4, 8 and 24 hours.

Results: Nine men with documented prostate cancer were enrolled. Seven of the nine subjects were evaluable. One patient did not receive a full iv dose and another received poorly labeled DUPA-99mTc (70%). The remaining seven patients, who received DUPA-99mTc in excess of 95% labeled product, demonstrated localization to all cancerous areas seen on pre-enrollment images (CT and Bone Scans) plus additional lesions in several of the patients. Two men who had biopsy-confirmed locally recurrent prostate cancer had scans prior to resection, and tissue was monitored intra-operatively and ex-vivo to confirm the higher 99mTc counts in malignant tissue compared to normal tissue. No significant toxicity was demonstrated with administration of the DUPA-99mTc in any subject.

Conclusions: DUPA-99mTc compound can be reliably administered to men with prostate cancer without toxicities and with equal or superior imaging compared to conventional CT and bone scans. A Phase I/II trial will be conducted to confirm the performance of this imaging agent in a larger patient population.

Citation Format: Thomas A. Gardner, James W. Fletcher, Song-Chu Ko, Philip S. Low, Timothy L. Ratliff. DUPA-99mTc localizes to prostate cancer in men with locally advanced and metastatic disease. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-90. doi:10.1158/1538-7445.AM2013-LB-90
Abstract LB-92: RVX-2135 is a novel, orally bioavailable epigenetic BET inhibitor that synergizes with cytarabine and idarubicin to inhibit proliferation of acute myeloid leukemia cells.
Authors: Campeau Eric , Jahagirdar Ravi , Wu Jin , Gesner Emily M. , Kharenko Olesya , Yu Raymond , Attwell Sarah , Hansen Henrik C. , Wagner Gregory S. , McLure Kevin G. , Young Peter R.
Published: August 2014

Current treatment of acute myeloid leukemia (AML) often includes a combination of intravenous cytarabine (Ara-C) and an anthracycline such as idarubicin. Bromodomain and extra-terminal domain (BET) proteins contain two bromodomains that bind to acetylated lysines in histones and regulate gene transcription by an epigenetic mechanism. Here we describe a novel small molecule BET inhibitor, RVX-2135, which selectively binds recombinant BET bromodomains of BRD2, BRD3, and BRD4 but not non-BET bromodomains. RVX-2135 inhibited BRD2, BRD3, and BRD4 dual bromodomains binding to acetylated histones in vitro with sub to low micromolar IC50 values. In the human AML cell line MV4-11, RVX-2135 displaced BET proteins from chromatin and significantly reduced expression of c-MYC and BCL-2 mRNAs, with IC50s of 4 and 5 μM, respectively. RVX-2135 inhibited proliferation of cultured MV4-11 cells with an IC50 value of 6 μM, and induced cell cycle arrest and apoptosis. In vivo, nude mice bearing MV4-11 xenografts were treated orally with RVX-2135 at doses of 75 and 120 mg/kg b.i.d, and showed tumor growth inhibition of 77 and 92% respectively. There was a corresponding inhibition of c-MYC and BCL-2 mRNA expression in the xenograft tumors. In combination therapy in vitro, RVX-2135 synergized with idarubicin and cytarabine, with Chou-Talalay's combination indices of 0.17 and 0.18, respectively. The synergistic effect also translated into increased apoptosis when cytarabine was combined with RVX-2135. Similar data were seen with BET inhibitors from different chemical scaffolds, suggesting that this may represent a promising new class of drugs for AML.

Citation Format: Eric Campeau, Ravi Jahagirdar, Jin Wu, Emily M. Gesner, Olesya Kharenko, Raymond Yu, Sarah Attwell, Henrik C. Hansen, Gregory S. Wagner, Kevin G. McLure, Peter R. Young. RVX-2135 is a novel, orally bioavailable epigenetic BET inhibitor that synergizes with cytarabine and idarubicin to inhibit proliferation of acute myeloid leukemia cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-92. doi:10.1158/1538-7445.AM2013-LB-92
Abstract PR11: Doxorubicin enhances nucleosome turnover around active gene promoters
Authors: Yang Fan , Kemp Christopher J. , Henikoff Steven
Published: August 2014

Doxorubicin (also known as Adriamycin) is a DNA intercalator that is among the most commonly used anti-cancer drugs. Doxorubicin causes DNA double-strand breaks in rapidly dividing cells, although whether it also affects general chromatin properties is unknown. Here, we use a metabolic labeling strategy for directly measuring nucleosome turnover to examine the effect of doxorubicin on chromatin dynamics in squamous cell carcinoma cell lines derived from genetically defined mice. We find that doxorubicin enhances nucleosome turnover around promoters of active genes. Consistent with a direct action of doxorubicin, enhancement of nucleosome turnover around promoters gradually increases with time of exposure to the drug. Interestingly, enhancement occurs both in wild-type cells and in cells lacking the p53 tumor suppressor gene or the master regulator of the DNA damage response, Atm, suggesting that doxorubicin action on nucleosome dynamics is independent of the DNA damage checkpoint. In addition, another anthracycline intercalator, aclarubicin, shows similar effects on enhancing nucleosome turnover around promoters. Our results suggest that anthracycline intercalation promotes nucleosome turnover by its effect on DNA topology, with possible implications for cancer chemotherapies that combine traditional DNA intercalators with targeted epigenetic drugs.

This abstract is also presented as Poster A48.

Citation Format: Fan Yang, Christopher J. Kemp, Steven Henikoff. Doxorubicin enhances nucleosome turnover around active gene promoters. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr PR11.
Abstract B51: Tumor ER stress transmission to infiltrating myeloid cells in vivo require IRE1alpha and TLR4
Authors: Rodvold Jeffrey J. , Hiramatsu Nobuhiko , Chiu Kevin T. , Mahadevan Navin R. , Lin Jonathan , Zanetti Maurizio
Published: August 2014

The unfolded protein response (UPR) facilitates tumor outgrowth through evoking a variety of cell intrinsic processes that promote cancer survival, angiogenesis, and chemoresistance. The UPR can be transmitted from stressed cancer cells to receiver myeloid cells in vitro through a process termed transmissible endoplasmic reticulum stress (TERS) in which receiver cells undergo a UPR and acquire tumor promoting pro-inflammatory (IL-6, TNF-alpha, IL-23) and immune-suppressive (Arg1) characteristics. Here, we confirmed that CD11b+ myeloid cells isolated from subcutaneous murine melanoma tumors in C57BL/6 mice display the TERS signature. In light of the fact that TERS signaling in myeloid receiver cells is partly TLR4-dependent, we interrogated subcutaneous tumors in TLR4 mice. We found that these tumors had delayed onset, reduced growth kinetics, and improved survival over tumors growing in wildtype mice. Most significantly, isolated CD11b+ cells from TLR4-/- tumors did not undergo a UPR nor upregulate inflammatory genes when compared to splenic controls, though, interestingly, still upregulated Arg1. Next, we probed individual signaling arms of the UPR in relation to TERS production. We utilized a panel of novel transgenic cell lines in which specific arms of the UPR can be conditionally activated and found that activated inositol requiring enzyme-1alpha (IRE1alpha) transmitted stress to myeloid cells. The remaining two UPR arms (PERK and ATF6) had little transmitting potential, if any. Bone marrow derived myeloid cells treated with TERS generated from IRE1alpha KO mouse embryonic fibroblasts (MEFs) had a markedly reduced UPR than those treated to wildtype MEF TERS. Subcutaneous tumors consisting of IRE1alpha KO TERS-conditioned myeloid dendritic cells and melanoma cancer cells had delayed onset and grew at reduced rate compared to tumor mixtures in which wildtype MEF TERS was used. Based on these data, we probed a patient melanoma for its co-localization of stress, myeloid infiltrate, and inflammation. Together, these data identify a novel signaling mechanism dependent on IRE1alpha and TLR4 used by stressed tumor cells to co-opt infiltrating myeloid cells to become tumor promoting.

Citation Format: Jeffrey J. Rodvold, Nobuhiko Hiramatsu, Kevin T. Chiu, Navin R. Mahadevan, Jonathan Lin, Maurizio Zanetti. Tumor ER stress transmission to infiltrating myeloid cells in vivo require IRE1alpha and TLR4. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr B51.
Abstract B26: Identification of molecular and functional differences in tumor-associated macrophage subsets
Authors: Arwert Esther N. , Harney Allison S. , Entenberg David , Wang Yarong , Pollard Jeffrey W. , Condeelis John S.
Published: August 2014

During breast cancer metastasis motile tumor cells migrate within the primary tumor to blood vessels and enter the bloodstream which leads these cells to other organs where they can found a new metastasis. These cancer cells have to navigate from their primary site to the blood vessel, and make their way through the extra cellular matrix of the basement membranes of mammary ducts and blood vessels. Cancer cells are not acting alone during the metastatic process. Tumor associated macrophages (TAMs) play an important role during breast cancer development and metastasis.

The on-going research aims to gain a better understanding of the origin, location and flexibility in function of different TAM subsets, including the metastasis-assisting macrophages. Using high-resolution multi-photon live-imaging we have identified different TAM subsets based on location and phenotype. For example TAMs can be found at the outside of the tumor (cortical), around tumor blood vessels (perivascular) or in fast moving cell streams (streaming). All these different TAM subsets perform different functions. Cortical TAMs are suggested to be immunosuppressive, while streaming TAMs appear to guide motile cancer cells towards blood vessels, and perivascular macrophages seem to attract the streams and mediate cancer cell intravasation.

Currently, there are no (surface) markers to differentiate these unique TAM subsets and little is known about the underlying molecular mechanisms relevant for the differentiation of monocytes into any of these subtypes. The current research is using single-cell laser capture dissection, high-resolution multi-photon live-imaging and lineage tracing experiments to elucidate some aspects of the interplay between cancer cells and macrophages

Citation Format: Esther N. Arwert, Allison S. Harney, David Entenberg, Yarong Wang, Jeffrey W. Pollard, John S. Condeelis. Identification of molecular and functional differences in tumor-associated macrophage subsets. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B26.
Abstract PR13: microRNAs: Master regulators of human tumor dormancy
Authors: Almog Nava , Ma Lili , Christine Briggs , Rietman Edward , Beheshti Afshin , Abdollahi Amir
Published: August 2014

Tumor dormancy refers to a critical stage in cancer progression in which tumors remain small and occult for a prolonged period until they eventually progress and become clinically apparent. Although escape from tumor dormancy has long been recognized as an important problem in the treatment of cancer, the molecular and cellular regulators underlying this transition remain poorly understood. We have previously generated and characterized in vivo models of human tumor dormancy. In these models dormancy of micro-tumors is angiogenesis dependent and the spontaneous escape of the tumors from dormancy requires a stable transcriptional reprogramming.

We show here that dormant tumors undergo a stable microRNA switch during their transition to the fast-growing angiogenic phenotype and report the identification of a consensus set of dormancy-associated microRNAs (DmiRs). Loss of DmiR expression is associated with the spontaneous transition of dormant tumors to rapid growth. The expression pattern of two DmiRs was confirmed to correlate with disease stage in human glioma specimens. Reconstitution of a single DmiR (miR580, 588 or 190) led to phenotypic reversal of fast-growing tumors towards prolonged tumor dormancy. Transcriptional reprogramming of tumors via DmiR over-expression resulted in downregulation of pro-angiogenic factors such as TIMP-3, bFGF, TGF alpha or Bv8 and decreased tumor recruitment of pro-angiogenic bone marrow-derived CD11b+ Gr-1+ myeloid cells. In contrast, antiangiogenic and dormancy promoting pathways such as EphA5 and Angiomotin were upregulated in DmiR expressing tumors.

We further investigated the transcriptional targets of mir-190 which exerts the strongest tumor inhibiting effect and show that mir-190 affects mRNA levels of a very large set of genes in both direct and indirect ways. Many of the genes affected by mir-190 are related to the transcription process, are associated with tumor suppressors and with the interferon pathway.

The identification of tumor dormancy associated microRNAs, along with improved understanding of their mechanistic actions could lead to the development of novel means to revert the malignant tumor phenotype to a dormant state. This work may also provide promising targets for early detection or prevention of cancer.

This abstract is also presented as Poster C97.

Citation Format: Nava Almog, Lili Ma, Briggs Christine, Edward Rietman, Afshin Beheshti, Amir Abdollahi. microRNAs: Master regulators of human tumor dormancy. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr PR13.
Abstract B65: IgG4 subclass antibodies impair antitumor immunity in melanoma.
Authors: Karagiannis Panagiotis , Gilbert Amy E. , Josephs Debra H. , Ali Niwa , Dodev Tihomir , Saul Louise , Roberts Luke , Beddowes Emma , Koers Alexander , Ferreira Silvia , Geh Jenny L.C. , Healy Ciaran , Harries Mark , Hobbs Carl , Blower Philip J. , Mitchell Tracey , Fear David , Spicer James F. , Lacy Katie E. , Nestle Frank O. , Karagiannis Sophia N.
Published: August 2014

Host-induced antibodies and their contributions to cancer inflammation are largely unexplored. IgG4 subclass antibodies are present in IL-10-driven Th2 type immune responses in a range of inflammatory conditions. Since Th2-biased inflammation is a hallmark of tumor microenvironments, we investigated the presence and functional implications of IgG4 in malignant melanoma. We found that CD22+ B cells and IgG4+ infiltrating cells accumulated in melanoma lesions. When compared to B cells from patient lymph nodes and blood, tumor-associated B cells were polarized to produce IgG4. Consistent with modified Th2-biased inflammation and in situ production of IgG4, we detected IL-10 and IL-4 cytokine mRNA in melanoma lesions. Tumor cells enhanced IL-10, IL-4 and VEGF secretion and production of IgG4 by B cells ex vivo. Despite accumulation in tumors, and in contrast to IgG1, an engineered tumor antigen-specific IgG4 was ineffective in triggering effector cell-mediated tumor killing in vitro and in vivo. Furthermore, treatment with IgG4 significantly impaired the potency of tumoricidal IgG1 in a human melanoma xenograft mouse model. These findings suggest that IgG4 promoted by tumor-induced Th2-biased inflammation may restrict effector cell functions by blocking of FcgammaRI against tumors, providing a novel perspective on tumor-induced immune escape and a basis for biomarker development and patient-specific therapeutic approaches.

Citation Format: Panagiotis Karagiannis, Amy E. Gilbert, Debra H. Josephs, Niwa Ali, Tihomir Dodev, Louise Saul, Luke Roberts, Emma Beddowes, Alexander Koers, Silvia Ferreira, Jenny L.C. Geh, Ciaran Healy, Mark Harries, Carl Hobbs, Philip J. Blower, Tracey Mitchell, David Fear, James F. Spicer, Katie E. Lacy, Frank O. Nestle, Sophia N. Karagiannis. IgG4 subclass antibodies impair antitumor immunity in melanoma. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B65.
Oncologic Validity of Recipient Vessel Preservation in Microvascular Free-Flap Reconstruction
Authors: DeConde Adam S. , Thompson Christopher F. , Zaghi Soroush , Vira Darshni , Blackwell Keith E. , Nabili Vishad
Published: August 2014

Objectives: The use of free-flap reconstruction requires a more limited neck dissection to allow for microvascular anastomosis. This study seeks to determine the oncologic validity of cervical vessel preservation. Materials and Methods: The current study is a prospective review of cervical vessel biopsies from patients undergoing resection of squamous cell carcinoma (SCCA) tumors of the head and neck with free tissue reconstruction. Results: From June 2010 to March 2012, 227 recipient vessel biopsies were performed on 100 patients. Three of these patients had grossly abnormal vessels, with malignancy confirmed by frozen section analysis. One patient had a vessel positive for malignancy that was grossly normal but found to have SCCA on the final pathology. Conclusions: When the recipient vessel appears grossly suspicious, a frozen section biopsy and re-resection should be considered. Recipient vessel trimmings should routinely be sent for permanent pathology since in rare cases, they can be involved by tumor, affecting the margin status, prognosis, and indications for adjuvant therapy.
Changes in Sleep Characteristics and Airway Obstruction in OSAHS Patients with Multi-Level Obstruction following Simple UPPP, UPPP-GA, or UPPP-TBA: A Prospective, Single-Center, Parallel Group Study
Authors: Chen Shicai , Shi Song , Xia Yanghui , Liu Fei , Chen Donghui , Zhu Minhui , Li Meng , Zheng Hongliang
Published: August 2014

Objective: To investigate changes in S3 sleep and the apnea hypopnea index (AHI), SpO2 desaturation and CT90, and to determine changes in the degree of airway collapse and in the cross-sectional area of the retropalatal and lingual region in obstructive sleep apnea hypopnea syndrome patients. Method: All subjects underwent overnight polysomnography and were evaluated using Müller's test and magnetic resonance imaging at baseline, 3, and 12 months following surgery. Result: The mean S3 scores in patients receiving uvulopalatopharyngoplasty combined with genioglossus advancement (UPPP-GA) or UPPP combined with tongue base advancement using the Repose™ system (UPPP-TBA) noticeably increased. Marked improvement was seen in the mean AHI, LSO2, and CT90 scores 3 and 12 months following surgery compared to baseline. Airway collapsed by 25-50% in the greatest proportion undergoing surgery at the tongue base. Conclusion: UPPP-GA and UPPP-TBA more effectively improve S3 sleep, and mean AHI, LSO2, and CT90 scores. In addition, they effectively alleviate airway obstruction by improving the cross-sectional area of these regions.
Early-Onset Alzheimer's Disease in Two Iranian Families: A Genetic Study
Authors: Noroozian Maryam , Azadfar Parisa , Akbari Leila , Sadeghi Arghavan , Houshmand Massoud , Vousooghi Nasim , Zarrindast Mohammad Reza , Minagar Alireza
Published: August 2014

Background: Early-onset Alzheimer's disease (EOAD) represents less than 5% of all AD cases. Autosomal dominant EOAD has been defined as the occurrence of at least three cases in three generations. Mutations in the amyloid precursor protein (APP), presenilin-1 and presenilin-2 genes have been recognized to be the cause of EOAD. Objective: We investigated the genotype of EOAD in two generations of two families with EOAD living in an Iranian village. Methods: The polymerase chain reaction method was used to study the presenilin-1 and APP genes in 25 subjects of these generations. Results: A guanine-to-adenine transition in exon 17 of the APP gene resulting in a valine-to-isoleucine substitution at codon 717 was detected in 14 subjects including 6 patients with EOAD. Conclusion: This mutation demonstrates the importance of γ-secretase, the necessity of early detection of patients with memory decline in the susceptible population and raising public awareness of consanguinity marriages.
Increased Serum Levels of Interleukin-18, -23 and -17 in Chinese Patients with Alzheimer's Disease
Authors: Chen Jin-Mei , Jiang Guo-Xin , Li Qing-Wei , Zhou Zhi-Ming , Cheng Qi
Published: August 2014

Aims: To evaluate the serum levels of interleukin (IL)-18, IL-23 and IL-17 in Chinese patients with Alzheimer's disease (AD), and explore correlations between the three cytokines and relevant parameters. Methods: Serum concentrations of IL-18, IL-23 and IL-17 were measured by ELISA for 53 AD patients and 53 sex- and age-matched healthy controls in a community of elderly individuals in a Shanghai suburb. Results: Serum concentrations of IL-18, IL-23 and IL-17 were significantly higher in AD patients than controls. The serum level of IL-23 was observed to be significantly higher (p = 0.049) in female AD patients than male AD patients. In addition, a significantly inverse correlation was found between IL-18 and MMSE score (rs = -0.356, p = 0.011) for all AD patients. Conclusion: Elevated IL-18, IL-23 and IL-17 levels are observed in AD patients and differences may exist between males and females. Besides, IL-18 may correlate with the severity of AD.
Fetal Bronchoscopy as a Useful Procedure in a Case with Prenatal Diagnosis of Congenital Microcystic Adenomatoid Malformation
Authors: Cruz-Martinez Rogelio , Méndez Antonio , Perez-Garcilita Oscar , Monroy Araceli , Aguilar-Vidales Karla , Cruz-Martinez Miriam Alejandra , Martinez-Morales Cecilia
Published: August 2014

Massive microcystic congenital cystic adenomatoid malformation (CCAM) and bronchial atresia are associated with a high perinatal mortality secondary to lung hypoplasia and cardiac dysfunction, and fetal intervention should be considered to improve prognosis. Therapeutic options include open fetal surgery with pulmonary resection, fetal sclerotherapy and fetoscopy. We present a case with a severely enlarged left lung without ultrasound signs of dilated airways compatible with the diagnosis of microcystic CCAM, hydrops and severe contralateral lung hypoplasia that was treated successfully at 30 weeks of gestation by fetal bronchoscopy, through which bronchial atresia was identified at the end of the left mainstem bronchi and permeabilized by laser ablation. After fetal surgery, weekly follow-up showed a progressive decrease in the affected lung size and an increase in the contralateral hypoplastic lung size, demonstrating normal dimensions of both lungs at 34 weeks of gestation, reversal of the mediastinal shift, and complete disappearance of hydrops. A healthy neonate was delivered uneventfully at term with no need for respiratory support, and the boy is now doing well at 15 months of age. This report demonstrates that in cases with prenatal diagnosis of large microcystic CCAM, fetal bronchoscopy can be used to refine the diagnosis of bronchial atresia and as a therapeutic tool with good outcome.
Hyalurosome Gene Regulation and Dose-Dependent Restoration of Skin Atrophy by Retinaldehyde and Defined-Size Hyaluronate Fragments in Dermatoporosis
Authors: Nikolic Damjan S. , Ziori Charis , Kostaki Maria , Fontao Lionel , Saurat Jean-Hilaire , Kaya Gürkan
Published: August 2014

Background: Dermatoporosis is an emerging clinical condition caused by chronological skin aging, long-term sun exposure and chronic use of corticosteroids; however, genomic expression in dermatoporosis and the efficacy of different therapeutic approaches to prevent and treat dermatoporosis have not been investigated so far. Objective: We examined the possible effect of topical retinaldehyde (RAL) and defined-size hyaluronate fragments (HAFi) on the expression of hyalurosome genes potentially involved in the pathogenesis of dermatoporosis. We also explored the effect of different concentrations of HAFi on skin thickness. Methods: 13 persons were separated into a young control group (n = 8) and a dermatoporosis group (n = 5). Topical treatment of both groups with a combination of 0.05% RAL and 1 or 0.2% HAFi was applied on the forearm twice daily for 30 days. Forearm skin biopsies of both groups were performed before and after application. Hyalurosome genes CD44, heparin-binding epidermal growth factor (HB-EGF), ErbB1, hyaluronate synthase 3 (HAS3) and Hyal2 were chosen as potential markers of dermatoporosis. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed for quantification of mRNA expression of the target hyalurosome genes. Measurement of forearm skin thickness before and after treatment was performed by ultrasonography. Analysis of the results was done by Student's t test. A p value <0.05 was considered statistically significant. Results: In qRT-PCR analysis the relative expression of hyalurosome (CD44, HAS3, HB-EGF) genes was found to be reduced in patients prior to topical treatment and to be notably increased following treatment. The reduced expression of CD44 and HAS3 in patients was specifically restored in dermatoporotic patients after treatment. No difference in skin thickness was observed in controls after treatment. The treatment caused a significant increase in skin thickness in dermatoporotic patients. This increase was more significant with 1% HAFi when compared to 0.2% HAFi. RAL and HAFi also caused a significant reduction in purpuric lesions in patients with dermatoporosis. Conclusion: Our results indicate that topically applied RAL and HAFi regulate hyalurosome gene expression in dermatoporosis and that they show a dose-dependent effect on the correction of skin atrophy in dermatoporotic patients. However, the small number of patients analyzed in both groups somehow limits the statistical power of this study.
PlasmaKinetic™ versus Cold Knife Internal Urethrotomy in Terms of Recurrence Rates: A Prospective Randomized Study
Authors: Cecen Kursat , Karadag Mert Ali , Demir Aslan , Kocaaslan Ramazan
Published: August 2014

Objective: To evaluate the efficacy and outcomes of PlasmaKinetic™ urethrotomy against cold knife direct vision internal urethrotomy in terms of recurrence rates. Patients and Methods: A total of 136 male patients with urethral strictures were enrolled into the study. The patients were allocated to cold knife or PlasmaKinetic urethrotomy groups sequentially by using computer-generated numbers. Group A (PlasmaKinetic) and group B (cold knife) included 70 and 66 patients, respectively. All patients were reevaluated at the 3rd, 9th and 18th month postoperatively with uroflowmetry. Results: Group A patients had a postoperative 3rd-month maximum flow rate value of 16.09 ml/s, whereas this same parameter was 15.15 ml/s in group B (p < 0.05). The urethral stricture recurrence rate up to the 9-month period was statistically significant for group A (14%) compared with group B (30%). When we compared the recurrence rates of these groups from postoperative day 1 up to the 18th month, the results were 37% for group A and 33% for group B (p > 0.05). Conclusion: PlasmaKinetic urethrotomy provides a better recurrence-free rate during the early period compared with conventional cold knife therapy. Nevertheless, the outcome of the stricture did not change and fibrotic tissue reformed between the 9th and the 18th month.
CyberKnife Treatment for Kaposiform Hemangioendothelioma of the Ilium in an Adult: Case Report and Review of the Literature
Authors: Wang Zhen , Kong Qing-Tao , Wu Xin-Hu , Li Bing , Shen Ze-Tian , Li Jing , Zhu Xi-Xu
Published: August 2014

Background: Kaposiform hemangioendothelioma (KHE) is a rare vascular neoplasm that mainly affects infants. KHE rarely develops in adolescents and adults. These tumors tend to be locally invasive, but are not known to produce distant metastases. Numerous treatment modalities are available for KHE, but the optimal therapy is unknown. Case Report: A 51-year-old woman was diagnosed with KHE of the ilium in September 2005. The lesion recurred within 5 years of local excision, and was subsequently treated with CyberKnife. Within 1 month of CyberKnife therapy, pain intensity was significantly reduced and the patient's quality of life was significantly improved. Since January 2011, she has remained pain-free and has had no signs of recurrence or metastasis for more than 2 years following CyberKnife therapy. Conclusion: We report the first CyberKnife treatment of an adult with KHE of the bone without accompanying cutaneous changes and Kasabach-Merritt syndrome. CyberKnife treatment could be a useful temporizing measure for bone KHE.
Potentiation of the in vitro Antistaphylococcal Effect of Oxacillin and Tetracycline by the Anti-Inflammatory Drug Diacetyl Rhein
Authors: Nguon Samnang , Novy Pavel , Kokoska Ladislav
Published: August 2014

Background: The anti-inflammatory drug diacetyl rhein has been found to possess promising antistaphylococcal effects against various drug-resistant strains in our previous study. In the present work, we explored the in vitro combinatory interactions of diacetyl rhein with oxacillin and tetracycline against 13 standard strains and clinical isolates of Staphylococcus aureus, including those resistant to erythromycin, methicillin and tetracycline. Methods: Minimum inhibitory concentrations were determined by broth microdilution assay, and the effects of combinations were evaluated according to the sum of fractional inhibitory concentrations (ΣFICs). Results: Synergistic or additive effects were observed against all S. aureus strains (ΣFIC 0.258-1), whereas diacetyl rhein-oxacillin appeared to be the most effective combination, synergistically inhibiting the growth of 4 strains tested. Conclusion: To our best knowledge, this is the first report on a synergistic antibacterial effect of diacetyl rhein. Our results suggest this promising compound for further evaluation of its synergistic anti-infective potential as an agent with a combined anti-inflammatory and synergistic antibacterial action.
Thymic Epithelial Tumors: Analysis of Prognostic Factors with Emphasis on the Role of Adjuvant Radiation Therapy
Authors: Yirmibeşoğlu Erkal Eda , Akgül Aslı G. , Halis Hatice , Liman Tuba , Sarper Binnaz , Topçu Salih , Aksu Görkem
Published: August 2014

Background: The prognostic impacts of histopathological classification, Masaoka staging system, extent of surgery, and adjuvant treatment approaches in thymic epithelial tumors (TETs) were investigated. Material and Methods: Records of 22 patients were retrospectively reviewed. Total thymectomy was performed on 5 patients and thymectomy on 17. Complete resection was achieved for 14 patients. Radiation therapy (RT) was considered for all patients with stage III or IV disease and all patients undergoing incomplete resections. Results: Local control had been achieved in all patients and all were alive with no evidence of disease (ANED) at 0.2-7.8 years (median, 2.3 years). Of 4 patients with stage II disease, 2 (favorable group) had undergone complete resections and 2 (intermediate group) had undergone incomplete resections. Those undergoing incomplete resections had received RT. Of these 4 patients, all were ANED. All 4 patients with Masaoka stage III disease that were involved in the study had undergone incomplete resections and had received RT. Also, these patients were ANED. Conclusions: Patients with TETs undergoing less than complete resections might be referred for RT in the postoperative setting, while the role of RT in patients undergoing complete resections remains unclear.