tbuckley/cabot-search huggingface dataset:
Abstract 5342: Epigenetic polymorphisms and human papillomavirus E6/E7 oncoproteins transfection: Induce ATM gene deletion11q22-23 and chromosomal instability
Authors: Eva McGhee, Liliana Zarate, Chiamaka Opara, Antoinette Alugbue, Meidrah Tyler, Bileko Wissa, Billy Ballard, Roland Pattillo
Journal: Cancer Research (2017)

Abstract Persistent infections involving high-risk types 16 and 18 of Human Papillomavirus (HPV) have been established as the etiological agent of cervical cancer. Recent data indicate that several polymorphisms of key regulators from the DNA damage repair pathways are associated with cancer development susceptibility. The long arm of chromosome 11 has received much attention as a high frequency of epigenetic deletions of various sites, observed in HPV-long term infection that lead to cervical cancer, indicating the presence of putative tumor suppressor genes and its association with disease progression. To better understand the importance of chromosome 11q22-23 region in the development of cervical cancer, we investigated genetic and epigenetic alterations of the tumor suppressor ATM gene in human keratinocytes transfected with HPV E6/E7 oncoproteins (16-MT). In the present study we examined 16-MT cells for epigenetic changes and chromosome imbalances, using FISH, and arrayCGH. We used several FISH probes, mapping to region 11q22-23 where the ATM gene is located. Our study revealed that the ATM gene located on chromosome 11q is deleted, relating to chromosome deletions, that are recurrent abnormalities in cervical cancer, implicating the loss of tumor suppressor genes as a significant mechanism that drive cells to become cancerous. This study was designed to investigate genetic instability using HPV16 E6/E7 oncoproteins to better understand the importance of chromosome 11q epigenetic changes. Deletion of 11q22-23 was observed in all metaphases scored. With restricted areas of deletions, two chromosomal regions of possible importance in cervical carcinomas could be distinguished. The first region is D11S1325 and the second region is D11S2179. The second region may contain part of the ATM gene. The results indicate that a tumor suppressor gene on chromosome 11q22-23 may be involved in the carcinogenesis of the cervix and the involvement of the ATM gene, as the driving factor remains a possibility. Citation Format: Eva McGhee, Liliana Zarate, Chiamaka Opara, Antoinette Alugbue, Meidrah Tyler, Bileko Wissa, Billy Ballard, Roland Pattillo. Epigenetic polymorphisms and human papillomavirus E6/E7 oncoproteins transfection: Induce ATM gene deletion11q22-23 and chromosomal instability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5342. doi:10.1158/1538-7445.AM2017-5342
Abstract 5157: Preparation of curcumin analog nanoparticles and determination of their anticancer activity in prostate cancer
Authors: Maylein C. Juan-Rivera, Maria M. Sánchez-Vázquez, Gamalier Maldonado, Geovanny Ruíz, Noralejandra Vázquez, Christian Vélez, Beatriz Zayas, Carlos Cabrera, Magaly Martínez-Ferrer, David Sanabria-Ríos
Journal: Cancer Research (2017)

Abstract Prostate cancer is the most frequently diagnosed cancer and the second cause of cancer-related deaths in American men. Bioavailability of therapeutic agents is important for the treatment effectiveness. Previous studies have shown that the development of nanoparticles (NPs) drug delivery vehicles offers an opportunity for targeted drug delivery to tumor cells. Natural compounds such as curcumin have shown decreased bioavailability and stability when used as anticancer agents. Therefore, the purpose of this study is to synthesize the curcumin analog m-nitrochalcone (3bNchalc) encapsulated into poly (lactic-co-glycolic acid) (PLGA) NPs and determine the anticancer activity against prostate cancer cell lines. In our approach, 3bNChalc were encapsulated into PLGA NPs in the presence of PVA using the single emulsion-solvent evaporation method. 3bNChalc loading, encapsulation efficiency, and drug release was determined by spectrophotometric techniques. Physico-chemical properties such as zeta potential, particle size, polydispersity index (PDI), and morphology was measured using a combination of Dynamic Light Scattering (DLS) and Scanning Electron Microscopy (SEM). Cell viability and proliferation of PC3 and 22RV1 prostate cancer cell lines treated with 3bNchalc NPs and control were assessed using the MTS assay. 3bNchalc PLGA NPs were found to have a particle size of 250 nm and smooth spherical shape. In addition, zeta potential and mobility values revealed that 3bNChalc PLGA NPs are negatively charged and they tend to repel each other avoiding the tendency to flocculate. Moreover, 22RV1 cells treated with 3bNchalc PLGA NPs showed decreased in viability and proliferation when compared to control. We demonstrated that 3bNChalc was successfully encapsulated into PLGA NPs. In addition, our results showed that 3bNchalc PLGA NPs decreased the viability of 22RV1 prostate cancer cells when compared to control, suggesting that PLGA improves the delivery of 3bNChalc inside the cell. Results of our study will impact broadly the field by developing more effective and less toxic PLGA NPs based therapies. Citation Format: Maylein C. Juan-Rivera, Maria M. Sánchez-Vázquez, Gamalier Maldonado, Geovanny Ruíz, Noralejandra Vázquez, Christian Vélez, Beatriz Zayas, Carlos Cabrera, Magaly Martínez-Ferrer, David Sanabria-Ríos. Preparation of curcumin analog nanoparticles and determination of their anticancer activity in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5157. doi:10.1158/1538-7445.AM2017-5157
Abstract 5469: Low dose ionizing radiation induces persistent activation of NADPH oxidase pathway in mouse colon
Authors: Santosh Kumar, Shubhankar Suman, Bo-Hyun Moon, Albert J. Fornace, Kamal Datta
Journal: Cancer Research (2017)

Abstract Exposure to ionizing radiation has been linked to persistent oxidative stress. The purpose of the current study was to characterize the role of NADPH oxidase pathway in radiation-induced increased oxidant production in colon epithelial cells. Mice (C57BL/6J; 6-8 weeks, male) were exposed to either sham or 0.5 Gy γ radiation, and NADPH oxidase pathway and oxidative stress markers were assessed in colon samples 60 d after exposure. Radiation exposure led to higher elevation of 4-HNE and 8-oxo-dG staining relative to unirradiated control. We also observed increased staining for the proliferative marker phospho-histone H3 in colon sections of irradiated mice. PCR analysis showed increased expression of two NADPH oxidase isoforms, Nox1 and Nox3, in irradiated samples. Additionally, expression of NoxA1 and Noxo1 along with Hif1α were also increased after radiation. Immunoblot analysis confirmed the PCR results, and ChIP assay revealed greater binding of stress response factor GATA6 and Hif1α to Nox1 and Nox3, and Nox3 promoters respectively after radiation exposure relative to control. Co-immunoprecipitation experiments show enhanced binding of Rac1, an activator of NADPH oxidase, to Nox1 and Nox3. In summary, we demonstrated that exposure to a low dose of γ radiation caused long-term upregulation of NADPH oxidase isoforms as well as its regulators and activators such as NoxA1, Noxo1, Hif1α, TLR4, GATA6, Doux1, and Doux2. When considered along with our results on oxidative stress and proliferative markers, our observations on NADPH oxidase pathway provides new insight into molecular events contributing to radiation-induced persistent oxidative stress and cell proliferation in colon, and have implications for colorectal carcinogenesis. Note: This abstract was not presented at the meeting. Citation Format: Santosh Kumar, Shubhankar Suman, Bo-Hyun Moon, Albert J. Fornace, Kamal Datta. Low dose ionizing radiation induces persistent activation of NADPH oxidase pathway in mouse colon [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5469. doi:10.1158/1538-7445.AM2017-5469
Abstract 5683: Evaluation of the utilization of blood collection tubes for cell-free DNA research
Authors: Fumitaka Endo, Takeshi Iwaya, Takehiro Chiba, Mizunori Yaegashi, Kei Sato, Kohei Kume, Atsuhiro Arisue, Yutaka Nishinari, Ryoko Kawagishi, Takenori Segawa, Satoshi Nishizuka, Akira Sasaki
Journal: Cancer Research (2017)

Abstract Many studies have been conducted investigating cell-free DNA (cfDNA) for disease diagnosis. To prevent cellular DNA release into the plasma, plasma separation within 2 hours of blood collection is required, when utilizing the most commonly used type of tube (BD Vacutainer® CPTTM; CPT). These temporal restrictions render operations requiring plasma separation a laborious task. It has been demonstrated that Cell-Free DNA BCT® tubes (Streck Inc; BCTs) prevented nucleated cell disruption. The use of BCTs may enable us to separate plasma without temporal restrictions. The aim of this study was to evaluate changes in DNA levels in plasma after preservation using two types of collection tubes. Samples were drawn from 7 healthy donors into CPTs and BCTs, and stored at room temperature. Plasma was separated immediately (d0), and on days 3, 6, 9, 12, and 14 after blood collection. The concentrations of DNA in the extracted plasma samples were measured. Blood stored in CPTs showed increases in plasma DNA concentrations over time. The mean DNA concentrations at each time-point were 0.39 (d0), 2.96 (d3), 40.4 (d6), 84.9 (d9), 91.4 (d12), and 94.9 ng/μl (d14). However, plasma DNA levels remained stable in BCTs from 6 days. There were significant differences between the DNA concentrations in BCTs on d0 (0.74 [0.43-1.44] ng/µl) and d14 (1.78 [0.63-4.20] ng/µl) (p = 0.0378). Although significant differences were only observed between d0 and d14 in BCTs, the amount of plasma DNA gradually increased after d6. Furthermore, obvious color changes in the plasma were observed, and the boundary between plasma and PBMCs became unclear over time. These results indicate that BCTs may yield stable cfDNA samples for up to 6 days after blood collection. BCTs may be a novel collection tube for cfDNA research, including liquid biopsies in cancer patients. Citation Format: Fumitaka Endo, Takeshi Iwaya, Takehiro Chiba, Mizunori Yaegashi, Kei Sato, Kohei Kume, Atsuhiro Arisue, Yutaka Nishinari, Ryoko Kawagishi, Takenori Segawa, Satoshi Nishizuka, Akira Sasaki. Evaluation of the utilization of blood collection tubes for cell-free DNA research [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5683. doi:10.1158/1538-7445.AM2017-5683
Abstract 4132: Roles of the acetyltransferases CBP/p300 in breast cancer
Authors: Iqbal Muhmud, Guimei Tian, Daiqing Liao
Journal: Cancer Research (2017)

Abstract Intrinsic drug resistance renders certain breast cancer (BC) patients unresponsive to standard-of-care therapies. For example, ~50% of patients with estrogen receptor-positive (ER+) tumors do not respond to endocrine therapies (ETs, e.g., tamoxifen). Acquired drug resistance is another cause for treatment failure and deadly relapse. Therefore, new strategies that tackle both intrinsic and acquired resistance are needed for improving clinical outcome for BC patients. ER-alpha, the defining factor for ER+ tumors, is an estrogen-activated transcription factor (TF) that drives tumor growth and progression. It critically depends on the coactivators CBP/p300 for gene expression underpinning tumor biology of ER+ subtypes that account for ~75% of all BC cases. Recent advances revealed that another hormone receptor, the androgen receptor (AR), is expressed in the majority of ER+ BCs as well as in a subset of ER- BCs. Evidence has shown that AR signaling is implicated in ET resistance. For the HER2-enriched tumors, high levels of AR expression correlate with poor prognosis. Similarly for ER-alpha, CBP/p300 act as key coactivators for AR-mediated gene expression. Additionally, other oncogenic TFs (e.g., beta-catenin/TCF and STAT3) also depend on CBP/p300 for gene activation. Importantly, these pathways are active in all BC subtypes, regardless of the hormone receptor status. CBP/p300 overexpression and heightened acetyltransferase activity are detected in clinical BC samples and correlate with disease progression. Thus, CBP/p300 represent attractive targets for developing novel therapies broadly applicable for treating all major BC subtypes. We have discovered a novel class of highly potent CBP/p300 inhibitors. Our previous studies indicated that this class of compounds is highly effective to suppress tumor growth in vivo using a xenograft mouse model. We will present genomic features of CBP/p300 in different breast cancer subtypes and experimental data underlying potential mechanisms by which CBP/p300 regulate oncogenic phenotypes, as well as effects of pharmacologic inhibition of CBP/p300 on sensitivity of breast cancer cells to standard anticancer therapeutics. Citation Format: Iqbal Muhmud, Guimei Tian, Daiqing Liao. Roles of the acetyltransferases CBP/p300 in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4132. doi:10.1158/1538-7445.AM2017-4132
Genistein induces apoptosis in acute myeloid leukemia cells and affects Proteasome pathway by proteomic analysis
Authors: Stephen Ching-Ho Wong, Mavis Low, Jing Shen, Qingsong Lin, Choy Leong Hew, Jin-Hua Han, Matiullah Khan, C. S. Chen
Journal: Cancer Research (2005)

2365  Introduction Acute myeloid leukemia (AML) in general, has a poor long term outcome even after intensive debilitating chemotherapy. Novel and less toxic therapy are urgently needed. Genistein, an isoflavone which is a naturally occurring tyrosine kinase inhibitor present in soybeans has been shown to be an active agent in APL (NB4) harboring PML-RAR fusion gene in our previous study (Khan M et al. 46th ASH poster# 554274). We extended our study to test genistein and its related compound daidzein in other AML cell lines with different doses and time points with comparative proteomic analysis between control and treated leukemia. Methods Leukemia cells were cultured in RPMI 1640 + 10% FBS. Genistein was dissolved in DMSO (final conc.
Abstract 5899: Compartment-resolved proteomics reveal NNMT as a master metabolic regulator of cancer associated fibroblasts
Authors: Mark A. Eckert, Fabian Coscia, Shawn Pan, Samantha M. Tienda, Agnieszka A. Chryplewicz, Chun-Yi Chiang, Anthony Montag, S. Diane Yamada, Matthias Mann, Ernst R. Lengyel
Journal: Cancer Research (2017)

Abstract The poor outcome of ovarian cancer patients is due to late detection and the ability of ovarian cancer cells to metastasize quickly throughout the abdominal cavity. Recent research, including histopathological studies and experiments with mouse models, suggest that ovarian cancer may actually arise in the fallopian tube as serous tubal intraepithelial carcinomas (STIC). Lesions of the ovary would, therefore, represent metastases from the fallopian tube. To better understand the molecular events that occur in both the tumor and stromal compartment during ovarian cancer progression, we performed shotgun proteomics on laser-microdissected tumor and stromal compartments from anatomic sites representing the hypothetical progression series for ovarian cancer (STIC → fallopian tube → ovary → omentum). With an optimized sample preparation technique, we successfully quantified 4-5000 proteins per anatomic site with high reproducibility and with as few as several thousand microdissected cells derived from formalin-fixed and paraffin-embedded (FFPE) biobank specimens. Proteomics of the tumor compartments revealed high inter-patient heterogeneity, with no conserved protein signatures associated with invasion or metastasis. In strong contrast, a highly conserved molecular signature of stromal proteins associated with metastasis to the omentum was identified. In particular, nicotinamide N-methyl transferase (NNMT) was highly upregulated in the stroma of omental and peritoneal metastases. Functionally, NNMT was necessary and sufficient for multiple aspects of the cancer associated fibroblast (CAF) phenotype, including expression of CAF markers and secretion of cytokines and oncogenic extracellular matrix. NNMT expression was necessary for the ability of CAFs to support ovarian cancer cell migration, proliferation, adhesion, and in vivo growth. Mechanistically, high expression of NNMT in CAFs led to a depletion of S-adenosyl methionine (SAM) and a reduction in histone methylation associated with gene expression changes in the tumor stroma. This work supports the use of ultra-low input proteomics for compartment-resolved identification of candidate drivers of disease phenotypes and identifies NNMT as a central, metabolic regulator of CAF differentiation. Citation Format: Mark A. Eckert, Fabian Coscia, Shawn Pan, Samantha M. Tienda, Agnieszka A. Chryplewicz, Chun-Yi Chiang, Anthony Montag, S. Diane Yamada, Matthias Mann, Ernst R. Lengyel. Compartment-resolved proteomics reveal NNMT as a master metabolic regulator of cancer associated fibroblasts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5899. doi:10.1158/1538-7445.AM2017-5899
Abstract 2014: Genitourinary cancer-derived cells produce microenvironment proteinases that regulate proteinase activated receptors (PARs) to drive oncogenic signaling
Authors: Stacy G. Gibson, Koichiro Mihara, Andries Zijlstra, Matthew E. Hyndman, Morley D. Hollenberg
Journal: Cancer Research (2017)

Abstract Background: Thrombin-triggered activation of proteinase-activated receptor-1 (PAR1) is recognized as a key stimulus for driving epithelial malignancies (IUBMB life.63:397, 2011; PMID:21557443). However, the enzymes for regulating PAR1 in the tumour microenvironment are not known. Hypothesis: We hypothesize that prostate (PC) and urinary bladder cancer (UBC) cells can regulate microenvironment signaling to drive cancer progression via the secretion of proteinases that cleave/regulate proteinase-activated receptors (PARs). Aims: 1.) Visualize the cleavage status of N- and C-terminally-dual-labelled PARs in receptor-transfected UBC- and PC-derived cells. 2.) Measure PAR cleavage by UBC and PC-secreted proteinases. 3.) Identify the UBC &amp; PC-derived proteinases that cleave/regulate PAR function. Methods: The cleavage status of dual-labeled PARs (N-terminus-mCherry/C-terminus-YFP) expressed in PC &amp; UBC cells was determined by confocal image analysis as already described (JBC 288:32979, 2013; PMID: 26957205). Intact receptors look 'yellow' and cleaved receptors look 'green'. The cleavage of PARs in UBC and PC cells was studied for dual-tagged-PAR-expressing UBC and PC cells exposed or not to cell-derived culture supernatants, enzyme agonists for PAR1 and 2 (thrombin and trypsin, respectively), and proteinase inhibitors (e.g. for MMPs and other enzymes). The impact of CRISPR-mediated elimination of MMPs from PC3 cells on PAR1 cleavage status was also monitored. Results: UBC- and PC-produced enzymes can cleave PAR1 as efficiently as thrombin, an established PAR1 agonist. None of the UBC cell lines produce proteinases that cleave PAR2. Inhibition of MMP activity partially prevents PAR1 cleavage by UBC cells and completely prevents PAR1 cleavage in PC3-PC cells. Conclusions: We conclude that UBC and PC cells secrete PAR-regulating proteinases that can directly regulate PAR1 in the tumour microenvironment so as to drive cancer progression. Funding: Alberta Innovates CRIO Grant, Prostate Cancer Canada Discovery Grant, Motorcycle Ride for Dad, Johnson &amp; Johnson Alberta Health Partnership and CIHR Note: This abstract was not presented at the meeting. Citation Format: Stacy G. Gibson, Koichiro Mihara, Andries Zijlstra, Matthew E. Hyndman, Morley D. Hollenberg. Genitourinary cancer-derived cells produce microenvironment proteinases that regulate proteinase activated receptors (PARs) to drive oncogenic signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2014. doi:10.1158/1538-7445.AM2017-2014
Abstract 3107: Targeting nanotherapeutics to the invasive glioblastoma margin via the cell surface receptor Fn14
Authors: Aniket S. Wadajkar, Jimena G. Dancy, Nina P. Connolly, Jeffrey A. Winkles, Graeme F. Woodworth, Anthony J. Kim
Journal: Cancer Research (2017)

Abstract The most common and deadly form of primary brain cancer, glioblastoma (GBM), is characterized by significant intratumoral heterogeneity, high vascularity, and infiltrative growth. Delivering effective and sustained treatments to the invading GBM cells without worsening damage to the adjacent brain is a major challenge. We aim to develop an innovative, local delivery approach that couples chemotherapy-loaded brain penetrating biodegradable nanoparticles with tumor cell-targeting capabilities and convection enhanced delivery (CED). We formulated sub-100 nm sized, close to neutrally charged, poly(lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) nanoparticles with ~5% w/w carmustine (BCNU) payload coated with a fibroblast growth factor-inducible 14 (Fn14) antibody to specifically target Fn14-positive brain-invading tumor cells. We observed that PLGA surface modification using non-adhesive PEG allowed nanoparticles to rapidly move through brain tissue in ex vivo rat brain slices, potentially increasing the distribution of delivered therapeutics. We showed that Fn14-targeted nanoparticles were able to selectively bind to recombinant Fn14 but not to brain extracellular matrix proteins in surface plasmon resonance assays, as well as diffuse within brain tissue in multiple particle tracking assays. In addition, when administered intracranially, Fn14-targeted nanoparticles showed improved brain tumor retention in C57BL/6 mice bearing orthotopic KR158B tumors compared to non-targeted nanoparticles. We propose that targeting treatments to invading cancer cells using non-adhesive nanoparticles will limit non-specific interactions within brain and tumor tissue and thereby allow specific interactions at target structures and increase the BCNU therapeutic index. To test this hypothesis, we plan to determine the therapeutic efficacy of Fn14-targeted and non-targeted, non-adhesive nanoparticles, capable of releasing BCNU over a 3 week period, by intracranial CED injections in C57BL/6 mice bearing orthotopic KR158B invasive tumors. Citation Format: Aniket S. Wadajkar, Jimena G. Dancy, Nina P. Connolly, Jeffrey A. Winkles, Graeme F. Woodworth, Anthony J. Kim. Targeting nanotherapeutics to the invasive glioblastoma margin via the cell surface receptor Fn14 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3107. doi:10.1158/1538-7445.AM2017-3107