bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2663: Dual cytoprotective and cytotoxic functions of autophagy in the response ofbreast tumor cells to radiation and in radiosensitization by vitamin D3
Authors: Bristol Molly L. , Di Xu , Gewirtz David A. 
Published: June 2012

Abstract
Introduction: While chemotherapy and radiation treatment may be initially effective at suppressing breast cancer growth, disease recurrence and tumor metastasis are major clinical problems. A number of strategies have been developed in an attempt to enhance the response to radiation and prevent tumor cell recovery by interfering with cytoprotective signaling. Autophagy, a cellular process in which the degradation of subcellular organelles generates energy and metabolic precursors, may be cytoprotective or cytotoxic, depending on the cells and the nature of the stressful challenge. Our studies were designed to evaluate the involvement of autophagy in radiosensitization by the hormonally active form of vitamin D3, 1,25D3. Additionally, studies were designed to test the premise that interference with autophagy would influence sensitivity to treatment with 1,25D3 + radiation.
Results: Our studies demonstrate radiosensitization of breast tumor cells by vitamin D (1,25D3) through the promotion of autophagy as well as a concurrent cytoprotective function of autophagy in irradiated cells. 1,25D3 promoted autophagy (as well as autophagic flux) in irradiated MCF7 cells and suppressed the proliferative recovery that occurs after radiation alone. 1,25D3 also enhanced radiosensitivity and promoted autophagy in p53 mutant Hs578t breast tumor cells as well as MCF7 cells that overexpress Her-2/neu. In contrast, 1,25D3 failed to alter radiosensitivity or promote autophagy in the BT474 breast tumor cell line with low-level expression of the vitamin D receptor. Enhancement of MCF-7 cell sensitivity to radiation by 1,25D3 was not attenuated by either a pharmacological or genetic block to autophagy due to a shift in the mode of cell death to apoptosis. In contrast to autophagy mediating the cytotoxic impact of the 1,25D3 and radiation combination treatment, radiation alone promoted a low level of autophagy that was cytoprotective. Specifically, pharmacological or genetic interference with autophagy induced by radiation resulted in cell killing (primarily by apoptosis). These studies demonstrate that in the same experimental system, autophagy can function both as a mechanism for evading cell killing by radiation and as a pathway for mediating the killing of breast tumor cells by radiation.
Conclusions: Both the suppression of cytoprotective autophagy and the promotion of cytotoxic autophagy represent potential strategies for radiation sensitization in breast cancer.
Supported, in part, by American Institute for Cancer Research Grant # 06A058-REV and by DOD predoctoral training grant W81XWH-09-1-0020.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2663. doi:10.1158/1538-7445.AM2011-2663
Abstract 2666: Relationship between chromatin structure and sensitivity to molecularly-targeted radiation therapy
Authors: Terry Samantha Y.A , Vallis Katherine A. 
Published: June 2012

Abstract
The open structure of euchromatin renders it more susceptible to DNA damage by ionising radiation (IR) compared to compact heterochromatin. The goal was to investigate whether chromatin accessibility also affects the toxicity of Auger electron-emitting radiopharmaceuticals.
SAHA is a histone deacetylase inhibitor that results in chromatin remodelling to an open structure and is used to treat cutaneous T-cell lymphoma. Epidermal growth factor receptor (EGFR)-overexpressing MDA-MB-468 and MDA-MB-231/H2N breast cancer cells were treated with SAHA and irradiated (137Cs source, 1Gy/min, 0.5Gy) or incubated with 111Indium-DTPA-hEGF (111In-EGF) for one hour. Cells were stained for γH2AX, a marker of DNA double-strand breaks, 30min after γ-irradiation or after exposure to 111In-EGF. Nuclear uptake of 111In following SAHA was evaluated in cellular fractionation experiments. Total cellular H2AX protein expression after SAHA treatment was analysed by western blot. Cells treated with SAHA and consequently irradiated (up to 6Gy) or incubated with 111In-EGF (24h), were plated and incubated for 7-10 days in clonogenic survival experiments. Cells were exposed to calyculin A (50nM) or NaCl (0.5M), which result in chromatin condensation, irradiated (1Gy) or incubated with 111In-EGF (1h) and stained for γH2AX as before.
In both MDA-MB-468 and MDA-MB-231/H2N cells, SAHA resulted in an increase in the number of γH2AX foci (16 and 14 per cell respectively) compared to IR alone (12 and 11 foci/cell respectively). SAHA plus 111In-EGF also increased DNA damage (22 and 12 foci/cell respectively) compared to 111In-EGF alone (15 and 7 foci/cell respectively). SAHA did not alter the extent of nuclear uptake of 111In in either cell line (0.4-0.6% of total administered), nor did it alter total cellular H2AX protein expression. Preliminary clonogenic data suggest that SAHA decreases cell survival after either irradiation or incubation with 111In-EGF in both cell lines. MDA-MB-468 cells treated with calyculin A accumulated less damage after γ-irradiation (11 foci/cell) compared to IR alone (20 foci/cell). Treatment of both cell lines with NaCl before irradiation (11 and 9 foci/cell) also protected against DNA damage compared to IR alone (19 and 16 foci/cell). Preliminary data suggests that cells treated with NaCl prior to incubation with 111In-EGF also acquired less DNA damage.
Chromatin density modification alters radiosensitivity and DNA damage after γ-irradiation. The results of this study indicate that this is also the case for Auger electron-emitting molecularly-targeted radiation therapeutic agents.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2666. doi:10.1158/1538-7445.AM2011-2666
Abstract 2677: Novel Hsp90 inhibitor, STA-9090, for combination with radiotherapy
Authors: Sang Jim , Smith Donald , Korbut Tim , Zhang Chaohua , Proia David A. , Wada Yumiko 
Published: June 2012

Abstract
Introduction: Radiation is accepted as an important standard therapy for locally unresectable cancers, and as such is given to approximately 60% of cancer patients. However, radio-resistance and repair of sublethal radiation damage can limit its efficacy. Recent studies have shown that Heat Shock Protein 90 (Hsp90), a molecular chaperone that mediates maturation and activation of client proteins, plays a critical role in establishing resistance to radiation therapy. Inhibiting Hsp90 has been reported to sensitize tumors to radiation, resulting in tumor growth suppression and augmenting therapeutic cell death induction. Unfortunately, many of the Hsp90 inhibitors currently in clinical trials exhibit hepatotoxicity as well as ocular toxicity, hindering their clinical use. Taken together, development of clinically acceptable Hsp90 inhibitors for combination with radiation could serve as an important strategy for improving radiotherapy success.
STA-9090 is a second generation Hsp90 inhibitor that has shown potent preclinical activity and is currently in twelve Phase II trials across a broad range of indications. STA-9090 has demonstrated encouraging activity in a Phase II trial in patients with stage IIIB and IV non-small cell lung cancer. Importantly, STA-9090 has displayed a favorable safety profile with substantially lower incidence of hepatic or ocular toxicity than that reported for other Hsp90 inhibitors.
Results: We evaluated the radiosensitizing potential of STA-9090 in vivo. Monotherapy treatment with either STA-9090 or 2 Gray (Gy) ionizing irradiation resulted in moderate reductions in human tumor growth rates in a mouse xenograft model. Combination of STA-9090 with 2 Gy irradiation resulted in substantial tumor regression. Increasing the dose of radiation in the combination arm to 4 Gy further enhanced tumor regression, resulting in a 50% reduction in tumor volume. In summary, STA-9090 offers a safe and effective strategy for improving the outcome of radiotherapy in human cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2677. doi:10.1158/1538-7445.AM2011-2677
Abstract 2679: Gold nanoparticles enhance the radiation therapy of a murine squamous cell carcinoma
Authors: Hainfeld James F. , Dilmanian Avraham , Zhong Zhong , Slatkin Daniel N. , Kalef-Ezra John A. , Smilowitz Henry M. 
Published: June 2012

Abstract
The purpose of this study is to test the hypothesis that gold nanoparticle (AuNP, nanogold)-enhanced radiation therapy (nanogold radiation therapy, NRT) is efficacious when treating the radiation resistant and highly aggressive mouse head and neck squamous cell carcinoma model, SCCVII, and to identify parameters influencing the efficacy of NRT. Subcutaneous (sc) SCCVII leg tumors in mice were irradiated with x-rays at the Brookhaven National Laboratory (BNL) National Synchrotron Light Source (NSLS) with and without prior intravenous (iv) administration of AuNPs. Variables studied included radiation dose, beam energy, temporal fractionation and hyperthermia. AuNP-mediated NRT was shown to be effective for the sc SCCVII model. AuNPs were more effective at 42 Gy than at 30 Gy (both at 68 keV median beam energy) compared to controls without gold. Similarly, at 157 keV median beam energy, 50.6 Gy NRT was more effective than 44 Gy NRT. At the same radiation dose (∼42 Gy), 68 keV was more effective than 157 keV. Hyperthermia and radiation therapy (RT) were synergistic and AuNPs enhanced this synergy, thereby further reducing TCD50 s (tumor control dose 50%) and increasing long-term survivals. It is concluded that gold nanoparticles enhance the radiation therapy of a radioresistant mouse squamous cell carcinoma. The data show that radiation dose, energy and hyperthermia influence efficacy and better define the potential utility of gold nanoparticles for cancer x-ray therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2679. doi:10.1158/1538-7445.AM2011-2679
Abstract 2680: Characterization of tumor associated antigens using a recombinant expression of a patient derived breast cancer cDNA library and autologous serum using the SEREX technique
Authors: Novinger Leah J. , Shukla Girja , Pero Stephanie , Krag David N. 
Published: June 2012

Abstract
Autoantibodies to tumor proteins in patient serum may serve as biomarkers in breast cancer diagnosis or as a potential targeted therapeutic when conjugated to drugs or radiotherapies. The tumor associated antigens (TAAs) to which they bind may be of further diagnostic or prognostic value. In order to identify TAAs, a cDNA library was created from a patient breast tumor, recombinantly expressed with lambda phage in XL1-Blue cells, and tested against autologous patient serum to identify potential TAAs using a modified technique based on serological analysis of recombinant cDNA expression libraries (SEREX) that allows for much smaller quantities of source material and reduces library production time. Identified TAAs and serum autoantibody concentrations against those proteins will be presented in the context of developing a new customized therapy for patients with breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2680. doi:10.1158/1538-7445.AM2011-2680
Abstract 2689: XAGE-1b(GAGED2a) immunity in non-small cell lung cancer
Authors: Ohue Yoshihiro , Eikawa Shingo , Matsumoto Hirofumi , Mizote Yu , Isobe Midori , Uenaka Akiko , Fukuda Minoru , Nakayama Eiichi , Oka Mikio 
Published: June 2012

Abstract
BACKGROUND: Several cancer/testis(CT) antigens such as NY-ESO-1 antigen, etc., have been shown to elicit immune responses in cancer patients spontaneously. Because of their restricted expression in normal tissues and high immunogenicity, CT antigens have been thought to be attractive targets for cancer vaccine. We previously described XAGE-1b (GAGED2a), one of the CT-associated antigens, was predominantly expressed in lung adenocarcinoma by immunohistochemistry using XAGE-1b mAb (clone USO 9-13) and could elicit both humoral and cellular immune response in patients with non-small cell lung cancer (NSCLC). In this study, we established CD4 and CD8 T cell clones from PBMC in XAGE-1b antibody-positive patients and analyzed the antigen recognition.
MATERIALS AND METHODS: Sera and PBMCs were obtained from NSCLC patients who visited Kawasaki Medical School Hospital between 2005 and 2010. Antibody response to XAGE-1b was analyzed by ELISA using synthesized XAGE-1b protein. CD4 and CD8 T cell responses against XAGE-1b were examined by IFN-γ ELISA and/or capture assay using 17 16- or 17-mer XAGE-1b-overlapping peptides (OLPs) spanning the entire XAGE-1b protein by FACS in antibody-positive patients. Cytotoxicity was analyzed by bioluminescence assay (GAPDH).
RESULTS: Spontaneous CD4 and CD8 T cell responses were also detected in most of the antibody positive patients. Occurrence of antibody response, and CD4 and CD8 T cell responses in XAGE-1b (GAGED2a) antibody positive patients indicated strong immunogenicity of XAGE-1b (GAGED2a) antigen in NSCLC patients. Furthermore, We identified the minimal epitope peptide bound to HLA-DR4.1 and DP5 recognized by CD4 and those bound to HLA-A2, B61 and Cw1 recognized by CD8 T cell clones. CD4 and CD8 T cell clones recognized naturally processed XAGE-1b (GAGED2a) antigen on APC (antigen-presenting cell) and the CD8 T cell clone was stained with the peptide/MHCI tetramer and showed cytotoxicity against XAGE-1b (GAGED2a)-expressing, appropriate HLA class I expressing tumor cell line.
CONCLUSION: Our findings indicate validity of XAGE-1b (GAGED2a) for cancer vaccine. Now we plan to global clinical trial of cancer vaccine against XAGE-1b in NSCLC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2689. doi:10.1158/1538-7445.AM2011-2689
Abstract 2691: Regulation of ultraviolet radiation induced cutaneous tumor development by Toll like receptor-4
Authors: McConnell Matthew , Yusuf Nabiha 
Published: June 2012

Abstract
Ultraviolet (UV) B radiation, in particular the mid-wavelength range (UVB; 290-320 nm), is one of the most significant risk factors for the development of skin cancer. Toll like receptor-4 (TLR4) has been shown to play an important role in cancer, but the role that it plays apparently depends on the stage of tumor development, the tumor type and the initiating agent. The purpose of this study was to delineate the contribution of TLR4 in UVB induced cutaneous tumor development using TLR4 deficient C3H/HeJ mice and TLR4 proficient C3H/HeN (WT) mice. We observed that UVB induced skin carcinogenesis was retarded in terms of tumor incidence, and tumor latency, in mice deficient in TLR4 compared to WT mice, whereas significantly greater (p&lt;0.05) numbers of tumors occurred in WT mice. Further, we found that tumor-bearing WT mice produced more IL-17 and IL-10 (p&lt;0.05), whereas TLR4 deficient mice produced more IFN-γ (p&lt;0.05). CD4+CD25+ regulatory T-cells from WT mice produced more IL-10 (p&lt;0.05) than regulatory T-cells from TLR4 deficient mice. There was a significant increase (p&lt;0.05) in Foxp3 expression in skin of WT mice than TLR4 deficient mice. Time course kinetics of tumor development revealed an increase in MyD88 and TRAF6 expression in skin and tumors of WT mice in comparison to TLR4 deficient mice. These results indicate that, TLR4 promotes tumor development in this model. Strategies to inhibit TLR4 may allow us to develop immunopreventive and immunotherapeutic approaches for management of UVB induced skin cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2691. doi:10.1158/1538-7445.AM2011-2691
Abstract 2693: Amplification of tumor immunity with cryoablation
Authors: Veenstra Jesse , Littrup Peter , Wei Wei-zen 
Published: June 2012

Abstract
Tumor cryoablation, the use of freezing temperatures to destroy tumor tissue while preserving tumor-associated antigens, has the potential to initiate or amplify tumor immunity. However, enhanced tumor immunity is not consistently observed in treated patients, suggesting inadequate immune priming by cryoablation itself. We hypothesize that cryoablation in coordination with DNA vaccination and/or immune modulation will amplify effector mechanisms to provide long-term anti-tumor protection. BALB/c mice implanted with a neu expressing mammary tumor TUBO received two electro-vaccinations 10 days apart, with neu DNA or blank vector, followed 4 days later with cryoablation or sham surgery of the tumor. Mice receiving both neu vaccination and cryoablation produced a 3-fold higher anti-neu antibody titer over neu vaccination alone (P&lt;0.02) and a 16-fold higher titer over cryoablation alone (P&lt;0.003). Combination treatment also provided full protection against TUBO re-challenge, supporting enhanced immunity by cryoablation. To test the effect of combining cryoablation with the depletion of regulatory T cells (Treg), 12 week old BALB Neu transgenic mice which had spontaneously developed ductal carcinoma in situ in the mammary glands were treated with α-CD25 mAb to deplete Tregs, partial cryoablation of the 4th mammary gland, or a combination of both. Development of palpable mammary tumor throughout all ten mammary glands was significantly delayed in mice receiving combination treatment over either treatment alone, indicating amplification of tumor immunity in Treg depleted mice by cryoablation. The mechanisms of amplified immunity are being investigated by analyzing a panel of inflammatory cytokines in the serum as well as gene expression in lymphocytes in the tumor, spleen, and tumor draining lymph nodes at different points after cryoablation. Phenotyping of tumor infiltrating immune cells post-cryoablation is also being assessed.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2693. doi:10.1158/1538-7445.AM2011-2693
Abstract 2702: Sorafenib modulates immune responses in patients with hepatocellular carcinoma
Authors: Cabrera Roniel , Ararat Miguel , Cao Mengde , Xu Yiling , Wasserfall Clive , Brusko Todd , Atkinson Mark A. , Liu Chen , Nelson David R. 
Published: June 2012

Abstract
Background/Aim: We have previously shown that patients with hepatocellular carcinoma (HCC) have impaired immunity. The poor immune reactivity is marked by blunted effector CD4 T cell responses (Teff), elevations in immunosuppressive soluble factors, and an increase of CD4+CD25+ regulatory T cells (Tregs) with enhanced suppression. Presently, sorafenib is the only systemic agent with a proven survival benefit for unresectable HCC. We hypothesize that sorafenib has immune modulatory properties that may partially explain the clinical benefit. In this study, we characterize the effects of sorafenib on the function of CD4 Teffs and Tregs.
Methods: PBMC cells isolated from normal healthy controls (NHC), disease controls (DC) and HCC patients were used to isolate CD4+CD25- Teffs and Tregs to use in functional immune assays. The 3H thymidime incorporation and the IFNg ELISpot were used to assess CD4 Teff responses.
Results: Sorafenib increased Teff proliferation in HCC patients during dose response cultures. We observed a similar positive effect by sorafenib on Teff IFNg production in HCC patients. The dose related effect of sorafenib on Teff proliferation and INFg production occurred in all three groups – HCC, DC, and NHC. However, Teff responses in HCC patients improved with lower concentrations of sorafenib (0.1uM) while the Teff responses from DC/NHC increased only after the introduction of higher concentrations of sorafenib (0.7uM). Further, while sorafenib improved Teff immune responsiveness in HCC patients in a dose dependent manner (0.1uM to 2 uM), the increase in Teff responsiveness in DC/NHC peaked and leveled off at lower concentrations (0.7 uM). However, sorafenib was unable to abrogate the suppressive properties of autologous HCC derived serum on Teff responses at the dose range studied. Interestingly, sorafenib decreased Treg mediated suppression during suppression assays using Treg:Teff co-cultures at a 1:1 ratio.
Conclusion: Sorafenib appears to have a positive modulatory effect on immune responses by enhancing CD4 Teff function and decreasing Treg suppressive function in HCC patients. Studies that investigate new approaches that combine sorafenib with other agents that target inhibitory immune pathways are needed.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2702. doi:10.1158/1538-7445.AM2011-2702