bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4187: Phospho-Akt status as a predictor of disease free interval in patients with muscle invasive transitional cell carcinoma of the bladder
Authors: McPherson Victor A. , Williams Andrew , Chan Susanne , Rizkalla Kamilia , Izawa Jonathan , Lewis John 
Published: July 2012

Abstract
Background: Akt is an ubiquitous signaling molecule that is associated with a wide array of biological effects including cell growth and proliferation. The dysregulation of Akt has been associated with cancer cell transformation, invasion and metastasis. While the roles of mutations in FGFR3, p53 and Ras have been the focus of the majority of studies of Transitional cell carcinoma (TCC) of the bladder, recent evidence suggests a link between the Akt pathway and the progression of TCC. Mutations in Akt pathway members have been identified in subsets of bladder TCCs, and Akt activation in TCC cell lines confers resistance to chemotherapeutics and promotes invasion in vitro. This led us to hypothesize that activated Akt may be an important biomarker in the progression of muscle invasive TCC. Methods: Tissue was obtained from 67 patients who had undergone radical cystectomy procedures for treatment of muscle invasive TCC. Tissue sections were taken from paraffin embedded samples and subjected to immunohistochemical analysis with anti Akt antibody to detect the activated form of Akt. A database of patient demographics, disease, treatment and survival parameters was generated and used to correlate 4, 12, 24 and 36 month disease-free intervals (DFI). Results: 53 of the 67 patients had sufficient follow-up to allow for DFI analysis. Of these 53 patients, 48 stained positively for pAkt, while 5 stained negatively. None of the pAkt negative patients had recurrent disease, while the pAkt negative patients suffered cumulative recurrence in 10, 19, 24, and 25 of the 48 patients at 4, 12, 24 and 36 months respectively. Chi square analysis reveals statistically significant differences in recurrence rates between pAkt negative and negative patients at 24 (p=0.0235) and 36 months (p=0.016). Tumor stage and nodal status were also strong predictors of recurrence. Conclusions: pAkt negative patients were found to have a significantly better prognosis for TCC recurrence, which indicates that pAkt status could be useful in helping to determine the prognosis for patients with muscle invasive TCC. These results lead us to speculate that the use of a serine threonine kinase inhibitor may prove to be therapeutically beneficial for TCC patients undergoing concurrent chemotherapy for their disease.
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 4187. doi:10.1158/1538-7445.AM2011-4187
Abstract 4193: Identification of a novel SIRT1/FEN1 interaction and their regulation by karyopherins
Authors: Feurstein Daniel , Anderson Jessica , Duckett Derek 
Published: July 2012

Abstract
The structure-specific flap endonuclease 1 (FEN-1) is a multifunctional enzyme that participates in various activities such as DNA replication, DNA repair and apoptotic DNA fragmentation. Several mechanisms, including protein-protein interactions, sub-cellular compartmentalization and posttranslational modifications have been proposed to explain how FEN1 accomplishes these various activities. For example, the C-terminus of FEN1 has been shown to be acetylated by the histone acetyl transferase protein (HAT) p300 which is known to result in a significant reduction in the DNA binding and nuclease activities of FEN1. We now demonstrate that the NAD-dependent class III histone deacetylase SIRT1 physically interacts with FEN1 and that the opposing deacetylation by SIRT1 subsequently restores the endonuclease activity of FEN1. Moreover, clonogenicity experiments suggest that genetic knockdown of FEN1 or SIRT1 in cancer cells sensitizes those cells to irradiation treatment. This is of significance as it has been observed that increased SIRT1 levels protect mice from irradiation-induced cancer. Furthermore, we have also identified two nuclear shuttling proteins, Karyopherin α2 and Karyopherin β1 as interacting partners of both SIRT1 and FEN1. Using mass spectrometry, immunoprecipitation combined with subsequent western-blot analysis and confocal microscopy we demonstrate that, under basal conditions, a significant amount of both SIRT1 and FEN1 is located in the cytoplasm of cells. However, after induction of DNA damage by the methylating agent MMS, Karyopherin α2 and Karyopherin β1 mediate the translocation of SIRT1 and FEN1 into the nucleus in a time dependent manner. In summary we describe a novel interaction between SIRT1 and FEN1, demonstrate that acetylation/deacetylation regulates FEN1 activity and that the Karyopherins α2 and β1 mediate the nuclear import of SIRT1 and FEN1 following DNA damage. Our results suggest that inhibiting the nuclear import or activation of FEN1 or SIRT1 could represent potential anticancer strategies.
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 4193. doi:10.1158/1538-7445.AM2011-4193
Abstract 4201: Role of adenomatous poliposis coli (APC) in cigarette smoke condensate-induced accumulation of apurinic/apyrimidinic lesions and enhanced transformation of normal breast epithelial cells
Authors: Panda Harekrushna , Jaiswal Aruna S. , Gairola C. Gary , Narayan Satya 
Published: July 2012

Abstract
Active and passive smoking are major risk factors for cancer and have been implicated in the etiology of breast cancer. The mechanisms through which smoking promotes breast cancer are poorly understood. Our previous studies have shown that cigarette smoke condensate (CSC), a surrogate for cigarette smoke, induces transformation of normal human breast epithelial (MCF10A) cells in culture. We have described the involvement of a multifunctional protein, adenomatous polyposis coli (APC), in the CSC-induced transformation of MCF10A cells through the interaction with DNA polymerase β and 5’-flap endonuclease 1 (Fen1), and thus, the blockade of the BER pathway. In the present study, we have examined the underlying mechanisms involved in CSC and Benzo[α]pyrene (B[α]P)-induced transformation of MCF10A cells in which APC was overexpressed or knocked down. Our results suggest a positive correlation between the increased levels of APC expression with the decreased BER activity and concomitant accumulation of apurinic/apyrimidinic (AP)-site lesions. If not repaired on time, the cytotoxic and mutagenic AP-site lesions ultimately lead to enhanced transformation of MCF10A cells. These studies suggest a possible mechanism by which active and/or passive cigarette smoking might be linked with breast carcinogenesis. This work was supported by Flight attendant Medical Research Institute, Miami, FL to SN.
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 4201. doi:10.1158/1538-7445.AM2011-4201
Abstract 4203: EF24, a novel curcumin analogue inhibits oncogenic activation induced by radiation abscopal effect in distant mice lungs
Authors: Veeraraghavan Jamunarani , Natarajan Mohan , Awasthi Vibhudutta , Herman Terence S. , Aravindan Natarajan 
Published: July 2012

Abstract
Ascertaining the ionizing radiation (IR)-induced carcinogenesis through an abscopal effect would raise a paradigm shift in our understanding of the radiobiological effects and radiation carcinogenesis. EF24, a synthetic analog of curcumin with improved physicochemical properties has been shown to possess potent anticancer activity, both in vitro as well as in vivo. In this study, we investigated the oncogenic activation after IR in an organ (lung) distant from the exposure field. C57/BL6 mice either mock irradiated, exposed to single dose IR (SDR: 2 or 10Gy) or fractionated IR (FIR, 2 Gy/day for 5 days) with or without EF24 (i.p. 200μg/Kg, 3h prior to IR) treatment were sacrificed 1h through 2 weeks post-irradiation. All IR exposures were limited to the lower abdomen area (1cm diameter), while the rest of the animal was protected by a specially designed cerrobend shield. DNA binding activity of AP-1, E2F1, cFOS and FRA1 were examined using EMSA analysis. Transcriptional activation of 88 oncogenes was assessed using QPCR profiling. Phosphorylation of CREB and JNK were examined using immunoblotting. Cellular localization of JunB, JunC and JunD were analyzed by immunohisto staining. IR significantly induced AP-1, E2F1, cFOS and FRA1 DNA binding activity in lungs distant from the exposure fields. EF24 completely and persistently (up to 2wks) suppressed IR-induced distant effect on AP-1, E2F1, cFOS and FRA1 DNA binding activity. Second, EF24 completely suppressed all 52, 31 and 64 oncogenes that were significantly upregulated after 2 Gy, 10Gy and 2Gyx5D exposures. We observed a similar inhibitory effect of oncogene transcriptome even after 2wk with EF24 treatment. Third, a profound increase in JunB, JunC and JunD levels observed in distant lung tissue after IR were significantly inhibited by EF24. Fourth, we observed a profound inhibition of IR-induced CREB phosphorylation with EF24 treatment in distant lungs. Taken together, these data clearly demonstrated an induced abscopal carcinogenic response in mice lungs after clinically relevant doses of IR exposure. The findings further imply that systemic administration of EF24 could potentially inhibit DNA binding activity, transactivation and translation of oncogenes and thereby mitigate IR-induced oncogenic activation at distant site.
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 4203. doi:10.1158/1538-7445.AM2011-4203
Abstract 4219: Lysosomal membrane permeabilization, a novel anticancer mechanism induced by pterostilbene
Authors: Mena Salvador , Rodriguez Maria , Asensi Miguel , Estrela Jose M. , Ortega Angel 
Published: July 2012

Abstract
Pterostilbene (Pter) (3,5-dimethoxy-4′-hydroxystilbene), a natural dimethylated analog of resveratrol, is a phytoalexin abundant in plants and fruits with a number of potential benefits for human health. Darakchasava, an Indian herbal preparation of Vitis Vinifera, contains Pter and is prescribed as a cardiotonic in ayurvedic and traditional medicine. Furthermore, some observations indicate that Pter can be beneficial in the prevention and treatment of different diseases such as diabetes, dyslipidemia, or cancer.
Pter shows higher bioavailability than resveratrol. The substitution of two OH groups (positions 3 and 5) by methyl groups increases the stabilityof the molecule and its resistance to hepatic glucuronidation and sulfonation. Nevertheless, despite these pharmacokinetic advantages, the anticancer potential of Pter is still undefined.
Lysosomal membrane permeabilization (LMP) has been postulated as a mechanism leading to cell death. In an initial step LMP causes cytosol acidification and release of cathepsins and other hydrolases from the lysosomal lumen. Ectopic presence of proteases causes the hydrolysis of vital proteins and the activation of other cell death-related proteases such as caspases. Thus linking LMP and cell death type I. In addition, LMP may also induce caspase-independent cell death mechanisms. In fact morphology of cells affected by LMP may be confused with a subapoptotic or necrotis appearance. The aim of our present study was to investigate the mechanisms of cell death activated by Pter in different tumor cells. For this purpose we used a range of Pter concentration between 10uM (below the IC50) and 100uM (an unachievable in vivo concentration). Acridin orange staining was determined by flow cytometry and fluorescence microscopy. Total and cytosolic cathepsin extractions were performed with different digitonin concentration and activity was measured by spectrofluorimetry. Cytosolic pH was evaluated by staining cultured cells with the fluorochrome SNARF. Apoptosis induction was checked through caspase 3 and 7 measurements.
The effects observed in the presence of Pter, under in vitro conditions, were concentration and time dependent. An increase in LMP induced an acidification of cytosolic pH, an increase in cathepsin activity and, only at long time exposure, apoptosis stimulation. Our results demonstrate that tumor cell death induction elicited by Pter is preferentially mediated through LMP.
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 4219. doi:10.1158/1538-7445.AM2011-4219
Abstract 4221: Inhibition of hedgehog signaling by extracts of sutherlandia
Authors: Lu Yuan , Lin Hui , Drenkhahn Sara K. , Starkey Nicholas J.E. , Jackson Glenn A. , Folk William , Fritsche Kevin L. , Lubahn Dennis B. 
Published: July 2012

Abstract
Many botanical compounds that have been proposed to prevent cancer may potentially work via inhibition of the hedgehog-signaling pathway. Here we investigated the potential of Sutherlandia frutescens (also called “cancer bush” in South Africa) to prevent and/or treat prostate cancer. We hypothesize that the anti-cancer effects of Sutherlandia are due to its inhibition of hedgehog-signaling pathway activity. To determine hedgehog pathway inhibitory activity, we treated Shh light II cells with multiple doses of a methanol extraction of Sutherlandia and measured Gli1 reporter activities.
Results: We found that a methanol extract of Sutherlandia was able to inhibit hedgehog pathway activity in a dose-dependent manner as monitored by Gli reporter assay (IC50=1:4000). Moreover, the Sutherlandia extract can inhibit the growth of human prostate cancer cells PC3 and LNCaP with IC50 of 1:400 and 1:1500 fold dilutions, respectively. At these same extract dilutions normal prostate cancer cell growth was not inhibited. Our data indicate that Sutherlandia contains potent anti-cancer botanicals that have hedgehog inhibitory activity.
Conclusion: Our results suggest that this plant offers a potentially cheap and effective alternative for hedgehog-driven cancer therapies. Additionally, Sutherlandia may yield novel targets that potentially could lead to a second generation hedgehog inhibitor, as resistance has been found to the first generation drugs currently in clinical trials.
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 4221. doi:10.1158/1538-7445.AM2011-4221
Abstract 4225: Thymoquinone induces cell death in glioblasotma cell through production of reactive oxygen species and induction of DNA damage
Authors: Arafa El-Shaimaa , Racoma Ira , Wani Gulzar , Wani Altaf 
Published: July 2012

Abstract
Glioblastoma is the most aggressive and common type of brain tumors in humans. Surgical resection followed by radiation and chemotherapy is the current standard treatment; however, due to up-regulation of several survival pathways, tumor recurrence is quite common with a median survival of 12 to 15 months. Therefore, there is an urge for more effective therapeutic strategies for the treatment of glioblastoma. Over years the use of natural compounds as anticancer agents acquired great importance. Thymoquinone (TQ) is the bioactive component of the volatile oil extracted from the black seed, Nigella sativa. TQ has shown anti-oxidant, anti-inflammatory, and anti-neoplastic actions in in-vitro and in-vivo models with a selective cytotoxicity for human cancer cells compared to several normal cells. Here, we report that TQ greatly inhibited cell proliferation of radioresistant glioma cells (U87 and T98) in a concentration-dependent manner. Moreover, TQ mediated reactive oxygen species-induced DNA breaks in glioma cells, as detected by the appearance of post-DNA damage sensitive marker γH2AX. Our results also showed that TQ up-regulated p53 in U87 cells while down-regulated phospho-Akt in T98 cells in a dose-dependent manner. Current investigations are ongoing to use TQ in combination with ionizing radiation as a promising modality to overcome resistance, thereby reducing ionizing radiation doses used for glioma treatment. This work was supported by NIH grants CA93413, ES2388 and ES12991 to A. A. W.
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 4225. doi:10.1158/1538-7445.AM2011-4225
Abstract 4250: A novel thrombospondin-1 mimetic peptide, ABT-898, decreases angiogenesis in a mouse model of glioblastoma multiforme
Authors: Yamada Ryosuke , Nakano Ichiro 
Published: July 2012

Abstract
Prognostic outlook for patients with glioblastoma multiforme (GBM) still appears bleak in spite of medical advances in treatment of other malignant tumors in the past decades. With optimal therapy, of surgical resection, radiation therapy, and chemotherapy, a median survival merely approximates to 12 months. However, a recent dogma that the microvascular niche of such tumors plays a critical role in their maintenance has led to development of “anti-angiogenenic” therapies that target it. To evaluate the apoptotic effect of ABT-898, a TSP-mimetic, anti-angiogenic peptide on endothelial cells, we used human umbilical vein endothelial cells (HUVEC) to model human brain microvasculature. Furthermore, to then assess its clinical applicability, an orthotopic xenograft mouse model was established using human-derived GBM cells lines, and its therapeutic effect evaluated in vivo. We found that ABT-898 induced apoptosis on HUVEC as evidenced by increased fraction of annexin-V positive cells on flow cytometry. Systemic treatment of BTSC-derived immunodeficient mouse tumors with ABT-898, either alone or in combination with temozolomide, significantly reduced tumor size at day 14 post-injection of GBM cells, compared with that of a vehicle, which was used as a control. In addition, treatment with ABT-898 allowed increase in median survival in the xenograft models compared to the control mice. These observations suggest that ABT-898 is a plausible candidate for use in future treatment of GBM.
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 4250. doi:10.1158/1538-7445.AM2011-4250
Abstract 4260: Sunitinib treatment induces Notch expression and activation in renal carcinoma cell lines
Authors: Ziouti Fani , Touplikioti Panagiota , Kontovini Maria-Ekaterini , Vadeka Christina , Kontovinis Loukas , Papazisis Konstantinos 
Published: July 2012

Abstract
Introduction. Notch signaling is an evolutionary conserved pathway that plays a central role in stem cell biology, tumor formation, angiogenesis and cell fate decisions. Currently there is not any clear view as to whether Notch plays an oncogenic role in renal cell cancer (RCC). Notch-1 is activated after cytotoxic stimuli and may induce mTor pathway activation, leading to increased cell survival.
We have investigated the role of Notch expression and activation in RCC cell lines in response to sunitinib treatment and the role of Notch in the activation of the mTor pathway. We elaborated three cell lines with a different VHL and PTEN mutation status: Caki-1 cells (VHL-wt, PTEN-wt), Caki-2 (VHL-mut, PTEN-wt) and 786-O (VHL-mut, PTEN-mut).
Results: When Caki-1 and Caki-2 cells were exposed to sunitinib there was a marked upregulation in the expression of the Notch-1 mRNA and the target transcription factors RUNX1, RBPJ and HES1. The PI3K – mTor – S6K pathway was aslo upregulated. This upregulation was reversed when cells were pre-treated with a gamma-secretase inhibitor. However, both gamma secretase inhibitors and everolimus (an m-Tor inhibitor) had an antagonistic effect when combined with sunitinib (Combination Index &gt;&gt; 1.0). On the other hand, PTEN-mutant 786-O cells have a dysregulated mTor pathway and are more sensitive to inhinition of the m-Tor with everolimus. Sunitinib exposure did not result in further increase of the PI3K-mTor-S6K activation. Interestingly, combination of sunitinib with everolimus was synergistic in 786-O.
Conclusions: VHL-wt and VHL-mutant RCC cells treated with sunitinib activate the Notch pathway. There are reports that Notch plays a tumor suppressor role in RCC and our results are on concert with that. Furthermore, Notch seems to regulate m-Tor pathway activation in cells with a wild-type PTEN.
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 4260. doi:10.1158/1538-7445.AM2011-4260
Abstract 4270: Targeting cancer cells resistant to hypoxia and nutrient starvation double-deprivation stress as a novel cancer therapy
Authors: Osawa Tsuyoshi , Muramatsu Masashi , Tsuchida Rika , Wang Feng , Yuasa Yasuhito , Shibuya Masabumi 
Published: July 2012

Abstract
Anti-angiogenesis is an effective cancer treatment, however, tumor progression and refractoriness to anti-angiogenesis are observed in both clinical and preclinical cancer models. Stress under hypoxia and nutrition deprivation might play an important role in the tumor aggressiveness and refractoriness. Here we show that a long term hypoxia and nutrient starvation double-deprivation stress (DDS) stimulates migration, invasion and anchorage independent growth of tumor cells in vitro and an increased tumor progression and angiogenesis in vivo associated with an increase in blood vessels and infiltration of CD11b+ cells. We also observed up-regulation of DDS-responsive genes including VEGF-A, FGF18, and JHDM2A. We found that histone demethylase JHDM2A is commonly up-regulated under DDS in human and mouse cancer cell lines in vitro and in vivo at the phase of pre-angiogenic switch and refractory phase of anti-angiogenic treatments. Specific inhibition of JHDM2A by siRNAs significantly suppressed tumor growth in vivo. Importantly, suppression of JHDM2A demonstrated synergetic effects in treatment with anti-VEGF neutralizing antibody (bevacizumab) or small molecular inhibitor for VEGF receptors (sunitinib), and improved an efficacy of anti-angiogenesis. Collectively, our results indicate that minor population of cancer cells resistant to both hypoxia and low nutrition acquires tumor aggressiveness through specific mechanisms upon the DDS responses. Our observations suggest that the targeting of cancer cells resistant to hypoxia and nutrient starvation by inhibition of DDS-responsible genes such as JHDM2A can be utilized for a novel treatment to overcome the refractoriness to anti-angiogenic 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 4270. doi:10.1158/1538-7445.AM2011-4270