bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3297: Survival predictors of Burkitt's lymphoma in children, adults and elderly in the United States during 2000-2013
Authors: Mukhtar Fahad , Boffetta Paolo , Risch Harvey A. , Park Jong Y. , Bubu Omonigho M. , Womack Lindsay , Tran Thuan V. , Zgibor Janice C. , Luu Hung N. 
Published: July 2017

Abstract
Background. Burkitt’s Lymphoma (BL) has three peaks of occurrence, in children, adults and elderly, at 10, 40 and 70 years respectively. To the best of our knowledge, no study has been conducted to assess predictors of survival in the three age groups. We hypothesized that the predictors of survival may differ by age group. We, therefore, sought to determine the predictors of survival for BL in these three groups: children (&lt;15 years of age), adults (40-70 years of age) and elderly (&gt;70 years of age).
Methods. Using the Surveillance, Epidemiology, and End Results (SEER) database covering the years 2000-2013, we identified 797 children, 1,994 adults and 757 elderly patients newly diagnosed with BL. We used Cox proportional hazards regression models to determine prognostic factors for survival for each age group.
Results. Five-year relative survival in BL for children, adults and elderly were 90.4%, 47.8%, and 28.9%, respectively. Having at least stage II disease and multiple primaries were associated with higher mortality in the elderly group. In adults, multiple primaries, stage III or IV disease, African American race and bone marrow primary were associated with increased mortality whereas stage IV disease and multiple primaries were associated with worse outcome in children.
Conclusion. These findings demonstrate commonalities and differences in predictors of survival that may have implications for management of BL patients.
Financial Support: This work was supported by the US National Institutes of Health/National Cancer Institute 1P20CA210300-01 (PI: Shu XO, Tran T/Sub-contract-PI: Luu HN) and the University of South Florida start-up grant (PI: Luu HN).
Note: This abstract was not presented at the meeting.
Citation Format: Fahad Mukhtar, Paolo Boffetta, Harvey A. Risch, Jong Y. Park, Omonigho M. Bubu, Lindsay Womack, Thuan V. Tran, Janice C. Zgibor, Hung N. Luu. Survival predictors of Burkitt's lymphoma in children, adults and elderly in the United States during 2000-2013 [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 3297. doi:10.1158/1538-7445.AM2017-3297
Abstract 3299: Radiation induced p53-dependent cytoprotective autophagy fails to reduce radiation sensitivity in H460 non-small cell lung cancer cells
Authors: Xu Jingwen , Saleh Tareq , Tyutynuk-Massey Liliya , Wu Yingliang , Gewirtz David A. 
Published: July 2017

Abstract
Our previous studies showed that radiation-induced autophagy could be either cytoprotective or nonprotective in A549 non-small cell lung cancer cells, HN30 and HN6 head and neck cancer cells and 4T1 breast tumor cells, and that this functional difference was related to the status of p53 in the cells (i.e. cytoprotective autophagy in p53 wild type (wt) cells and nonprotective autophagy in cells with mutant or null p53) [1]. Despite the fact that inhibition of autophagy has been proposed as a strategy to overcome resistance to radiation and chemotherapy, there is little direct information in support of the premise that the induction of autophagy confers resistance. As an example, studies in HCT-116 cells that are either wt or null in p53 demonstrate essentially identical radiation sensitivity [2], although the nature of radiation induced autophagy was not determined in these cell lines. To address this question, p53 wt and p53 null H460 cell lines were utilized to evaluate whether cytoprotective autophagy actually suppressed radiation sensitivity. Acridine orange staining, flow cytometric analysis and western blotting (LC3B, p62, Atg5) showed that following exposure to 6 Gy of radiation wtp53 and p53-null H460 cells exhibited a significant induction of autophagy. p53 wt H460 cells showed sensitization to radiation upon pharmacological autophagy inhibition and Atg5 knock down. However, pharmacological inhibition of autophagy and knock down of Atg5 genes failed to influence sensitivity to radiation in p53-null H460 cells. Furthermore, clonogenic survival assays showed that while exposure to radiation induced a dose-dependent (2, 4, 6, 8 Gy) decrease in clonogenicity in both p53wt and p53-null H460 cells, radiation sensitivity was not decreased in the p53 wt cells. Taken together, these findings indicate that cytoprotective autophagy may not actually alter the nature of radiation (and possibly chemotherapeutic) sensitivity in tumor cells. [1] Chakradeo, S, et al. Mol Pharm (2015): [2] Lindgren, T, et al. Int J Rad Biol (2015). Acknowledgments We would like to thank Dr. Santiago Lima (Virginia Commonwealth University) for the H460 p53-null cells.
Citation Format: Jingwen Xu, Tareq Saleh, Liliya Tyutynuk-Massey, Yingliang Wu, David A. Gewirtz. Radiation induced p53-dependent cytoprotective autophagy fails to reduce radiation sensitivity in H460 non-small cell lung cancer cells [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 3299. doi:10.1158/1538-7445.AM2017-3299
Abstract 330: SGK1 activation is essential for PI3K-dependent tumor development
Authors: Orlacchio Arturo , Cristofano Antonio Di 
Published: July 2017

Abstract
The PI3K signaling cascade is frequently activated in human cancer, with AKT being commonly considered its major transforming conduit.
Conditional deletion of Pten in the mouse thyroid epithelium induces constitutive activation of the PI3K pathway, which causes thyroid hyperplasia at birth that progresses to invasive and metastatic follicular carcinoma. Concomitant loss of p53 or activation of KRAS dramatically accelerates the development of aggressive and lethal tumors.
The PDK1 kinase plays a key role in the PI3K signaling cascade, directly activating, in a PI3K-dependent manner, not only AKT but also a set of additional AGC kinases, including, S6K, PKC, and SGK.
Using in vivo, ex vivo, and in vitro genetic and pharmacological approaches, we now show that AKT activation is not sufficient to transform thyroid epithelial cells. Concomitant activation of additional PDK1-dependent pathways is absolutely required to develop neoplastic lesions in vivo, and to induce cell proliferation ex vivo, in mouse models based on Pten loss, alone and in combination with additional genetic alterations.
In particular, we show that one member of the SGK family, SGK1, is an essential mediator of the transformation process downstream of PI3K.
Genetic and pharmacological SGK1 inhibition strongly reduces cell proliferation in Pten-/-and PIK3CA-mutant cell lines.
Moreover we show that concomitant SGK inhibition significantly increases the efficacy of inhibitors targeting AKT or PI3K.
Taken together, our data identify an essential and druggable signaling cascade that critically cooperates with AKT activation to transform thyroid epithelial cells.
Citation Format: Arturo Orlacchio, Antonio Di Cristofano. SGK1 activation is essential for PI3K-dependent tumor development [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 330. doi:10.1158/1538-7445.AM2017-330
Abstract 3304: Inhibition of autophagy enhances mitochondria-mediated apoptosis in malignant mesothelioma cells by cisplatin and sulforaphane
Authors: Lee Yoon Jin , Lee David M. , Nam Hae , Lee Sang 
Published: July 2017

Abstract
Drug resistance to current chemotherapy regimens has been considered a cell survival adaptive response in malignant mesothelioma cells. Therefore, new strategies to enhance the apoptotic signal and overcome resistance to chemotherapeutics are necessary to improve treatment outcomes for this deadly disease. Here, the effect of sulforaphane, an isothiocyanate compound derived from glucoraphanin present in cruciferous vegetables, on enhancing anticancer role of cisplatin was investigated in malignant mesothelioma cells. At concentrations showing little toxicity in normal human mesothelial MeT-5A cells, the combined treatment with both compounds exhibited synergistic growth-inhibiting and apoptosis-promoting effects, as demonstrated in a series of pro-apoptotic events including reactive oxygen species (ROS) accumulation, loss of mitochondrial membrane potential, up-regulation of p53, increased Bax/Bcl-2 ratio, activation of caspase-3, and the occurrence of a sub-G0/G1 peak with an increase in the cells with pyknotic and fragmented nuclei, Annexin V-PE(+), and G2/M phase transition delay in the cell cycle. The levels of phosphorylation of both Akt and mTOR were decreased by the combined treatment, which was accompanied by a significant increase in the level of autophagosomal marker protein LC3-II and the accumulation of acidic vesicular organelles. Furthermore, scavenging of ROS by antioxidant N-acetylcysteine inhibited both the apoptosis and autophagy, while the inhibition of autophagy by bafilomycin A1 potentiated apoptotic cell death following the combination treatment of sulforaphane and cisplatin, indicating the cytoprotective role of autophagy counteracts apoptosis of malignant mesothelioma cells. Considering the pro-oxidant-based combinational approach, our data provide a rationale for targeting cytoprotective autophagy as a potential therapeutic strategy for malignant mesothelioma.
Citation Format: Yoon Jin Lee, David M. Lee, Hae Nam, Sang Lee. Inhibition of autophagy enhances mitochondria-mediated apoptosis in malignant mesothelioma cells by cisplatin and sulforaphane [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 3304. doi:10.1158/1538-7445.AM2017-3304
Abstract 3315: Cancer cells upregulate autophagy as a survival mechanism in response to tumor treating fields (TTFields)
Authors: Porat Yaara , Shteingauz Anna , Giladi Moshe , Schneiderman Rosa S. , Voloshin Tali , Munster Mijal , Blat Roni , Kirson Eilon D. , Weinberg Uri , Palti Yoram 
Published: July 2017

Abstract
Tumor treating fields (TTFields) are an established anti-neoplastic treatment modality in patients with glioblastoma. TTFields are delivered via noninvasive application of low-intensity, intermediate-frequency, alternating electric fields to the region of the tumor. Previous studies have shown that TTFields treatment lead to increased cellular granularity, which is often associated with autophagy. Autophagy has been shown to regulate cell survival and proliferation under stress conditions and to influence cellular response to cytotoxic drugs. This study evaluated the role of autophagy in cancer cells treated with TTFields.
Immunoblot analysis showed significant elevations in levels of lipidated Microtubule Associated Protein Light Chain (LC3-II) in TTFields-treated glioma and lung cancer cells. Increased autophagy following TTFields application in these cell lines was also detected using fluorescence microscopy, where punctate distribution of LC3-II was observed. TEM micrographs demonstrated the presence of autophagy typical, autophagosome-like structures in TTFields-treated U-87 MG cells. Combination of TTFields with autophagy inhibitors, chloroquine and melfoquine, resulted in a significant dose-dependent reduction in cell growth compared with TTFields treatment alone. Inhibition of autophagy with chloroquine triggered apoptosis as indicated by elevated levels of AnnexinV/7AAD double staining. Increased levels of autophagic flux in TTFields-treated cells were not associated with reduced mTOR activity, which was monitored by p70S6K phosphorylation immunoblot analysis.
TTFields are known to exert anti-mitotic effects by disrupting highly dipolar structures that play critical roles in mitosis. Our results demonstrate that TTFields additionally induce cellular autophagy by an mTOR-independent mechanism. TTFields- treated cell lines appear to utilize autophagy as a survival mechanism. Thus, inhibition of autophagy sensitizes tumor cells to TTFields treatment, resulting in elevated apoptotic cell death.
Future studies are warranted to examine the extent to which TTFields-elicited autophagy may affect treatment outcomes and to investigate the therapeutic implications of combining TTFields with autophagy inhibitors in vivo.
Citation Format: Yaara Porat, Anna Shteingauz, Moshe Giladi, Rosa S. Schneiderman, Tali Voloshin, Mijal Munster, Roni Blat, Eilon D. Kirson, Uri Weinberg, Yoram Palti. Cancer cells upregulate autophagy as a survival mechanism in response to tumor treating fields (TTFields) [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 3315. doi:10.1158/1538-7445.AM2017-3315
Abstract 3316: Mieap, the mitochondria-eating protein, induces cell death by eating unhealthy mitochondria
Authors: Nakamura Yasuyuki , Tsuneki Masayuki , Yamamoto Makoto , Arakawa Hirofumi 
Published: July 2017

Abstract
Mieap, a p53-inducible protein, controls mitochondrial quality by repairing or eliminating unhealthy mitochondria. Mieap suppresses murine intestinal tumor via its mitochondrial quality control (1). Mieap-regulated mitochondrial quality control is frequently inactivated in human colorectal cancer (2). To explore the role of the Mieap-regulated mitochondria quality control function in human colorectal cancer tissues, we examined the Mieap expression in primary colorectal cancer tissues by performing immunohistochemical analysis with anti-human Mieap antibody. Mieap expression was very low in normal colorectal epithelial cells, whereas the strong expression of the Mieap protein was detected in the hypoxic cell death regions of colorectal adenoma and adenocarcinoma, suggesting the role of Mieap in hypoxic cell death. Overexpression of Mieap in vitro induced large vacuole structures (MIV: Mieap-induced vacuole) in HCT116 colorectal cancer cells (Mieap-deficient colorectal cancer cells). MIV engulfed and degraded unhealthy mitochondria, leading to caspase-dependent cancer cell death. Re-expression of Mieap in HCT116 cells resulted in striking suppression of tumor growth in vivo. These results suggest that Mieap plays a critical role in hypoxic tumor cell death via lysosomal degradation of unhealthy mitochondria.
(1) Tsuneki et al. Mieap suppresses murine intestinal tumor via its mitochondrial quality control. Sci. Rep. 5: 12472 (2015). (2) Kamino et al. Mieap-regulated mitochondrial quality control is frequently inactivated in human colorectal cancer. Oncogenesis 5: e181 (2016).
Citation Format: Yasuyuki Nakamura, Masayuki Tsuneki, Makoto Yamamoto, Hirofumi Arakawa. Mieap, the mitochondria-eating protein, induces cell death by eating unhealthy mitochondria [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 3316. doi:10.1158/1538-7445.AM2017-3316
Abstract 332: Loss of primary cilia promotes LPA-driven proliferation in glioblastoma
Authors: Loskutov Yuriy 
Published: July 2017

Abstract
Glioblastoma is one of the most common brain cancers with a median survival of 13 months. Therapeutic approaches for this type of cancer are very limited, creating an urgent need to develop new strategies for the treatment. Recently several groups reported that glioblastoma have a drastic decrease in primary cilia, suggesting that loss of cilia might be important for glioblastoma biology. The primary cilium is a ubiquitous microtubule based organelle presented on most of human cells. It plays significant role in embryonic development and tissue homeostasis, serving as a hub for multiple signaling cascades including RTK, Sonic Hedgehog, Wnt and Hippo. Here we report that loss of primary cilia in immortalized astrocytes stimulate cell proliferation and drastically change ERK1/2 activation in response to serum. These changes depend on lysophosphotidic acid (LPA), a water-soluble lipid metabolite, implicated in chemotactic and proliferative signaling. The receptor to LPA type 1 tends to accumulate in the primary cilia, indicating its potential role in inhibition/restriction of LPA-dependent mitogenic signaling via dynamic changes in primary cilium. Loss of primary cilia can lead to LPA receptors 1 redistribution to the plasma membrane and switch cellular response for the LPA, allowing it to act as mitogen. Inhibition of LPA receptors with a small molecule inhibitor, Ki16425, is significantly decreasing the growth of glioblastoma PDXs. Overall, our findings clearly indicate that loss of primary cilia is sufficient to severely change mitogen-driven signal transduction and point towards the new therapeutic target for glioblastoma.
Citation Format: Yuriy Loskutov. Loss of primary cilia promotes LPA-driven proliferation in glioblastoma [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 332. doi:10.1158/1538-7445.AM2017-332
Abstract 3326: Identification of a novel androgen receptor co-regulator in prostate cancer
Authors: Shatnawi Aymen A. , Malkaram Sridhar Acharya , Tsouko Efrosini , Frigo Daniel E. 
Published: July 2017

Abstract
Prostate cancer (PC) is one of the most frequently diagnosed tumors in the United States, affecting one in six men during their lifetime and second only to lung cancer as a cause of cancer death in men. One of the major drivers of prostate cancer is the androgen receptor (AR). It has been shown that deregulation of AR co-regulators play a crucial role in PC through modulating the transcriptional activity of the receptor. While the importance of the AR complex is well established, there is still an incomplete understanding of what all the associated co-regulators are and how they modulate AR signaling. Here, we have identified that the inhibitor of growth family member 4 (ING4), a protein that has been implicated in the pathogenesis of several solid tumors such as gastric and breast cancer, is a novel AR co-regulator. Overexpression of ING4 increased AR activity in an androgen-dependent manner as assessed using luciferase reporter gene assays. Supporting a role as a potential AR co-activator, RNA Next-Generation Sequencing of prostate cancer cells with ING4 knocked down revealed a repression of endogenous AR/R1881-activated genes and expression of AR/R1881 suppressed genes. Further, mining of existing clinical datasets revealed that the ING4 gene expression is de-regulated in PCs compared relative to normal tissue and tracks with poor patient prognosis. Collectively, the current findings strongly support the involvement of ING4 in AR signaling and PC progression and development.
Citation Format: Aymen A. Shatnawi, Sridhar Acharya Malkaram, Efrosini Tsouko, Daniel E. Frigo. Identification of a novel androgen receptor co-regulator 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 3326. doi:10.1158/1538-7445.AM2017-3326
Abstract 3327: Sortilin controls the EGFR nuclear translocation
Authors: Akhrass Hussein Al , Naves Thomas , Jauberteau Marie-Odile , Vincent François , Lalloué Fabrice 
Published: July 2017

Abstract
The epidermal growth factor receptor (EGFR) deregulations play a central role in cancer progression. EGFR generates extra- and intracellular signals through various pathways, including its release in the tumor microenvironment through extracellular vesicles, as well as the nuclear EGFR signaling. That ultimately results in oncogenic signals promoting the tumor aggressiveness. Our previous report showed that sortilin, a member of the VPS10P sorting proteins, is associated with EGFR to allow its secretion through exosomes in non-small cell lung cancer (NSCLC) cells. Furthermore, sortilin is mainly present in the Golgi which is an essential compartment involved in the EGFR bypass towards the nucleus. Therefore, our aim is to investigate the potential role of sortilin in EGFR nuclear translocation.
EGFR and sortilin translocation into the nucleus has been validated by proximity ligation assay and confocal microscopy analysis. Moreover, to study the sortilin function in the EGFR nuclear translocation, we resorted to the NSCLC cell line A549 in which the sortilin expression was silenced using a shRNA delivery. Subcellular fractionations and nuclear protein extractions were performed to study the impact of the sortilin loss on the EGF-induced EGFR nuclear translocation.
EGF stimulation highly increases the nuclear translocation of the EGFR and sortilin complex. Interestingly, sortilin depletion significantly decreases the EGF-induced EGFR nuclear translocation in the A549 cells. Strikingly, sortilin-depleted cells exhibit an overexpression of EGFR target genes (MYC, ABCG2, AURKA and CCND1) compared to the control cells. These results suggest that the overexpression of the EGFR target genes is independent of EGFR nuclear translocation in sortilin-depleted cells. Thus, we analyze the activation of the known transcription factors directly involved in the control of EGFR up-regulated genes to determine whether they are activated in sortilin-depleted cells. Moreover, to better understand the sortilin-dependent EGFR nuclear translocation, we compare functional properties (proliferation,
migration and angiogenesis assays) of sortilin-depleted and control cells.
Altogether, our findings suggest a key role of sortilin in the regulation of the EGFR nuclear transport, towards the control of target genes that are widely involved in cancer progression.
Citation Format: Hussein Al Akhrass, Thomas Naves, Marie-Odile Jauberteau, François Vincent, Fabrice Lalloué. Sortilin controls the EGFR nuclear translocation [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 3327. doi:10.1158/1538-7445.AM2017-3327