bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5233: Modeling ionizing radiation exposure in vitro and in vivo using the Virtual Tumour.
Authors: Fernandez Eric , Orrell David , Brightman Frances , Fell David , Chassagnole Christophe 
Published: August 2014

Abstract
Ionizing radiation exposure induces DNA double strand breaks in mammalian cells. In response, cells activate repair mechanisms which involve cell cycle arrest at discrete transition points of the cell cycle. The results in an accumulation of cells in S and G2 phase in an irradiated cell population over a period of time following exposure.
Using the Virtual Tumour, a cell population simulator of cancer cells and tissue, we have built a model of irradiation of tumour cell culture in vitro as well as tumour tissue in vivo for various cancer cell types. We show how cell cycle timings and radiosensitivity can accurately reproduce both in vivo and in vitro response to irradiation-induced DNA damage. We also study how the radiosensitization effect of gemcitabine is time-dependent. This demonstrates how the Virtual Tumour can help maximise therapeutic efficacy of combinations involving irradiation.
Citation Format: Eric Fernandez, David Orrell, Frances Brightman, David Fell, Christophe Chassagnole. Modeling ionizing radiation exposure in vitro and in vivo using the Virtual Tumour. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5233. doi:10.1158/1538-7445.AM2013-5233
Abstract 5240: Differential anticancer drug response by high-dimensional protein monitoring.
Authors: Nishizuka Satoshi S. , Ishida Kazushige , Wakabayashi Go 
Published: August 2014

Abstract
Cellular signal transduction responses to drugs are not always identical; rather, they depend on concentration, administration method, and time after administration. To monitor drug-induced signaling, we produced “reverse-phase” protein arrays (RPPAs) using cell lysates from three anticancer drugs (5FU, CIS, CPT), two administration methods (sustained, Sus; temporal, Tem), and three concentrations (High, Medium, Low) of drug administration over a 24-hour period. The combination of drug types, concentrations, and administration methods collectively yielded 18 unique drug administration conditions. Each RPPA was individually probed with 37 primary antibodies from our antibody panel; these antibodies recognize the proteins involved in genotoxic stress response. The quantitative readout was then analyzed to see if there was: (i) a general trend in protein dynamics in response to each drug condition; and (ii) significance in those proteins that exhibited similar dynamics. We first classified 666 time-course protein dynamics. About 38% of the protein dynamics showed an increasing trend, whereas about 32% showed a decreasing trend. Proteins exhibited earlier peaks when stimulated by Low or Medium concentrations for all drugs, while proteins exhibited later peaks when stimulated by High concentrations. Clustering analysis of protein dynamics induced by drugs revealed that each dynamic class included proteins of diverse functions. Hence, it is unlikely for cells to respond to particular drugs in a defined pattern. Subsequently, to clarify whether any functional associations are prioritized in drug responses, we evaluated the similarities between the protein dynamics by distance correlation (DC, which is known to have a higher value the tighter the association), to see if any pair of protein dynamics demonstrated a geometric similarity associated with its known interaction. It appeared that apoptosis-related proteins tended to show high DC to other proteins when anticancer drugs were administrated at high enough concentrations to induce apoptosis. We also found that structural cell proteins, such as keratins, showed high DC to apoptosis-related proteins, and confirmed that when these two functional protein groups interact, what results is degradation in the progression of drug-induced apoptosis.These observations indicate that high-dimensional drug response protein dynamic monitoring by RPPAs may offer a unique opportunity to find drug-specific general dynamic trends and potentially novel protein interactions unique to drug administrative conditions such as dose.
Citation Format: Satoshi S. Nishizuka, Kazushige Ishida, Go Wakabayashi. Differential anticancer drug response by high-dimensional protein monitoring. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5240. doi:10.1158/1538-7445.AM2013-5240
Abstract 5241: Identifying signaling pathways associated with medulloblastoma subtypes from "omic" data.
Authors: Archer Tenley C. , Weeraratne Shyamal Dilhan , Francois Jessica Pierre , Pomeroy Scott L. 
Published: August 2014

Abstract
Medulloblastoma, the most common malignant pediatric brain tumor, comprises four subtypes classified by their distinct molecular signatures. Wnt and SHH subtypes up-regulate those respective signaling pathways, while Group 3 and Group 4 tumors are less understood and have the worst prognosis. Treatment is currently limited to surgical resection, radiation and broad-spectrum cytotoxic chemotherapy drugs that frequently devastate cognition in survivors. In order to develop patient-specific targeted therapies we need to understand the underlying molecular events that drive the tumor in each patient. Previously, our research group and others sequenced whole exomes from a total 92 primary tumors from patients in comparison to their matched normal blood. Over 1,700 mutated genes were identified. The overwhelming majority of mutations occurred only once in the entire cohort, and just 12 genes were recurrently mutated with statistical significance. Statistically significant mutated genes include genes involved in subtype-specific signaling events, such Wnt and SHH which have been shown to be causative in those subtypes, and others are involved in chromatin and epigenetic regulation. The diversity of mutations makes it difficult to resolve which mutations drive oncogenesis, especially in Groups 3 and 4. Most patients in these subtypes do not harbor a mutation in one of the 12 significantly mutated genes, leaving an open question as to why these patients developed cancer. The aim of this study is to employ systems biology to interweave singleton genes into networks to identify candidate drives in each patient and ultimately resolve the underlying common pathways that caused each cancer. We have identified singleton mutations in patients that substitute for the statically significant mutated genes. Modeling individual patient level data onto networks predicts novel driver events in each patient. These candidate driver events are then functionally validated in vitro. In addition to mutation, oncogenic events can occur via copy number changes, chromatin regulation, transcription regulation, mRNA processing, or protein degradation. We hypothesize that common pathways are targeted in multiple tumors of the same type, despite the obvious differences in the patterns of somatic mutations.
Citation Format: Tenley C. Archer, Shyamal Dilhan Weeraratne, Jessica Pierre Francois, Scott L. Pomeroy. Identifying signaling pathways associated with medulloblastoma subtypes from "omic" data. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5241. doi:10.1158/1538-7445.AM2013-5241
Abstract 5245: C-Kit isoforms predict melanoma drug sensitivity.
Authors: Phung Bengt , Steingrímsson Eiríkur , Rönnstrand Lars 
Published: August 2014

Abstract
The receptor tyrosine kinase c-Kit is an essential regulator of melanocyte and melanoma development. Alternative splicing of c-Kit produces one long variant, c-Kit(+), with a tetrapeptide GNNK located in the extracellular juxtamembrane domain, and one short variant, c-Kit(-), which lacks this sequence.
In this study we characterize for the first time the function of the GNNK tetrapeptide sequence in melanoma. Our results show that step by step elimination of the GNNK tetrapeptide gradually increases receptor tyrosine phosphorylation, ubiquitination and downstream MAP kinase ERK activation. Successively increasing insert length, progressively leads to reduced melanoma cell survival during dacarbazine or rapamycin drug treatment. Our results indicate that the ratio between c-Kit isoforms might be useful as a prognostic marker for melanoma drug response.
Citation Format: Bengt Phung, Eiríkur Steingrímsson, Lars Rönnstrand. C-Kit isoforms predict melanoma drug sensitivity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5245. doi:10.1158/1538-7445.AM2013-5245
Abstract 5247: Human melanoma cells resist oxidative stress due to overactive MEK/ERK and AKT/mTOR pathways and overproduction of melanin.
Authors: Calianese David , Cammarata Garrett , Brum Gabriella , Szulak Kevin , Best Charles , Higgins Katelyn , Wan Yinsheng 
Published: August 2014

Abstract
Melanoma is considered as one of the most aggressive and less treatable cancers. While various models of mechanisms have been proposed, the transformation from tranquil melanocytes to invasive melanoma cells remains an enigma. Alteration of cellular redox status has been suggested to be associated with cellular transformation. We compared primary human melanocytes and melanoma cells and their responses to oxidative stress. Both cells were treated with H2O2 at doses between 5 and 250μM. Microscopic data showed that melanoma cells are more resistant to H2O2 treatment. Western blot and confocal microscopic data showed that in melanoma cells, H2O2 does not induce CRT translocation which is considered as a mechanism through which melanocytes surrender to oxidative stress and induces immunogenic cell death. Furthermore, Western blot analysis showed that melanoma cells express EGFR, responsive to EGF treatment and have constitutive activation of AKT and mTOR, which are all related to better survival. In contrast, in the primary human melanocytes, EGFR expression is almost undetectable. And confocal microscopic data confirm this observation. Treatments of cells with MEK/ERK inhibitor U0126 and PI3K/AKT inhibitor LY294002 attenuates S6 phosphorylation. We also observed that in melanoma cells, but not in melanocytes, low dose (5 to 250μM) of H2O2 induces melanin production that is recognized to protect from further oxidative stress. Collectively, our data suggest that active MEK/ERK and AKT/mTOR pathways and up-regulation of melanin production contribute to the resistance of melanoma cells to oxidative stress and attribute to the aggressiveness of melanoma. Our data provides insights into the understanding of the molecular mechanisms of the transformation from melanocytes to melanoma and support the notion from the most recently published proteomic studies that EGFR remains one of the most important targets for better clinical management of melanoma.
Citation Format: David Calianese, Garrett Cammarata, Gabriella Brum, Kevin Szulak, Charles Best, Katelyn Higgins, Yinsheng Wan. Human melanoma cells resist oxidative stress due to overactive MEK/ERK and AKT/mTOR pathways and overproduction of melanin. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5247. doi:10.1158/1538-7445.AM2013-5247
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 526: Combined inhibition of mTOR and AKT activity induces potent apoptosis in epithelial ovarian cancer cells .
Authors: Hussain Azhar R. , Uddin Shahab , Ahmed Maqbool , Al-Kuraya Khawla S. 
Published: August 2014

Abstract
Mammalian target of rapamycin (mTOR) and Phosphatidylinositol 3-kinase (PI3K) are two key components of the PI3K/Akt/mTOR signaling pathway. These two signal transduction cascades regulate a number of physiological cell functions including differentiation, proliferation, apoptosis and autophagy. Dysregulation of these pathways have been found in many cancers including DLBCL, thyroid cancer, breast cancer, prostate cancer and lung cancer. mTOR has been shown to activate the PI3-kinase/AKT survival pathway and understanding the interplay among signaling molecules in the PI3K/Akt/mTOR pathway is of utmost importance. Two distinct mTOR complexes; mTORC1 and mTORC2, have been identified. mTORC1 is downstream of Akt, sensitive to rapamycin inhibition, and controls cap-dependent protein translation. In contrast, mTORC2 is directly upstream of Akt and is resistant to rapamycin. In this study, we investigated the effect of mTOR inhibition on cell viability and induction of apoptosis in epithelial ovarian cancer (EOC) cells, either alone or in combination with PI3-kinase/AKT inhibitor. We found that Torin2, an mTOR inhibitor, decreased cell viability and induced apoptosis in EOC cell lines in a dose dependent manner. Torin2 also inactivated mTOR1 and mTOR2 as well as downstream targets of mTOR; 4E-BP1 and p70S6. Torin2 treatment of EOC cell lines also induced mitochondrial dependent apoptosis via activation and cleavage of caspases. Finally, combination treatment of EOC cells with Torin2 and LY294002, a PI3-kinase/AKT inhibitor induced a synergistic apoptotic response via inactivation of AKT, mTOR1 and mTOR2 and activation of caspases. These studies will give us an insight on the molecular relationship between these survival pathways and suggest that simultaneous inhibition of mTOR and PI3-kinase/AKT pathways may be beneficial for the management of EOC.
Citation Format: Azhar R. Hussain, Shahab Uddin, Maqbool Ahmed, Khawla S. Al-Kuraya. Combined inhibition of mTOR and AKT activity induces potent apoptosis in epithelial ovarian cancer cells . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 526. doi:10.1158/1538-7445.AM2013-526
Abstract 5265: Akt regulates insulin-like growth factor binding protein-3 by modulating its expression in human non-small cell lung cancer cells.
Authors: Jin Quanri , Min Hye-Young , Whang Young Mi , Kim Yeul Hong , Lee Ho-Young 
Published: August 2014

Abstract
Since it has been suggested the insulin-like growth factor (IGF)-independent antitumor effect of insulin-like growth factor binding protein-3 (IGFBP-3) in human cancer cells, the mechanism underlying the regulation of IGFBP-3 in the cells has not been fully studied. Therefore, in this study, we investigated the precise role of Akt in the regulation of cellular IGFBP-3 in human lung cancer cells. Inhibition of PI3K/Akt by siRNA transfection targeting Akt or by treatment with an inhibitor (LY294002) enhanced antiproliferative and proapoptotic effects of IGFBP-3 in lung cancer cells. Additional pharmacological (by using a small molecule inhibitor) or genomic (by siRNA-based silencing of PTEN or overexpression of dominant-negative Akt) approaches suggest that Akt regulates the expression and stability of IGFBP-3 protein. Further characterization of the role of Akt in the regulation of IGFBP-3 by introduction of constitutively active form of each Akt subtype indicates that Akt3 destabilized cellular IGFBP-3 and suppressed retinoic acid-induced IGFBP-3 expression in both TSC2-/- MEF and H226B lung cancer cells. Collectively, these data suggest a novel function of Akt, especially Akt3, as a negative regulator of IGFBP-3 and, further, the possible implication of combined treatment targeting IGFBP-3 and Akt in the treatment of lung cancer.
Citation Format: Quanri Jin, Hye-Young Min, Young Mi Whang, Yeul Hong Kim, Ho-Young Lee. Akt regulates insulin-like growth factor binding protein-3 by modulating its expression in human non-small cell lung cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5265. doi:10.1158/1538-7445.AM2013-5265
Abstract 5267: STAT signaling is totally deregulated in malignant pleural mesothelioma: What are the reasons.
Authors: Arzt Lisa , Quehenberger Franz , Halbwedl Iris , Popper Helmut H. 
Published: August 2014

Abstract
Malignant pleural mesothelioma (MPM) is an aggressive tumor caused by former asbestos exposure with a mean overall survival of 12 months from diagnosis. The knowledge about predictive factors of outcome is poor and MPM is resistant to conventional therapy. The long latency period in MPM pathogenesis as well as the absence of early symptoms is responsible for the late diagnosis of this disease.
From our recent study and published data we know that the regular rapid progressive type of MPM uses several signaling pathways regulating cell growth and survival. Asbestos causes genetic modifications, most notably the upregulation of cell survival and growth signaling pathways as well as the expression of other proteins that favor the resistance of MPM to apoptosis and chemotherapy. In order to develop more effective therapy than the currently used chemotherapy, novel targets have to be identified in MPM.
The JAK/STAT signaling pathway is the principal signaling mechanism for lots of cytokines or growth factors in mammalians. JAK activation induces a variety of biological responses like cell proliferation, differentiation, cell migration, and apoptosis.
Our investigations demonstrate that the STAT signaling pathway is totally deregulated: STAT1 is upregulated, whereas STAT3 is downregulated. SOCS1 and SOCS3 - which represent a negative feedback loop and which are regulators of STAT1 and STAT3 - are totally missing in MPM. Investigations in six mesothelioma cell lines showed that STAT1 is highly expressed and that SOCS1 is missing whereas the expression of pSTAT1 (Tyr701) can be stimulated and therefore be increased by Interferon-gamma treatment. The expression levels of other components of the STAT signaling pathway in these cell lines are currently under investigation.
It is known that protein expression is controlled by noncoding RNAs, e.g. microRNAs (miRNA) and we investigated the possible impact of miRNAs on the STAT signaling pathway in MPM. We identified miR-30d* as a regulator of phosphorylated STAT1 (Ser727). Furthermore we found that miR-19b, miR-30b, miR-30c and miR-222 are upregulated which are predicted to target SOCS1 and SOCS3 - this could be an explanation for the missing expression of these proteins. MiR-21 is extremely upregulated in MPM, a miRNA that is associated with a wide variety of human tumors and which targets STAT3.
Understanding the role of STATs in MPM could be the first step into the development of a targeted therapy for these tumors.
Citation Format: Lisa Arzt, Franz Quehenberger, Iris Halbwedl, Helmut H. Popper. STAT signaling is totally deregulated in malignant pleural mesothelioma: What are the reasons. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5267. doi:10.1158/1538-7445.AM2013-5267
Abstract 5273: Systematic functional screening, miRNA and target expression analyses reveal miR-19, -124, -583, -129 and -876 as key nodes in prostate cancer proliferation networks.
Authors: Östling Päivi , Leivonen Suvi-Katri , Kohonen Pekka , Aakula Anna , Hintsanen Petteri , Aittokallio Tero , Perälä Merja , Kallioniemi Olli 
Published: August 2014

Abstract
To discover microRNA (miRNA) regulation of pathways relevant for proliferation of prostate cancer cells we performed gain-of-function screening with 1129 miRNA molecules in five prostate cancer (PCa) cell lines. Using proliferation, viability and apoptosis as read out we identified 25 miRNAs increasing and 48 miRNAs decreasing cell viability (threshold FDR q-value 3000 genes containing the predicted targets (TargetScan) and performed gene set enrichment analysis (MSigDB v. 2.07). Positively enriched gene sets (total of 17, q-value &lt;0.01) contained signatures such as mitosis and androgen signalling and the most enriched gene was AURKA. The negatively enriched gene sets (total of 207, q-value &lt;0.01) involved Ras-signaling and focal adhesion and the most down regulated gene was CAV1. Network visualization of the core target genes identified five miRNAs (hsa-miR-19a, −32, -124a, -583 and −876–3p) predicted to regulate both the positively and negatively enriched target genes suggesting a central role for both these miRNAs and the core targets in PCa. Our systematic screening approach combined with in vivo expression, gene set enrichment analyses and network visualization provide an unbiased way of revealing novel miRNAs -core targets important in PCa.
Citation Format: Päivi Östling, Suvi-Katri Leivonen, Pekka Kohonen, Anna Aakula, Petteri Hintsanen, Tero Aittokallio, Merja Perälä, Olli Kallioniemi. Systematic functional screening, miRNA and target expression analyses reveal miR-19, -124, -583, -129 and -876 as key nodes in prostate cancer proliferation networks. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5273. doi:10.1158/1538-7445.AM2013-5273