bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-478: MiRNA as biomarkers to predict de novo chemoresistance to neoadjuvant chemotherapy in patients with muscle invasive bladder cancer
Authors: Vinall Ruth L. , Tepper Clifford , Z.Ripoll Alexandra , Gandour-Edwards Regina , Durbin-Johnson Blythe , White Ralph deVere 
Published: August 2012

Abstract
The primary goal of this study was to determine whether miRNA expression profiling can predict de novo chemoresistance to treatment with neoadjuvant chemotherapy in patients with muscle invasive bladder cancer (MI-BC). The relative expression of 9 miRNAs in 41 annotated, diagnostic MI-BC patient samples was determined by quantitative real-time PCR (qPCR) and correlated with patient response to neoadjuvant chemotherapy, p53 status (SSCP/sequencing) and pRb, p21 expression (IHC). These 9 miRNA were chosen based on a known link to either transitional cell carcinoma (TCC) progression and/or chemoresistance. Expression of these miRNA was also assessed in 8 paired pre- versus post-chemotherapy patient samples from non-responders. Patients with higher let-7c expression levels had significantly higher odds of responding to neoadjuvant chemotherapy (p = 0.023, OR 2.493, 95% CI 1.121, 5.546). The odds of response was not significantly different between patients with vs. without p53 mutations (p = 0.948, OR 0.955, 95% CI 0.231, 3.945). Post-chemotherapy samples expressed significantly higher levels of let-7c (geometric mean ratio = 3.5, P = 0.006). Lower let-7c expression levels appear to predict chemoresistance in TCC patients, prospective studies will be needed to validate this finding. Pre- versus post-chemotherapy patient sample analyses indicate increased let-7c expression plays a role in mediating disease progression following treatment with chemotherapy. Future studies will focus on determining the functional role played by let-7c in chemoresistance and disease progression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-478. doi:1538-7445.AM2012-LB-478
Abstract LB-481: MicroRNAs as novel therapeutic targets to treat drug-resistant breast cancers
Authors: Chang Yao-Fu , Zoghi Behyar , Panneerdoss Subbarayalu , Pertsemlidis Alexander , Rao Manjeet K. 
Published: August 2012

Abstract
Acquired drug resistance continues to be a major clinical impediment to the successful treatment of cancer. For example, resistance to agents such as paclitaxel and trastuzumab accounts for treatment failure in more than 90% of patients with metastatic breast cancers. Understanding the mechanisms underlying such resistance is therefore crucial for the development of new, efficacious drugs against cancer. Unfortunately in spite of extensive inquiry in this field, little is known about the key molecules and signaling pathways that regulate this phenomenon. Recently, we have discovered that microRNAs (miRNAs) may play critical roles in mediating drug sensitivity/resistance in breast cancers. We have identified miRNAs that are differentially expressed between chemo-resistant and sensitive HER2+ breast cancer cells. Specifically, through high-throughput miRNA inhibitor library screens, we have identified miRNAs that sensitize drug-resistant breast cancer cells to paclitaxel and trastuzumab, a drug combination commonly used for the treatment of metastatic HER2+ breast cancers. MiRNA/s that alter/s the cellular response to these drugs may target a common signaling pathway. For example, resistance to paclitaxel/trastuzumab in breast cancer has been proposed to be a consequence of loss of PTEN expression, leading to altered AKT signaling. Our findings suggest that certain miRNAs are selectively cytotoxic in a drug-specific manner and that these miRNAs may provide novel adjuvant therapeutic tools for the treatment of drug-resistant metastatic breast cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-481. doi:1538-7445.AM2012-LB-481
Abstract LB-488: Induction of autophagy by heat shock factor 1 promotes breast cancer resistance to chemotherapy
Authors: Desai Shruti , Liu Zixing , Fodstad Oystein , Tan Ming 
Published: August 2012

Abstract
Breast cancer is the most common type of cancer as well as one of the leading causes of cancer-related deaths in women. The increasing emergence of drug resistance to commonly used chemotherapeutic agents has warranted the development of novel and robust treatment options for cancer patients. Carboplatin, a DNA damaging agent, is one of the therapeutic agents which has shown promising results in breast cancer clinical trials. Carboplatin is a second generation platinum drug, increasingly used in clinic to treat cancer patients because of its reduced toxicity and side effects when compared to Cisplatin. Heat Shock Factor 1 (HSF1) is the master regulator of heat shock responses which has also been shown to regulate certain non-heat shock reponse genes. As a transcription factor HSF1 can function as both an activator and repressor of its target genes, resulting in regulation of critical cellular processes invovled in managing cellular stress. The focus of this study is to identify the role of HSF1 in Carboplatin mediated-sensitivity in breast cancer cells, to provide novel insights to improve treatment strategies for cancer patients. Carboplatin treatment in multiple breast cancer cell lines induced growth inhibition which was significantly enhanced upon HSF1 knockdown. Interestingly, the treatment also induced autophagy in these cells. Autophagy is a type II programmed cell death, which is induced in response to metabolic stress and has been demonstrated to mediate drug resistance, since it can play a protective role and allow cells to survive under stressful conditions. Knockdown of HSF1 along with inhibition of autophagy by 3-Methyladenine (3-MA) led to increase in apoptosis in these cells. Furthermore, HSF1 was required for the induction of autophagy in Carboplatin treated cells. Knockdown of HSF1 by siRNA (transient) and shRNA (stable), inhibited induction of autophagy in the presence of Carboplatin, as measured by the punctate EGFP-LC3 structures as well as acridine orange staining. Chromatin immunoprecipitation (ChIP) assay along with Real time- PCR analysis revealed that HSF1 can regulate autophagy by directly regulating the expression of autophagy related genes in the presence of Carboplatin. These findings indicate that HSF1 activates autophagy in response to the Carboplatin induced cellular stress thus leading to cell survival and reducing sensitivity to Carboplatin. Our data strongly support a critical role for HSF1 in promoting chemoresistance through induction of autophgy. This finding has important implications in the development of targeted therapeutics for overcoming Carboplatin resistance in breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-488. doi:1538-7445.AM2012-LB-488
Abstract LB-493: Blocking the integrin αvβ3-CRAF axis with Cilengitide arrests glioblastoma cells in pro-metaphase
Authors: Franovic Aleksandra , Cheresh David A. 
Published: August 2012

Abstract
Glioblastoma multiforme (GBM) is the most prevalent brain tumor subtype, with a particularly high mortality rate due to frequent recurrence and poor response to standard therapies. Improving outcome for these patients will require new therapies which target the unique features of this disease. One such approach is geared toward integrin αvβ3, as high-grade GBM tumors express both the extracellular matrix protein vitronectin and its receptor integrin αvβ3 which drive several key cell signaling pathways to promote cell invasion and survival. Blocking the function of integrin αvβ3 with the antagonist Cilengitide shows potent anti-tumor activity in preclinical models and is currently completing the first Phase III trial for newly-diagnosed GBM. Understanding the mechanisms of activity for Cilengitide will be critical as this drug nears FDA-approval for GBM. Since αvβ3 is highly expressed in both the brain tumor vasculature and on glioma cells, it is not clear whether Cilengitide exerts its effects by disrupting tumor angiogenesis, tumor cell invasion and survival, or other hallmark tumor traits. Focusing on GBM cells, we have made the novel observation that αvβ3 ligation leads to phosphorylation of CRAF on serine 338, an event which we have recently linked to cell survival and cell cycle progression. Pharmacological inhibition or knockdown of integrin αvβ3 reduces activated CRAF levels, causes tumor cells to arrest in pro-metaphase, and suppresses the growth of orthotopic GBM in mice. Activating this pathway by expression of a phospho-mimetic CRAF S338D mutant independently drives cell cycle progression in vitro, accelerates tumor growth in vivo, and renders tumors resistant to the effects of Cilengitide. These findings reveal a previously unappreciated mechanism of action for Cilengitide. In addition to its well-known anti-angiogenic function, it also directly induces cell cycle arrest in GBM cells. The clinical implications of this observation are two-fold as it: 1) provides important insight that could aid in the design of combination treatment regimes; and 2) points at integrin αvβ3 and phosphorylated CRAF S338 expression as potential biomarkers which could serve to help identify the patient populations most likely to benefit from Cilengitide.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-493. doi:1538-7445.AM2012-LB-493
Abstract LB-69: Role of HDAC1 in epigenetic repression of E-cadherin after transient Epstein Barr virus infection
Authors: Queen Krista J. , Scott Rona S. 
Published: August 2012

Abstract
Epstein-Barr virus (EBV) is a gammaherpesvirus associated with a variety of lymphoid and epithelial tumors. Although EBV is a known tumor virus, incomplete association of EBV with any given tumor type has confounded its role in tumorigenesis. For example, only 15% of gastric carcinomas are EBV-positive compared to virtually all undifferentiated nasopharyngeal carcinomas. Upon entry into a cell, the viral genome is chromatinized and EBV rapidly shuts off its viral gene expression program via methylation of its viral promoters in an attempt to evade the host immune response. A similar restricted pattern of viral gene expression is present in EBV-positive tumors. We hypothesize that EBV infection of tumor cells results in virus-induced epigenetic alterations to host genes that remain after loss of the virus and may provide a selective advantage to the tumor cell. To identify virally induced epigenetic alterations, we established a transient model of infection to model the effects of viral redundancy and loss in carcinogenesis. Carcinoma cell lines were infected with recombinant EBV, passaged with selective pressure, and allowed to lose viral genomes by withdrawal of selection. Transient EBV infection of lung carcinoma cells resulted in numerous gene expression changes relative to uninfected controls suggestive of cellular epigenetic reprogramming. Two such gene expression changes, PYCARD and E-cadherin were found to be due to DNA methylation and loss of histone acetylation, respectively. To understand the mechanism behind loss of histone acetylation at the E-cadherin locus following transient EBV infection, we examined the role of histone deacetylases (HDACs) in mediating the epigenetic repression. We observed an increase in total HDAC activity in our transiently infected, EBV-negative clones. Through the use of specific inhibitors, we noted class I HDACs, specifically HDAC1, was involved in the repression of E-cadherin in transiently infected clones. EBV-modulation of HDAC1 activity may lead to host epigenetic alterations that are retained after loss of the virus. Future experiments are aimed at determining the viral and cellular players responsible for the epigenetic alterations that are seen in transiently infected, EBV-negative clones. These results suggest that EBV alters cellular gene expression in a heritable fashion in formerly infected cells, while its own contribution to the oncogenic process is masked.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-69. doi:1538-7445.AM2012-LB-69
Abstract SY11-03: Mechanisms of ATM activation
Authors: Paull Tanya T. , Lee Ji-Hoon , Ditch Scott , Guo Zhi 
Published: August 2012

Abstract
The Ataxia-Telangiectasia Mutated (ATM) kinase initiates a rapid cascade of protein phosphorylation in response to double-strand breaks in chromosomal DNA. The critical targets of ATM during this response include many tumor suppressors involved in cell cycle progression and apoptosis. The DNA damage response is thus defective in cells lacking ATM; however, there are also many indications that cells lacking ATM are defective in responses to other forms of stress, particularly oxidative stress. Mammalian cells lacking ATM exhibit high levels of reactive oxygen species and indications of chronic oxidative stress. In addition, the shortened lifespan, haematopoietic stem cell loss, and increased lymphomagenesis seen in A-T mouse models can be suppressed by antioxidants, suggesting that oxidative stress constitutes an important part of the A-T phenotype and is important for cancer progression. We have observed robust ATM activation in human cell lines in response to oxidative stress, in the absence of apparent DNA damage. In addition, oxidation of purified recombinant ATM in vitro induces ATM activation in the absence of DNA DSBs and the MRN complex. The oxidized form of ATM is a disulfide-crosslinked dimer containing several disulfide bonds. Mutation of a critical cysteine residue involved in disulfide bond formation specifically blocks activation via the oxidation pathway, both in vitro with purified components and in human cells. Identification of this pathway explains many observations of ATM activation under conditions of oxidative stress, and shows that ATM is an important sensor of reactive oxygen species (ROS) in vivo. Here we investigate how the oxidation pathway of ATM activation is affected by small molecules, specifically by resveratrol and related compounds, and how this affects cell cycle checkpoint responses in human cells. We also show in vitro that ATM is a direct target of these compounds and investigate the mechanism underlying the effects on ATM function.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY11-03. doi:1538-7445.AM2012-SY11-03
Abstract SY14-01: Investigating MTORC1 inhibition downstream of Apc loss in vivo
Authors: Sansom Owen J. 
Published: August 2012

Abstract
The Apc tumour suppressor gene is mutated in up to 80% percent of colorectal cancers (CRC), therefore strategies specifically targeting Apc deficient cells in vivo may be of therapeutic relevance. Thus far most work in murine models have focussed on models of adenomas where only Apc is lacking (and not other mutations that drive progression). In my talk, I will discuss our recent work inhibiting mTOR in Apc deficient cells in vivo either via small molecules or genetically deleting critical components of mTORC1 (Raptor) and mTORC2 (Rictor).
Here we show that Apc deficient cells are dependent on mTORC1 for proliferation (in a S6 kinase dependent manner). However additional mutation of KRAS or p53 renders the cells insensitive to mTORC1 inhibition. I will discuss the mechanisms underpinning this resistance and how overcoming these may allow us to target more advanced intestinal tumours in vivo.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY14-01. doi:1538-7445.AM2012-SY14-01
Abstract SY21-01: Chromatin remodeling proteins in transcription and development
Authors: Archer Trevor K. , Trotter Kevin W. , Singh Ajeet 
Published: August 2012

Abstract
The assembly of DNA with histones into chromatin provides a mechanism to regulate gene expression in time and space. The precise architecture of various DNA regulatory elements within the hierarchy of chromatin structures controls the access and activity of transacting factors, both protein and RNA. Epigenetic marks within DNA and histones allow regulatory information to act during development and across generations. The enzymes that mediate these processes are diverse and multifunctional, capable of posttranslationally modifying DNA and histones as well as remodeling the chromatin architecture. Among these enzymes the human SWI/SNF or BRG1 remodeling complex is particularly important with clear roles in signal transduction, development and cancer. In the presentation I will describe our recent work on the detailed mechanism of action of the BRG1 complex in gene expression and during early development in the mouse. We focus on the contribution that sub-domains in the BRG1 N terminus makes if protein partners outside the normal BRG1 associated Factors (BAFs) to initiate steroid receptor mediated transcription. Studies of the complex during development highlight the roles of individual BAF proteins and their contribution to organogenesis. These findings highlight the intimate connections between chromatin remodeling and epigenetics for normal healthy development.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY21-01. doi:1538-7445.AM2012-SY21-01
Protective effects of indomethacin and dexamethasone in a goat model with intrauterine balloon aortic valvuloplasty
Authors: Zhou Kaiyu , Wu Gang , Li Yifei , Zhao Liang , Zhou Rong , Zhu Qi , Huang Xupei , Mu Dezhi , Hua Yimin 
Published: August 2012

Abstract

Background
Intrauterine balloon aortic valvuloplasty (IUBAV) has been used for critical aortic stenosis. However, it is necessary to determine the fetal impairments such as preterm birth after this approach and to find a way to prevent or reduce them.

Methods
In the present study, we evaluated the therapeutic value of indomethacin (IDM) and dexamethasone (DXS) on reducing the preterm birth rate in experimental goats after IUBAV.

Results
Our results indicated that the administration of IDM/DXS significantly reduced the rate of premature birth. IDM/DXS treatment led to preservation of myocardial ultrastructure with less damage, and amelioration of the fetal and placental circulation. Furthermore, we found that norepinephrine (NE) level was positively associated with the degree of myocardial damage. IDM/DXS administration led to a significant decrease of operation-induced increase of NE levels, which may be associated with the protective effects of IDM/DXS. Lastly, we found that the administration of IDM/DXS did not induce the risk of ductus arteriosus closure or slow down fetal growth.

Conclusions
Our results indicate that IDM/DXS promotes a better gestational outcome at least partially by reducing stress response during and after the operation of IUBAV in the goat model. IDM/DXS may be a useful application in human patients during IUBAV intervention.
Cloudgene: A graphical execution platform for MapReduce programs on private and public clouds
Authors: Schönherr Sebastian , Forer Lukas , Weißensteiner Hansi , Kronenberg Florian , Specht Günther , Kloss-Brandstätter Anita 
Published: August 2012

Abstract

Background
The MapReduce framework enables a scalable processing and analyzing of large datasets by distributing the computational load on connected computer nodes, referred to as a cluster. In Bioinformatics, MapReduce has already been adopted to various case scenarios such as mapping next generation sequencing data to a reference genome, finding SNPs from short read data or matching strings in genotype files. Nevertheless, tasks like installing and maintaining MapReduce on a cluster system, importing data into its distributed file system or executing MapReduce programs require advanced knowledge in computer science and could thus prevent scientists from usage of currently available and useful software solutions.

Results
Here we present Cloudgene, a freely available platform to improve the usability of MapReduce programs in Bioinformatics by providing a graphical user interface for the execution, the import and export of data and the reproducibility of workflows on in-house (private clouds) and rented clusters (public clouds). The aim of Cloudgene is to build a standardized graphical execution environment for currently available and future MapReduce programs, which can all be integrated by using its plug-in interface. Since Cloudgene can be executed on private clusters, sensitive datasets can be kept in house at all time and data transfer times are therefore minimized.

Conclusions
Our results show that MapReduce programs can be integrated into Cloudgene with little effort and without adding any computational overhead to existing programs. This platform gives developers the opportunity to focus on the actual implementation task and provides scientists a platform with the aim to hide the complexity of MapReduce. In addition to MapReduce programs, Cloudgene can also be used to launch predefined systems (e.g. Cloud BioLinux, RStudio) in public clouds. Currently, five different bioinformatic programs using MapReduce and two systems are integrated and have been successfully deployed. Cloudgene is freely available athttp://cloudgene.uibk.ac.at.