bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5656: Preclinical evaluation of cytotoxic effect of photosensitive fluorescent protein in human cancer cells
Authors: Tazawa Hiroshi , Sasaki Tsuyoshi , Hashimoto Yuuri , Kikuchi Satoru , Kishimoto Hiroyuki , Mizuguchi Hiroyuki , Fujiwara Toshiyoshi 
Published: August 2012

Abstract
Photodynamic therapy (PDT) is an anticancer therapy to induce tumor-specific cytotoxicity by accumulation of photosensitizers (PSs) and following non-toxic light irradiation to tumor tissues. Non-toxic light irradiation induces the PS-mediated generation of reactive oxygen species (ROS) and subsequent cytotoxicity in tumor cells. For clinical application, some kinds of PSs, such as photofrin and laserphyrin, are intravenously injected before light irradiation in anticancer PDT. However, the lack of sufficient and continuous accumulation of PSs in tumor tissues makes difficult to eradicate tumor cells by PDT. Therefore, the development of novel PSs that accumulate to tumor tissues more efficiently and persistently is required to improve the antitumor effect of PDT. Recently, a bioengineered fluorescent protein KillerRed has been reported to generate ROS upon green light irradiation, suggesting a potential of KillerRed fluorescent protein as a novel PS. In this study, we investigated the antitumor effect of KillerRed fluorescent protein in human cancer cells in combination with PDT. Transient transfection with KillerRed expression vector induced the photosensitive cytotoxicity upon green light irradiation within a few hours in human cancer HeLa and OST cells. To further evaluate the cytotoxic effect of KillerRed fluorescent protein in human cancer cells, we obtained the stable transfectants expressing cytotoxic KillerRed or non-cytotoxic Katushka fluorescent protein from human lung cancer H1299 cells. Green light irradiation induced the cytotoxic effect within one hour in H1299-KillerRed cells, but not in H1299-Katushka or H1299 cells. H1299-KillerRed cells irradiated with green light showed significantly higher levels of ROS, which was confirmed by intracellular fluorescence level of 2′,7′-Dichlorodihydrofluorescein Diacetate, than H1299-Katushka or H1299 cells. Immunocytochemistry further revealed that green light-irradiated H1299-KillerRed cells showed the apoptotic cell death with the cleavage of caspase-3 24 hours after irradiation. These results suggest that KillerRed fluorescent protein is a potent novel PS inducing ROS generation and apoptotic cell death in tumor cells in anticancer PDT. The development of virus-mediated delivery system for tumor-specific induction of KillerRed fluorescent protein is under way.
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 5656. doi:1538-7445.AM2012-5656
Abstract 988: Oncogenic PI3K mutations lead to NF-κB-dependent cytokine expression following growth factor deprivation
Authors: Hutti Jessica , Pfefferle Adam , Perou Charles , Baldwin Albert 
Published: August 2012

Abstract
While growth factor-independent signaling and proliferation are well-established hallmarks of cancer, little is known regarding growth factor-independent changes in gene expression which occur downstream from oncogenes. The PI3K pathway is one of the most commonly misregulated signaling pathways in human cancers. Here, MCF10A cells expressing the two most common PI3K mutations, PIK3CA E545K and H1047R, were used to identify the repertoire of genes altered by oncogenic PI3K mutations following growth factor deprivation. This gene set most closely correlated with gene signatures from claudin-low and basal-like breast tumors, and categorical enrichment analyses suggested that NF-κB target genes were dramatically upregulated by these mutations. An IKKα inhibitor was used to identify the subset of PI3K-driven genes that is NF-κB dependent. Interestingly, virtually all of these NF-κB dependent genes were secreted proteins, suggesting a paracrine role for this gene set. Among these genes was IL-6, a cytokine frequently expressed in tumors which plays a critical role in generating a tumor-promoting microenvironment. Consistent with this, conditioned media from cells expressing the E545K or H1047R mutations led to increased STAT3 activation in recipient THP-1 monocytes or normal epithelial cells in a NF-κB and IL-6-dependent manner. Together, these data define a PI3K-driven, NF-κB-dependent gene expression profile which may play a critical role in promoting a microenvironment amenable to tumor 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 988. doi:1538-7445.AM2012-988
Abstract 990: Nucleosome occupancy at unmethylated promoter CpG islands represents a novel mechanism of epigenetic gene silencing in cancer
Authors: Hesson Luke B. , Wong Jason W.H. , Sloane Mathew A. , Pimanda John E. , Bourke Michael J. , Hawkins Nicholas J. , Ward Robyn L. 
Published: August 2012

Abstract
Promoter CpG island (CGI) hypermethylation is an established mechanism of silencing gene expression in cancer. Although the silenced state is thought to be consolidated by the recruitment of nucleosomes across the promoter, this has been observed in only a limited number of genes. Here we performed genome-wide MBD-Seq, MNase-Seq and RNA-Seq to investigate the relationship between CGI methylation, nucleosome occupancy around the transcription start site (TSS) and gene expression in a premalignant colorectal adenoma and matched normal mucosa. Analysis of RNA-seq data identified 1987 silent genes that were not expressed in the normal or adenoma tissues. Of these 1987 genes, 1401 (70.51%) showed either methylation in both the normal and adenoma tissues or nucleosome occupancy across the TSS, with 524 (26.37%) of genes showing both, suggestive of a consolidated silenced state. Our RNA-Seq data also revealed that 2010 genes were downregulated &gt;2-fold in the adenoma when compared to paired normal mucosa. Of these 2010 genes, only 67 (3.33%) genes showed aberrant CGI hypermethylation, and of these 67 genes, only six (8.96%) showed nucleosome occupancy across the TSS. Therefore, the presence of both CGI hypermethylation and nucleosome occupancy across the TSS of downregulated genes is significantly lower than at silent genes (p&lt;0.0001). Interestingly, 272 of the remaining 1966 (13.84%) genes that were downregulated in the absence of aberrant CGI hypermethylation showed clear evidence of nucleosome occupancy across the TSS, including the important cancer-related genes CDH1 and CDKN2B. Only seven of these 272 genes (2.57%) have previously been described as frequent targets of hypermethylation in cancer, suggesting nucleosome recruitment represents an alternative mechanism of inactivation of these genes. In summary, we identified some of the earliest epigenetic events in colorectal neoplasia by profiling the transcriptome and epigenetic landscape of a premalignant colorectal adenoma. Our data show that for the majority of genes showing adenoma-specific downregulation and aberrant CGI hypermethylation, nucleosomes are not recruited to the promoter. Moreover, our data reveals a potential novel mechanism of epigenetic gene inactivation in the absence of promoter hypermethylation, through physical occlusion of transcription by nucleosome occupancy at the TSS.
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 990. doi:1538-7445.AM2012-990
Abstract 991: The DNA methylome of castration-resistant prostate cancer
Authors: Kleb Brittney N. , Estecio Marcos , Zhang Jiexin , Tzelepi Vasso , Chung Woonbok , Maity Sankar , Logothetis Christopher , Troncoso Patricia , Navone Nora , Jelinek Jaroslav , Liang Shoudan , Issa Jean-Pierre , Aparicio Ana 
Published: August 2012

Abstract
Lethal prostate cancer is predominantly a castrate-resistant disease. However, castrate-resistant prostate cancer (CRPC) is clinically heterogeneous and a classification that is predictive of outcome and response to therapies is lacking. Previous epigenetic profiling studies in CRPC have been limited to a small number of genes or sequences and therefore we explored the DNA methylome of CRPC and its capacity to classify the disease. We performed methylated CpG island amplification microarrays (MCAMs) using a panel of xenografts derived from 24 patients with CRPC tumors, 8 prostate tumors, 1 local recurrence, 5 liver metastases, 3 pleural fluid samples, 2 adrenal gland metastases and 1 each of the following: bone, subcutaneous tissue, retroperitoneal lymph node, ascitic fluid and brain. The xenograft morphology consisted of 15 adenocarcinomas, 11 small cell carcinomas, 3 large cell neuroendocrine carcinomas, 1 squamous cell carcinoma, 2 mixed morphologies and 2 unknown. The Lowess-normalized M values were used for analysis and the MCAM results were validated by pyrosequencing of 20 sequences associated with 12 genes with a sensitivity of 61.9%, a specificity of 84.3%, a positive predictive value of 73.6% and a negative predictive value of 75.7%. An unsupervised hierarchal clustering analysis using M values for probes located in CpG islands was performed and these results were compared with the clinicopathological features of the tissues. We observed that, different xenograft sublines derived from the same donor tumor clustered together suggesting that the DNA methylome is homogenous throughout a given tumor mass, despite the presence of histological heterogeneity, and that it is maintained through serial passages in mice. Unsupervised hierarchal clustering classified the xenografts into 3 groups, which showed trend towards distinct clinicopathological features including overall survival and androgen receptor (AR) status. In summary, we found that DNA methylation is a frequent event in CRPC and well preserved in xenograft tumors. Furthermore, the methylation profile of CRPC may represent a marker of clinicopathological subgroups with differential survival and AR status.
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 991. doi:1538-7445.AM2012-991
Abstract 993: A high-throughput peptide array screen of H3K9 methyl effectors identifies UHRF1 as an exception to the “phospho/methyl switch.”
Authors: Rothbart Scott B. , Fuchs Stephen M. , Nady Nataliya , Krajewski Krzysztof , Tempel Wolfram , Xue Sheng , Iberg Aimee N. , Barsyte-Lovejoy Dalia , Martinez Jorge Y. , Bedford Mark T. , Arrowsmith Cheryl H. , Strahl Brian D. 
Published: August 2012

Abstract
Increasing evidence suggests that histone post-translational modifications (PTMs) function in combination to regulate the diverse activities associated with chromatin. However, the mechanisms through which multiple histone PTMs influence the association of effector proteins with chromatin is poorly understood. To address this problem, we recently developed a histone peptide array platform containing singly- and multiply-modified histone peptides to examine the binding of chromatin-associated proteins. Using these arrays, we surveyed protein domains that bound methylated H3K9, and uncovered a number of PTM “patterns” that influenced the association with this mark. Interestingly, while most H3K9 methyl binders were ejected by neighboring H3S10 phosphorylation (a PTM enriched in G2/M-phase chromatin), the tandem Tudor domain (TTD) of UHRF1 was insensitive to this known “phospho/methyl switch”. In agreement, structural and biophysical studies confirmed the insensitivity of the UHRF1 TTD to H3S10 phosphorylation. Furthermore, we found that UHRF1 remains bound to chromatin throughout the cell cycle in contrast to HP1, which is ejected from chromatin during mitosis. These results suggest an important role for this ubiquitin ligase during mitosis. Significantly, we further find that the TTD of UHRF1 regulates global DNA methylation, thus definitively linking H3K9me3 binding by UHRF1 to the maintenance of DNA methylation. Taken together, our data suggest that the regulation of DNA methylation by UHRF1 extends beyond S-phase and requires H3K9me3 recognition during mitosis.
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 993. doi:1538-7445.AM2012-993
Abstract 997: Oncogenic tyrosine kinases are localized to mitochondria and regulate cancer metabolism by phosphorylating key components of pyruvate dehydrogenase kinase complex
Authors: Chen Jing , Hitosugi Taro , Fan Jun , Kang Sumin , Gu Ting-Lei , Boggon Titus 
Published: August 2012

Abstract
The Warburg effect describes the observation that cancer cells take up more glucose than normal tissue and favor aerobic glycolysis. Many tumor cells rely on aerobic glycolysis instead of mitochondrial oxidative phosphorylation for their continued proliferation and survival. This may be, in part, due to attenuated mitochondrial function, which is suggested to be achieved through inhibition of pyruvate dehydrogenase complex (PDC) in cancer cells. Pyruvate dehydrogenase (PDH) is the first and most important enzyme component of PDC, which catalyzes the conversion of pyruvate to acetyl-CoA that subsequently enters into the Krebs cycle to produce ATP and electron donors including NADH. PDH activity is negatively regulated by phosphorylation at several serine sites. Phosphorylation of PDH by PDH kinase (PDHK) results in the inactivation of PDC, while dephosphorylation by pyruvate dehydrogenase phosphatase (PDP) restores PDC activity. Thus, PDHK and PDP coordinate to regulate the phosphorylation and consequently activation status of PDH. In cancer cells, c-Myc and HIF-1alpha are believed to promote inhibition of PDC by, in part, upregulating gene expression of PDHK. However, how oncogenic signals regulate PDH, and/or coordinate PDHK and PDP activity to inhibit PDH and ultimately attenuate PDC activity in cancer metabolism still remains unclear. We recently reported that, surprisingly, functional PDC can form in mitochondria outside of matrix in some cancer cells. Moreover, several oncogenic tyrosine kinases including FGFR1, FGFR1 fusion tyrosine kinase, and FLT3-ITD mutant, as well as BCR-ABL and JAK2 V617F mutants, are localized to different mitochondrial compartments including outer membrane and matrix, respectively, in cancer cells, where they phosphorylate PDHK1, PDP1 and PDHA. Our studies demonstrate that tyrosine phosphorylation enhances PDHK1 kinase activity by promoting ATP and PDC binding, which promotes cancer cell metabolism, proliferation and tumor growth. In consonance with these findings, we found that tyrosine phosphorylation attenuates PDP1 phosphatase activity but inhibits PDHA enzyme activity. These data suggest that mitochondrial oncogenic tyrosine kinases regulate PDC activity by inhibiting PDHA1 enzyme activity directly through tyrosine phosphorylation and indirectly by enhancing and attenuating PDHK1 and PDP1 activity, respectively. These findings represent an acute mechanism underlying the Warburg effect, in addition to the long-term regulation that is believed to be regulated by c-Myc and HIF-1alpha.
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 997. doi:1538-7445.AM2012-997
Abstract 999: Potential role of reactive oxygen species in mediating glioblastoma stem cell differentiation
Authors: Wang Feng , Yuan Shuqiang , Chen Gan , Kim Sangbae , Hammoudi Naima , Feng Li , Lu Weiqin , Lee Ju-Seog , Huang Peng 
Published: August 2012

Abstract
Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor with poor prognosis due in part to drug resistance and high incidence of tumor recurrence. The drug resistant and cancer recurrence phenotype may be ascribed to the presence of cancer stem cells, which seem to reside in special stem-cell niches in vivo and require special culture conditions including certain growth factors and serum-free medium to maintain their stemness in vitro. In this study, we used several stem-like glioblastoma cell lines (GSC11, GSC23 and GBM3752) derived from patients’ tissues by typical neurosphere culture system, and showed that addition of fetal bovine serum (FBS) to the medium induced an increase of ROS, leading to aberrant differentiation and decreases of stem cell markers such as CD133. We found that exposure of glioblastoma stem cells (GSCs) to serum induces their differentiation through activation of mitochondrial respiration, leading to an increase in superoxide (O2−) generation and a profound reactive oxygen species (ROS) stress response manifested by upregulation of oxidative stress response pathway. This increase in mitochondrial ROS leads to a down-regulation of molecules including SOX2, and Olig2, and Notch1 that are important for stem cell function and an upregulation of mitochondrial superoxide dismutase SOD2 that converts O2− to H2O2. Neutralization of ROS by antioxidant N-acetylcysteine in the serum-treated GSCs suppresses the increase of superoxide and largely rescues the expression of SOX2, Olig2, and Notch1, and prevents the serum-induced differentiation phenotype. Upregulation of ROS by chemical disruption of mitochondrial electron respiration chain induced further decrease of CD133. Our study suggests that mitochondrial function and cellular redox status may profoundly affect the fates of glioblastoma stem cells, and that modulation of ROS generation may be an effective way to impact CSCs, which may provide a new basis for developing novel therapeutic approaches.
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 999. doi:1538-7445.AM2012-999
Abstract LB-117: Phenotype and function of tumor-infiltrating macrophages and B cells in a novel humanized mouse model (NSG-HIS) for ovarian cancer
Authors: Nunez-Cruz Selene , Walter Marc , Danet-Desnoyers Gwenn , Scholler Nathalie 
Published: August 2012

Abstract
Anti-cancer treatments are often highly effective in human tumor xenografts grown subcutaneously in immune deficient hosts such as athymic (nude) or severe combined immune deficient (SCID) mice. However, such preclinical results are frequently followed by failure or limited activity of the drug/therapy in clinical trial, prompting the development of more sophisticated animal models engrafted with fully human immune system (HIS). We reconstituted NOD-Scid-IL2Rγcnull (NSG) mice with cord blood-derived CD34+ cells and 12 to 16 weeks after transplantation NSG-HIS mice were injected with human ovarian tumor cells (OVCAR5) orthotopically (io), subcutaneously (sc), or both (io/sc). Although sc tumor growth was the fastest in the absence of human immune system, four weeks after tumor implantation the average sizes of sc, io and sc/io tumors were similar across all NSG-HIS groups (0.3cm3); regardless of the tumor site, all tumors were infiltrated with human B cells, T cells and macrophages. However, sc tumors contained proportionally more human B cells and macrophages than io tumors. Macrophages infiltrating sc and io, but not sc or sc/io tumors, exhibited an IL10high immunosuppressive phenotype. Io tumor-infiltrating macrophages expressed the highest levels of CD32 (FcγRII) and mannose receptor (CD206), and the lowest level of CD64 (FcγRI) compared to macrophages infiltrating sc or io/sc tumors. Finally, io tumors were infiltrated with less human B cells than all the other tumors; B cells from tumor-bearing mice presented an altered phenotype compared to non tumor-bearing animals, characterized by the upregulation of plasma and activation markers and the production of IgM and IgG. Our results support the hypothesis that the location of the tumor implantation impacts the phenotype and function of human tumor cell infiltrate. The novel NSG-HIS mouse model of ovarian cancer may help understanding the role of tumor microenvironment during tumor 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 LB-117. doi:1538-7445.AM2012-LB-117
Abstract LB-128: Targeted RNAi screening of an EGFR network reveals molecular determinants of tumor cell sensitivity to antibody-dependent cellular cytotoxicity (ADCC)
Authors: Murray Joseph C. , Nasto Rochelle E. , Jablonski Sandra A. , Tang Yong , Weiner Louis M. 
Published: August 2012

Abstract
Monoclonal antibodies can modulate signal transduction and survival of tumor cells, and can induce antibody-dependent cellular cytotoxicity (ADCC) through immune effectors, such as natural killer (NK) cells. Although clinical evidence suggests a role for ADCC in effective antibody therapy, molecular determinants of ADCC responsiveness—in oncogenic signaling networks, for example—have not been identified. Using a novel high-throughput screening platform, siRNAs targeting 60 genes of an EGFR network were reverse transfected into A431 cells, and cetuximab and an NK-like cell line (NK92-CD16V) were used to induce ADCC. Primary and validation screens identified four genes whose knockdown enhanced ADCC: GRB7, PRKCE, RET and ABL1. Pharmacological inhibition of Abl kinase activity enhanced ADCC, recapitulating the effects of ABL1 gene knockdown. Additional studies revealed distinct mechanisms associated with enhanced ADCC, including increased EGFR surface expression and enhanced susceptibility to apoptosis. This screening strategy has revealed putative molecular determinants of tumor cell sensitivity to ADCC that may translate to increased monoclonal antibody efficacy in the clinic.
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-128. doi:1538-7445.AM2012-LB-128