bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4787: GILT regulates antigen processing and CD4+ T cell recognition of melanoma cells
Authors: Haque Azizul , Norton Duncan , Doonan Bently , Amria Shereen 
Published: February 2011

Abstract
Metastatic melanoma is one of the deadliest of skin cancers and is increasing in incidence. Since current treatment regimens are ineffective at curing the disease, novel approaches, such as immunotherapy, for treating this malignant disease are being explored to elicit long-lasting antitumor immunity. We have previously shown that the majority of metastatic melanoma cells express HLA class II molecules, but lack Gamma-Interferon-inducible Lysosomal Thiol reductase (GILT), which differentially regulates HLA class II-restricted antigen processing and presentation. The purpose of this study was to investigate the mechanisms by which GILT insertion influences CD4+ T cells recognition of human melanoma cells via the HLA class II pathway. Biochemical analysis of melanoma cells showed that GILT expression upregulated the HLA class II components such as HLA-DM and invariant chain while class II protein expression remained unchanged. An increase in endolysosomal cathepsin protein expression and activity was also observed in melanoma cells transfected with GILT. Data obtained from biochemical and functional assays suggest that GILT insertion may help melanoma cells generate more antigenic determinants that are readily accessible to class II loading and presentation to CD4+ T cells. Taken together, these data suggest that GILT-inserted melanoma cells could be used in the design of whole cell vaccines for the treatment of metastatic melanoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4787.
Abstract 4790: Docetaxel modulates phenotype of human carcinoma cells, including drug-resistant tumor cells, resulting in enhanced killing by CTLs
Authors: Garnett Charlie T. , Farsaci Benedetto , Schlom Jeffrey , Hodge James W. 
Published: February 2011

Abstract
Purpose: Recent studies have reported that docetaxel, in addition to its direct cytostatic effects on murine tumors, can modulate immune cell populations in nontumor-bearing mice and enhance CD8+ T-cell responses. This study investigated docetaxel's ability to alter human tumor phenotype and sensitize tumor cells to immune attack.
Experimental Design: We examined 18 human carcinoma cell lines (4 breast, 3 prostate, 2 lung, 2 ovarian, and 7 colon) for docetaxel-induced changes in surface protein expression and sensitivity to CTL-mediated lysis. We also analyzed docetaxel-resistant tumor cells. After in vitro treatment with docetaxel, we examined surface expression of 5 molecules involved in T cell-mediated attack by fluorescence-activated cell sorting analysis, and measured the sensitivity of tumor cells to lysis by antigen-specific CD8+ CTLs, cell death, and inhibition of proliferation.
Results: Of the 18 cell lines tested, 15 (83%) up-regulated one or more of the surface molecules Fas, ICAM-1, MUC-1, CEA, and MHC class I post-docetaxel treatment. Killing by either CEA-specific or MUC-1-specific HLA-A2-restricted CD8+ CTLs was significantly enhanced in 6 of 9 docetaxel-treated HLA-A2+ tumor cell lines compared with untreated cell lines. Furthermore, tumor cells that were resistant to direct docetaxel cytotoxicity modulated phenotype and became more sensitive to CTL killing after treatment with docetaxel.
Conclusions: The results of this study suggest that docetaxel can sensitize human tumor cells to immune recognition and attack, even cells resistant to the direct cytotoxic effects of the drug. These findings establish a rationale for the combined use of vaccine and taxane based chemotherapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4790.
Abstract 4794: Tn (GalNAcα1-O-Ser/Thr) in serum mucin: a potential cancer biomarker
Authors: Hwang Jaulang , Chiang Hsiao-Ling , Lin Chi-Yu , Jan Fan-Dan , Chen Chiao-En , Hsu Chia-Tse , Nieh Shin , Lin Chun-Cheng 
Published: February 2011

Abstract
Mucin-related carbohydrate epitope, Tn (GalNAcα1-O-Ser/Thr), is expressed in epithelial tumors including breast, prostate, and ovarian cancer. Since the expression of Tn was shown to define the stage, rate, and phenotype of tumor progression as well as the diagnosis, Tn may offer as useful information for prognostic purposes. However, Tn-based tumor diagnosis requires the immunohistochemistry (IHC) staining of tumor tissue. A simple and noninvasive assay for tumor diagnosis is desirable. This study is taken an effort to examine whether Tn in serum mucin can be used as biomarker for cancer diagnosis. To reach this goal, we must have an anti-Tn antibody with high affinity and high specificity. This study presents a novel carrier protein containing a binding domain to the receptor of antigen presenting cells and cysteine-rich repeat peptide to serve as docking sites for conjugating Tn, as a result, to collaboratively activate T-cells and B-cells. This novel carrier protein after conjugation with Tn can effectively elicit high titer of IgG1 antibodies rather than IgM against Tn with high specificity in all immunized mice and rabbits. Applying this anti-Tn antibody, we observed that Tn expression by IHC assay is highly significantly correlated with the malignancy of tumors. We then applied anti-Tn antibody to detect the Tn in serum mucin of 12 lung cancer patients. The results showed that the levels of Tn were high in serum mucin of 11 out of 12 lung cancer patients, while the levels of serum mucin Tn are relatively low in normal people, suggesting that the levels of Tn in serum mucin may be a potential cancer biomarker.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4794.
Abstract 4804: Identification of a functional network of human epigenetic silencing factors
Authors: Poleshko Andrey S. , Einarson Margret B. , Shalginskikh Natalia , Zhang Rugang , Adams Peter D. , Skalka Anna Marie , Katz Richard A. 
Published: February 2011

Abstract
Epigenetic silencing directs transcriptional shutoff of specific genes during development and cellular differentiation. This process is mediated by epigenetic “marks” including DNA methylation and a variety of posttranslational histone modifications (e.g. methylation). Errors in placement or removal of epigenetic marks can drive epigenetic silencing and tumorigenesis. Inhibitors of DNA methyltransferase (DNMT) and histone deacetylase (HDAC) enzyme families (DNMTi and HDACi, respectively) can reverse epigenetic silencing and produce anti-tumor effects, possibly through reactivation of silent tumor suppressor genes (so-called epigenetic therapy). As these inhibitors show little specificity within enzyme families, their precise mechanisms of action are not well understood. To identify cellular factors involved in maintenance of epigenetic silencing, HeLa cells harboring epigenetically silent GFP reporter genes were interrogated with an siRNA library targeting predicted epigenetic regulators, including potential activators, silencers, chromatin remodelers, and ancillary factors. Using this approach, individual, or combinatorial requirements for specific epigenetic silencing factors can be detected by measuring GFP reactivation after siRNA-based factor knockdown. In our analyses, we identified a specific subset of epigenetic factors that are candidates for participation in a functional epigenetic silencing network in human cells. These factors include the histone deacetylase HDAC1, the de novo DNA methyltransferase DNMT3A, components of the Polycomb PRC1 complex (RING1, HPH2), and the histone lysine methyltransferases KMT1E and KMT5C. Roles were also detected for two TRIM protein family members, the cohesin component Rad21, and the histone chaperone CHAF1A (CAF-1 p150). Remarkably, combinatorial knockdown of factors was not required for reactivation, indicating little functional redundancy. Consistent with this interpretation, knockdown of either KMT1E or CHAF1A resulted in a loss of multiple histone repressive marks and concomitant gain of activation marks on the promoter during reactivation. These results reveal how functionally diverse factors may cooperate to maintain gene silencing during normal development or in disease. Furthermore, the findings suggest an avenue for discovery of new targets for epigenetic therapies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4804.
Abstract 4807: FOXD3 regulates Rnd3 and invasion in mutant BRAF melanoma cells
Authors: Katiyar Pragati Dixit , Abel Ethan V. , Aplin Andrew E. 
Published: February 2011

Abstract
Melanoma occurs due to the transformation of melanocytes and is the deadliest form of skin cancer with an estimated 68,720 new cases and 8,650 deaths in 2009. During radial growth phase (RGP) that is confined to the epidermis and papillary dermis, melanoma is treatable by surgical excision. However, dermal invasion during the vertical growth phase (VGP) is associated with a worse prognosis. The mechanisms contributing to aberrant melanoma invasion are poorly elucidated. Activating mutations in BRAF (a serine kinase) are found in approximately 60% of melanoma cases. Mutant BRAF is required for the invasion and changes in actin cytoskeleton associated with invasion are in part controlled by Rnd3, a BRAF regulated Rho family GTPase. Melanocytes derive from the neural crest, a multipotent population of migratory cells. Pluripotency and self-renewal of neural crest cells is regulated by the transcription factor FOXD3. Since we have previously shown that BRAF inhibition results in up-regulation of FOXD3 and down-regulation of Rnd3, we examined the role of FOXD3 in regulation of Rnd3 in cellular migration and invasion. We used inducible lentiviral-based expression of FoxD3 in various mutant BRAF melanoma cell lines (WM793 and A375). Inducible expression of FoxD3 in WM793mFoxD3 and A375mFoxD3 was confirmed by western blot. Boyden chamber with or without matrigel coating and 3D tumor spheroid collagen assays were used to study cellular migration and invasion in a dermal mimetic microenvironment. We observed a significant decrease in the migration and invasion in WM793 (VGP) and A375 (metastatic) melanoma cell lines and a decreased spheroids formation in the soft agar colony formation assay after FoxD3 induction. This inhibition of migratory/ invasive properties correlated with a FOXD3-dependent down-regulation of Rnd3 both at protein and mRNA level. Our study for the first time showed that FoxD3 expression down-regulates Rnd3 that increased actin stress fiber formation and decreases migration, invasion and spheroids formation in the metastatic melanoma cells. This study is relevant to the current challenge of understanding mechanism of BRAF regulation of invasion and provides additional targets for therapeutic intervention for the effective treatment of melanoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4807.
Abstract 4837: Short-chain fatty acids induced autophagy serves as an adaptive strategy for retarding mitochondria-mediated apoptotic cell death
Authors: Tang Yong , Chen Yakun , Jiang Hongmei , Nie Daotai 
Published: February 2011

Abstract
Short-chain fatty acids (SCFAs) are the major by-products of the bacterial fermentation of undigested dietary fiber in the human large intestine. The role of SCFAs, mostly propionate and butyrate, in colon cancer apoptotic cell death and cell proliferation inhibition has been well studied. Herein we demonstrate that, in addition to apoptotic cell death, propionate and butyrate induce another type of cell death termed “autophagy” in human colon cancer cells. Propionate-treated cells exhibited extensive characteristics of autophagic proteolysis: increased LC3-I to LC3-II conversion and reduced expression of p62/SQSTM1; increased acidic vesicular organelle development as manifested by dramatic increase in punctate GFPLC3, LysoTracker and MDC staining. Propionate-induced autophagy was associated with decreased mTOR activity and enhanced AMP kinase activity, two events known to be linked to autophagy. The elevated AMPKa phosphorylation is believed to have been caused by cellular ATP depletion due to mitochondrial dysfunction involving induction of mitochondrial permeability transition, as evidenced by the loss of mitochondrial membrane potential and overproduction of reactive oxygen species. In this context, mitochondria biogenesis was initiated to recover cellular energy homeostasis. Importantly, when autophagy was prevented at an early stage by 3-methyladenine, or when autophagic degradation was inhibited at a late stage by Chloroquine, the colon cancer cells became sensitized toward propionate induced apoptosis through activation of caspase 7 and its downstream effector caspase-3. Potentiation of cell death was also observed when autophagy was abolished using shRNA against the autophagic gene ATG5. These observations indicate that propionate-triggered autophagy serves as an adaptive strategy for retarding mitochondria-mediated apoptotic cell death. As SCFAs widely exist in the human large intestine, application of an autophagy inhibitor, such as Chloroquine, is expected to enhance the therapeutic efficacy of SCFAs in inducing tumor cell apoptosis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4837.
Abstract 4859: Statin-induced autophagy in prostate cancer cells
Authors: Parikh Ankur , Childress Chandra , Lin Qiong , Rukstalis Daniel , Yang Wannian 
Published: February 2011

Abstract
Statins, a class of inhibitors of 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase, are commonly prescribed medications for treatment of hypercholesterolemia. Epidemiological studies have shown that statin use decreases the incidence of advanced prostate cancer. Here we report that atorvastatin (Lipitor), a broadly prescribed statin, induces autophagy and rapid cell death in androgen receptor (AR)-negative prostate cancer PC3 cells. Atorvastatin treatment of PC3 cells for 40 hrs increased expression of LC3-II by more than 10 fold in a dose-dependent manner. Treatment of the cells with pepstatin A and E64-d, the autophagic protease inhibitors, dramatically increased atorvastatin-dependent LC3-II expression level, indicating that atorvastatin induced autophagic flux. In addition, atorvastatin treatment caused rapid death of PC3 cells. Atorvastatin-induced autophagy and rapid cell death were reversed by addition of geranylgeraniol, not farnesol, in culture medium, indicating that atorvastatin-mediated inhibition of geranylgeranyl biosynthesis causes autophagy and cell death. Furthermore, atorvastatin did not induce autophagy or cell death in normal prostate RWPE1 cells and induced only a minor autophagic response in AR-positive prostate cancer LNCaP cells. Thus, our studies demonstrate that statins induce autophagy and autophagy-associated cell death in PC3 cells, likely through inhibition of geranylgeranylation, and suggest that autophagic response to statins may partially underlie the protective effects of statins on prostate cancer. Importantly, these findings highlight additional mechanisms by which statins might be used for therapy of prostate cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4859.
Abstract 4870: A Novel gamma-Lactam-Based Histone Deacetylase Inhibitor Potently Inhibits the Growth of Human Breast and Renal Cancer Cells
Authors: Park Sunyoung , Lee Jae Cheol , Jeon Ye Ji , Lee Hyunwoo , Kim Munkyung , Han Jeung-Whan 
Published: February 2011

Abstract
We evaluated the novel gamma-lactam-based analogue, KBH-A145, for its anticancer activities. KBH-A145 markedly inhibited histone deacetylase (HDAC) activity in vitro and in vivo to an extent comparable to suberoylanilide hydroxamic acid (SAHA). The proliferation of various types of cancers was significantly suppressed by KBH-A145, among which MDA-MB-231 and MCF, human breast cancer cells and ACHN human renal cancer cells, were most sensitive. This was accompanied by induction of p21WAF1/Cip1 through compromised recruitment of HDAC1, which leads to hyperacetylation of its promoter region and thus arrested both cells in the G2/M phase. Interestingly, this compound induced apoptosis of MDA-MB-231 cells, but not ACHN cells, through cleavage of poly(ADP-ribose) polymerase (PARP). Taken together, these results show that this novel gamma -lactam-based HDAC inhibitor potently inhibits the growth of human breast and renal cancer cells. Thus KBH-A145 is a potential therapeutic agent for the treatment of these types of cancer.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4870.
Abstract 4871: Genomic amplifications in ovarian carcinoma are associated with specific histone modifications
Authors: Thiaville Michelle M. , Wang Tian-Li , Shih Ie-Ming , Chen Lily , Xiong Jianghui , Xuan Jason J. 
Published: February 2011

Abstract
Genomic amplification is a frequent molecular genetic alteration in many cancer types that results in upregulation and thus activation of oncogenes located in the amplified regions. However, the mechanism by which amplified genes are upregulated is poorly understood. We hypothesized that epigenetic regulation of gene expression was important for activation in addition to the increased DNA copy number for genes within amplified genomic loci. To test this hypothesis, we used ovarian cancer as an example because it is a highly lethal disease and, more importantly, ovarian cancer cells are characterized by a high level of genomic instability as reflected by widespread DNA copy number changes. We analyzed the data from chromatin immunoprecipitation array (Chip-chip) and single nucleotide polymorphism (SNP) array to determine the correlation between specific histone modifications and genome-wide DNA copy number alterations in OVCAR3 ovarian cancer cells and ovarian surface epithelial cell culture. Among 8 histone marks examined, representing both heterochromatic and euchromatic chromatin, we identified the strongest correlation between increased DNA copy number and the active histone marks, histone H4 acetylation at lysine 5 (p-value 7.8×10^-6; FDR 5.2×10^-5) and lysine 12 (p-value 7.6×10^-5; FDR 2.6×10^-4). In contrast, there was no significant correlation between DNA amplification and repressive histone marks including histone H3 methylation at lysines 9 and 27. These correlations were validated by quantitative real-time PCR of ChIP samples at confirmed amplified regions on chromosomes 11 and 19, which harbor the RSF1 and AKT2 oncogenes. Furthermore, all genes within the amplicons were overexpressed in the OVCAR3 cell line harboring the amplicons as compared to a normal ovarian surface epithelial cell line. By using ovarian cancer as a disease model, our results indicate that an amplicon-associated specific histone modification pattern facilitates gene expression and suggest that both genetic (DNA copy number gain) and epigenetic (active histone marks) events contribute to upregulation of amplified genes which may ultimately contribute to the development of human cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4871.
Abstract 4879: Identification of the hSET1 as a unique marker to cancer cells
Authors: Yadav Sushma , Singahl Sharad S. , Singhal Jyotsana , Awasthi Sanjay 
Published: February 2011

Abstract
Our recent studies have shown that human SET1, a key element of highly conserved multi-protein histone methyl transferase (HMT) complex known to catalyze methylation of histone H3 lysine 4 (H3K4) and regulating expression of specific genes important for the malignant phenotype, differentially over-expressed in the cancer cells. RT-PCR competition assay were developed using oligonucleotides, designed from the conserved sequences from the flanking regions of hSET1 and have shown that the sequences of hSET1 are unique to the malignant tumor tissues. The studies have been extended to the cultured cells and hSET1 has been shown to be differentially over-expressed in the malignant cells as compared to the normal cells at the RNA as well as protein level.
The potential importance of these observations is underscored by our recently published studies showing complete regression of human colon cancer xenografts in nude-mice treated with phosphorothioate antisense to cause near complete depletion of SET1 in the animal. No significant adverse effects were seen, and all animals treated with antisense had regression of already established xenografts after i.p. injection of SET1 directed phosphorothioate antisense. In contrast, tumor progression was not affected by a paired scrambled antisense. These findings indicate that amplification by RT-PCR of specific circulating tumor-specific ribonucleotides may be a powerful tool for early detection of cancer, and perhaps a means for selecting patient-specific targeted therapies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4879.