bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 140: microRNA regulation of cell viability and drug response in cancer
Authors: Du Liqin , DeSevo Christopher , Borkowski Robert , Baker Michael , Wistuba Ignacio , Minna John , Pertsemlidis Alexander 
Published: August 2012

Abstract
Lung cancer is the leading cause of cancer-related deaths, with the majority of deaths due to failed therapy from tumor drug resistance. Third-generation chemotherapeutic agents represent the standard first-line treatment for advanced small cell (SCLC) and non-small cell (NSCLC) lung cancer patients. Response rates are poor (20-40%) with a median survival of 8-10 months. In an unbiased and comprehensive approach, we have combined a high-throughput screening platform with a library of chemically synthesized microRNA mimics and inhibitors. We have used this platform to identify mimics and inhibitors that reduce cell viability in general, and those that specifically sensitize cells to taxanes. We have identified several miRNAs for which over-expression or inhibition has a dramatic and selective effect on cell viability or drug response. We have demonstrated that miR-337-3p mimic sensitizes NSCLC cells to taxanes. By combining in vitro and in silico approaches, we identified STAT3 and RAP1A as direct targets that mediate the effect of miR-337-3p by enhancing taxane-induced arrest in the G2 phase of the cell cycle. We have identified an inhibitor of miR-139-5p as a potent and selective regulator of SCLC cell viability. Inhibiting miR-139-5p decreases SCLC cell viability by over 80%, but has a minimal cytotoxic effect on that of NSCLCs or immortalized human bronchial epithelial cells. We are currently investigating the targets of miR-139-5p that mediate its effect on SCLC cell viability. We also identified miR-10a inhibitor as increasing cell viability, with the converse observed for miR-10a mimic, suggesting that miR-10a acts as a tumor suppressor gene by directly decreasing expression of gene(s) that promote cell survival and growth. Manipulation of miR-10a levels also resulted in significant changes in both mRNA and protein levels of its predicted target, the catalytic subunit of phosphatidylinositol 3-kinase (PI3K), which has been shown to play a major role in proliferation and survival in a number of human cancers and is a significant therapeutic target. We have identified miR-337-3p as a regulator of taxane sensitivity, and miR-10a and miR-139-5p as modulators of cell viability. Increasing levels of miR-337-3p and inhibiting miR-10a and miR-139-5p may therefore provide novel therapeutic tools for the treatment of NSCLC and SCLC.
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 140. doi:1538-7445.AM2012-140
Abstract 1403: Multiorogan metastasis of human HER-2+ breast cancer in immunodeficient mice
Authors: Lollini Pier-Luigi , Nicoletti Giordano , Ianzano Marianna , Croci Stefania , Grosso Valentina , Palladini Arianna , Iezzi Manuela , Landuzzi Lorena , Giovanni Carla De , Nanni Patrizia 
Published: August 2012

Abstract
Metastatic spread is the major cause of morbidity and death among cancer patients. In vivo studies of the metastatic process are severely hampered by the fact that most human tumor cell lines derived from highly metastatic tumors, such as human HER-2+ breast cancer, fail to consistently metastasize in immunodeficient mice like athymic nude mice. We studied whether a highly immunodeficient double knockout mouse, Rag2−/−;Il2rg−/−, which lacks T, B and NK cell activity, was more permissive to metastatic spread than the nude mouse. Metastatic dissemination in Rag2−/−;Il2rg−/− mice was widespread, and reached all sites commonly affected in human patients, including lungs, liver, bones and brain. Interestingly, metastatic spread from local tumors was only marginally different between tumors growing orthotopically or subcutaneously, both for what concerned the more malignant MDA-MB-453 cell line and the less malignant BT-474. Intravenous administration of cells significantly enhanced the metastatic spread of BT-474 cells, with the proportion of affected mice attaining 100%. Different metastatic burdens were observed in different organs, and the use of EGFP-tagged cells was instrumental in allowing a precise detection of metastatic deposits in bones, liver and brain. Quantitative evaluation of metastatic spread in Rag2−/−;Il2rg−/- mice was not limited to EGFP detection, for example we used qPCR with human-specific primers to quantitate metastatic burden in the brain, and flow cytometry to detect HER-2-positive disseminated tumor cells in the bone marrow. The brain is a common site of metastatic spread, but tumor growth in immunodeficient mice fails to reproduce this fateful property of human tumors, unless unique cell lines, selected variants and/or special injection routes are used. In contrast, spontaneous brain metastases from local tumors were common in Rag2−/−;Il2rg−/- mice, and their frequency reached 100% after intravenous injection. Morphologic analysis of brain deposits showed that multiple metastases were present, both intracerebral and intraventricular or leptomeningeal, ranging from minimal deposits of few cells to huge masses. In conclusion, human HER-2+ human breast cancer cells in Rag2−/−;Il2rg−/− mice faithfully reproduce the multiorgan metastatic pattern observed in patients, thus allowing the investigation of metastatic mechanisms and the preclinical study of novel antimetastatic agents.
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 1403. doi:1538-7445.AM2012-1403
Abstract 141: Epigenetic silencing of miR-122 in hepatocellular carcinoma
Authors: Song Kyoungsub , Han Chang , Wu Tong 
Published: August 2012

Abstract
It has been reported that miRNAs potently influence cellular function through the regulation of extensive gene expression networks and most tumors are characterized by globally diminished miRNA expression. However, the potential mechanism of microRNA expression change in tumorigenesis remains to be further investigated. In this study, we focus on the epigenetic regulation of miRNA expression in hepatocellular carcinoma. We first performed miRNA microarray analysis in HepG2 cells, which reveals significant changes in miRNA expression profiling with 23 upregulated miRNAs and 15 downregulated miRNAs induced by the treatment with 5′aza-2′deoxycytidine (5′-aza, DNA methylation inhibitor) and 4-phenylbutyric acid (PBA, histone deaceltylation inhibitor). Interestingly, miR-122, the most abundant miRNA in the liver, is upregulated by 5′-aza and PBA, which is validated by qRT-PCR analysis in both HepG2 and Huh7 cells. In addition, miR-122 expression is increased by the overexpression of PPARγ or the treatment of PPARγ agonist (15-keto PGE2 or 15d-PGJ2).We then demonstrate that peroxisome proliferator-activated receptor gamma (PPARγ) and retinoid X receptor alpha (RXRα) bind to conserved DR-1 and DR-2 (peroxisome proliferator-activated response element) in the miR-122 promoter region and these bindings are significantly increased by 5′-aza and PBA with the biotinylated oligonicleotides precipitation assay. However, 5′-aza and PBA inhibit the binding of N-CoR (nuclear receptor corepressor) or SMRT (silencing mediator for retinoid and thyroid hormone receptor) to DR-1 or DR-2. And we found that 5′-aza and PBA inhibit PPARγ/N-CoR/SMRT protein complex formation in HepG2 cells with the immunoprecipitation assay. Furthermore, we observe that SUV39H1(H3K9 methyl transferase) protein is decreased by the co-treatment of 5′aza and PBA; and the suppression of endogenous SUV39H1 expression with SUV39H1siRNA increases miR-122 expression. Taken together, our results suggest that histone acethylation and demethylation lead to the release of PPAR-gamma from PPAR-gamma/N-CoR/SMRT protein complex to activate miR-122 transcription and to the inhibition SUV39H1 protein expression for the elimination of histone methylation to further facilitate miR-122 transcription. In conclusion, Epigenetic silencing is one of the most important mechanisms for diminished miR122 expression in hepatic carcinogenesis.
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 141. doi:1538-7445.AM2012-141
Abstract 1569: Multivalent melanoma vaccine using primary human melanoma cells and a vaccinia virus based antigen retrieval system
Authors: Suriano Robert , Rajoria Shilpi , George Andrea , Jussim Casey , Shanmugam Arulkumaran , Geliebter Jan , Tiwari Raj K. , Wallack Marc K. 
Published: August 2012

Abstract
Melanoma is the fifth most diagnosed cancer in men and seventh most diagnosed cancer in women and it is estimated that there will be over 70,000 new cases and 8,000 deaths in 2011. Prevention of both primary and secondary melanomas requires the development of a melanoma specific multi-valent vaccine. We have been involved in developing a vaccinia virus based vaccine consisting of melanoma cell membrane antigens and integrated vaccinia viral proteins, which serve as a potent adjuvant. This melanoma vaccine, referred to as viral membrane oncolysate (VMO), is composed of five primary cell lines derived from patient tumors each independently infected with vaccinia virus and has been shown to induce anti-cancer immune response in clinical trials. Notable results were obtained in node positive subsets of patients that showed a positive response in survival distribution function suggesting that this preparation is an active therapeutic immunogen but the mechanism of immune activation needs to be elucidated. In order for us to define the immunogens that impart the clinical efficacy of the this melanoma VMO vaccine, it is essential to characterize the primary cell lines with respect to their phenotypic characteristics as well as to define the melanoma antigen repertoire so that effective vaccine strategies can be designed that do not rely exclusively on tumor derived primary cells. Our study reveals that all the five primary cell lines expressed antigens, such as gp100, CD146, and tyrosinase, similar to several commercially available melanoma cell lines although at varying concentrations. In addition, the five primary cell lines demonstrated varying migratory/invasive properties using a Boyden Chamber assay and their tumorigenic potential is being tested in nude mice. The cells were also characterized with respect to BRAF mutations. We observed several similarities between the antigenic profile of the primary and established cell lines as well as some unique characteristics. We conclude that using a combination of defined antigens from primary tumor cells is useful in designing a pan-antigen immunotherapeutic vaccine. This melanoma pan antigen vaccine can be an effective tool in primary prevention of melanoma presumably having the highest clinical efficacy when combined with unique antigens from primary cells.
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 1569. doi:1538-7445.AM2012-1569
Abstract 1576: An oral therapeutic vaccine for colorectal cancer effectively eradicates intestinal tumors independently of target tumor-antigen specific immunities in APCMin/+ hCEA mice
Authors: Zhong Zhenyu , Zhai Yougang , Qiao Liang 
Published: August 2012

Abstract
Colorectal cancer is among the leading cause of cancer-related death in patients worldwide, and the requirement of an effective vaccine is urgent. Here, we designed a pseudovirus-based therapeutic vaccine for colorectal cancer, which is comprised of a plasmid encoding a colorectal tumor-associated antigen (human CEA) packaged inside the bovine papillomavirus like particles (VLP-CEA vaccine). Oral immunization of APCMin/+ hCEA mice (a mouse model of human colorectal cancer) with VLP-CEA vaccine greatly reduced the tumor number compared with those received PBS. More importantly, the APCMin/+ hCEA mice that received pseudovirus vaccine had dramatically enhanced survival rates than those only received PBS. Surprisingly, CEA-specific adaptive immunities are dispensible for tumor elimination as similar tumor number reductions are seen in the APCMin/+ or APCMin/+ hCEA mice that are immunized with either VLP-CEA or VLP-GFP (VLPs packaging a GFP-containing plasmid). Consistently, we found that CTL responses are not required for tumor eradication since depleting CD8 T cells prior to vaccinations didn't impair the vaccine efficacy. Finally, we found that VLP-CEA and VLP-GFP are both able to activate the inflammasome which might directly induce tumor cell death. Thus, our data indicate that independent of the target tumor-antigen specific adaptive immunity, our pseudovirus-based therapeutic vaccine for colorectal cancer effectively eliminates already established intestinal tumors in an animal model, and the understanding of the immune mechanism by which pseudovirus vaccines eradicate colorectal tumorigenesis will further our knowledge for designing vaccines for other 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 1576. doi:1538-7445.AM2012-1576
Abstract 158: Cyclopamine, an inhibitor of hedgehog signaling, induces monocytic differentiation of acute myelogenous leukemia cells
Authors: Bai Li-Yuan , Weng Jing-Ru , Chiu Chang-Fang , Lo Wen-Jyi , Lin Cheng-Wen 
Published: August 2012

Abstract
Introduction: Sonic hedgehog homolog (Shh) is known to play a critical role in normal cellular expansion and in the patterning of the early embryo of vertebrates and invertebrates, and is also implicated in some human cancers. While the sonic hedgehog homolog (Shh) pathway has been implicated in hematopoiesis and in maintenance of hematological malignancy, there is little evidence to demonstrate its importance to differentiation therapy. Procedures: We characterized the changes in HL-60 [an acute myelogenous leukemia (AML) cell line] after blocking the Shh pathway by an antagonist of Smoothened, cyclopamine. Findings: The existence of Shh signaling pathway in HL-60 cells was demonstrated by reverse transcription and PCR. Cyclopamine at 20 μM significantly down regulated the mRNA expression of Smo, Gli1 and Gli2. The flow cytometry showed that cyclopamine mediated apoptotic death of HL-60 cells in a dose- and time-dependent manner. After 12 h and 24 h, cyclopamine at 5 μM and 10 μM significantly increased the G0/G1-phase fraction of cells. Furthermore, treatment with cyclopamine increased the expression of monocytic cell markers CD 11b and CD 14, but the expression of CD 13, CD 33 and CD 38 was unchanged in HL-60 cells. The ability of cyclopamine to induce the monocytic differentiation of HL-60 cells was further evidenced by increased Egr-1 expression in a dose-dependent manner. Cyclopamine also down-regulated the phosphorylation of Akt and ERK, but activated AMPK signaling. We also analyzed the effect of cyclopamine on the primary leukemia cells from patients with AML. Conclusions: Blocking the Shh pathway via cyclopamine causes a time- and dose-dependent apoptotic cell death, increases the proportion of cells in G0/G1-phase and induces monocytic differentiation in HL-60 cells. Cyclopamine also down-regulates the mRNA expression of genes in Shh pathways. Further investigations are needed to determine the clinical application of modulating the Shh pathway in the treatment of hematological malignancies.
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 158. doi:1538-7445.AM2012-158
Abstract 1589: Isorhamnetin suppresses skin cancer through direct inhibition of MEK1 and PI3-K
Authors: Kim Jong-Eun , Lee Dong-Eun , Won Ki , Son Joe Eun , Seo Sang Kwon , Li Jixia , Kung Sung Keun , Heo Yong-Seok , Mottamal Madhusoodanan , Bode Ann M. , Dong Zigang , Lee Hyong Joo 
Published: August 2012

Abstract
Isorhamnetin is a plant flavonoid that is found in fruits and medicinal herbs and exerts anticancer effects. However, the underlying molecular mechanism of the chemopreventive potential of isorhamnetin remains unknown. Here, we report anti-skin cancer effects of isorhamnetin. In an in vivo mouse xenograft model injected with A431 human skin epithelial carcinoma cells, isorhamnetin reduced tumor growth and COX-2 expression. Isorhamnetin inhibited epidermal growth factor (EGF)-induced neoplastic cell transformation of JB6 mouse epidermis cells and anchorage-dependent and -independent growth of A431 cells. Isorhamnetin attenuated EGF-induced cyclooxygenase (COX)-2 expression in JB6 cells and A431 cells. The EGF-induced phosphorylation of extracellular signal-regulated kinases, p90 and p70 ribosomal S6 kinases, and Akt was suppressed by isorhamnetin. In vitro and ex vivo kinase assay data demonstrated that isorhamnetin inhibited the kinase activity of MEK1 and PI3-K and the inhibition was due to direct binding with isorhamnetin. Notably, isorhamnetin bound directly to MEK1 in an ATP-noncompetitive manner and to PI3-K in an ATP-competitive manner. Overall, these results indicate that isorhamnetin has potent anti-cancer activity and it primarily targets MEK and PI3-K, which might contribute to the chemopreventive potential of certain foods.
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 1589. doi:1538-7445.AM2012-1589
Abstract 1594: Chemopreventive action of Piper nigrum on cell proliferation and apoptosis in skin papillomagenesis and its influence on the levels/activity of enzymes associated with xenobiotic metabolism and antioxidant status in Swiss albino mice
Authors: Singh Manju 
Published: August 2012

Abstract
Piper nigrum a spice, has widely used in various systems of traditional medicine. Therefore, the present study was designed to investigate the chemopreventive potential of P. nigrum on cell proliferation, apoptosis in DMBA-induced skin papillomagenesis and its influence on the levels/activity of enzymes associated with xenobiotic metabolism and antioxidant status in mice. Two different doses (2 and 4%) of P. nigrum were given orally to the mice in the test diet at peri-initiational stage. DMBA and croton oil was used to induce and promote skin papillomagenesis respectively. For biochemical studies, mice were given with the same doses of P. nigrum in the test diet for two weeks. There was a significant reduction in (i) tumor burden to 3.0 and 2.4 (positive control: 6.4); (ii) tumor volume to 1.7 and 2.4 (positive control: 4.7); and (iii) tumor incidence 60 % and 50 %, respectively in case of 2 and 4% test diet treated animals relative control (100%). P. nigrum treatment resulted in upregulation of Bax with concomitant decrease in antiapoptotic protein Bcl-2 and PCNA in mouse skin tumors. P. nigrum showed a significant increase in the content/activities of phase I and phase II enzymes with the test diets. A significant enhancement in the activities of antioxidant enzymes were observed at 2 and 4% test diets of P. nigrum. Glyoxalase I activity and the content of reduced glutathione were significantly elevated. Expectedly, the activity of lactate dehydrogenase, exhibited a significant reduction at both the doses of test diets. The Chemopreventive effect of P. nigrum could be credited to its ability to inhibit cell proliferation and enhance apoptosis as well as to modulate phase I, phase II enzyme systems and also antioxidant status. The present findings may have some significance from the point of view of lowering the risk of cancer in human population.
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 1594. doi:1538-7445.AM2012-1594
Abstract 1632: Novel naproxen, resveratrol and sulforaphane (NRS) combinations demonstrate synergistic decrease in cell viability of human colon and pancreatic cancer cell lines
Authors: Grandhi B. Karthik , Thakkar Arvind , Prabhu Sunil 
Published: August 2012

Abstract
Gastrointestinal cancers, in particular colon and pancreatic cancer, account for almost 100,000 deaths each year in the United States, ranking third and fourth respectively, in the most common cause of cancer related deaths. Our lab has been focused on developing strategies for chemoprevention rather than treatment after diagnosis. For pancreatic cancer, the prognosis is usually poor with high mortality rates after diagnosis. Thus, the objective of this work was to study the effects of chemopreventive combination regimens of a non-steroidal anti-inflammatory drug (NSAID) naproxen (N), in combination with resveratrol (R, an antioxidant) and sulforaphane (S, a broccoli extract) on human colon (HT-29 and HCT-116) and pancreatic (MIA PaCa-2 and Panc-1) cancer cell lines. MTS cell proliferation assay was conducted on all cell lines. For the MTS assay, upon 75 % confluence, 100µL of 2.5X103 cells each of HT-29, HCT116 and MIA PaCa-2 and 4X10 3 cells Panc-1 cells were transferred into each well of 96-well plates. The NRS chemopreventive agents alone, or in combination, were added to the cells and incubated for 72 h. The plates were then incubated for 1-4 h at 37°C in a humidified, 5% CO2 atmosphere. Absorbance was recorded at 490 nm using an ELISA plate reader. For HT-29 and HCT 116 colon cancer cell lines, the combinations of naproxen (500µM/L) with resveratrol (50µM/L) and sulforaphane (5µM/L) showed reduction in cell viability of 56.74% and 52.9%, respectively. The IC50 values for NRS were 1.46 mM/L,104.54µM/L and 17.81µM/L respectively on HT-29 cell line. Similarly, for MIA PaCa-2 and Panc-1 pancreatic cancer cell lines, combinations of naproxen (500µM/L) with resveratrol (6µM/L) and sulforaphane (5µM/L) showed reduction in cell viability of 66.67% and 58.8% respectively. The IC50 values for NRS were 778µM/L, 74.8µM/L and 11.82µM/L respectively, on MIA Paca-2 cell line. When used individually, none of the chemopreventive agents at the above concentrations demonstrated any decrease in cell viability, however when combined together, a synergistic effect was observed. Our results demonstrate that NRS drug combinations at low concentrations exhibit significant decrease in cell proliferation in both human colon and pancreatic cancer cell lines. This data provides compelling evidence of the potential of these combination regimens for the chemoprevention of colon and pancreatic 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 1632. doi:1538-7445.AM2012-1632