bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5458: Identification of functional downstream gene of ABCB1 2677 G&gt;T/A polymorphism, LAMP-1, as a predictor gene to inhibitors of microtubule dynamics using integrative analysis of pharmacogenetics and genomics
Authors: Kwon Woo Sun 
Published: June 2012

Abstract
Objectives Overexpression of ABCB1 in cancers was first reported to encode a protein responsible for drug resistance. ABCB1 expression has been shown to be associated with single nucleotide polymorphisms.
Methods We studied chemosensitivity-related functionally downstream genes of ABCB1 non-synonymous 2677G&gt;T/A polymorphism using integrative genomics studies of ABCB1 (polymorphisms, expression profiling), chemo-sensitivity to various anticancer drugs, and functional association study of the selected gene.
Results The genes were identified based on the results of the significance analysis of microarray, and prediction accuracy was evaluated using the prediction analysis of microarray. Functional assay of the selected gene (LAMP1) was done by siRNA and drug accumulation. Association studies demonstrated correlations between 2677 genotypes and sensitivity to docetaxel, vincristine, and vinblastine. Based on the pharmacogenetic association of 2677 polymorphism, we performed expression profiling to select seven genes. Chemosensitivity was restored with LAMP1 siRNA by increased intracellular drug accumulation.
Conclusions We identified seven genes that predict the chemosensitivity to microtubule dynamics modulators using integrative pharmacogenetic genotyping and pharmacogenomic profiling assays. Biological validation of the role of the seven downstream genes of non-synonymous ABCB1 2677G&gt;T/A polymorphism, including the membrane function of LAMP1, and clinical validation of their predictivity are required for clinical application of these results.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5458. doi:10.1158/1538-7445.AM2011-5458
Abstract 5487: Anti-proliferative, apoptotic and immunological effects of ganoderic acid DM on prostate cancer cells
Authors: Haque Azizul , Johnson Benjamin M. , Doonan Bently P. , Hossain Azim , Radwan Faisal F. 
Published: June 2012

Abstract
Natural extracts have been the focus of recent investigation in the design of novel chemotherapeutics. One potential natural therapeutic agent is ganoderic acid DM (GA-DM), an extract from the Ganoderma lucidum mushroom previously shown to inhibit 5-α-reductase activity and prevent binding of dihydrotestosterone to the androgen receptor in prostate cancer cells. Studies in our laboratory used nonradioactive cell proliferation and cytotoxicity assays to investigate GA-DM's effect on both androgen dependent and independent prostate cancer cell lines, revealing dose dependent killing and inhibition of proliferation by this natural extract. Microscopic analysis using Hoechst staining showed DNA breakdown consisted with apoptosis in GA-DM-treated prostate cancer cells. Annexin V staining confirmed low levels of apoptotic cell death when treated with GA-DM. Western blotting and biochemical analysis revealed that GA-DM induced apoptotic cell death that was independent of caspase activation, cytochrome c release, and Bax induction. Further investigation showed that GA-DM treatment activated HLA protein expression, implying some immunological involvement contributing to GA-DM-induced cell death. This study outlines a novel mechanism of GA-DM-induced inhibition of proliferation, induction of apoptosis and immune components in both androgen dependent and independent prostate cancer cells, the implications of which support GA-DM's potential use in multimodal chemoimmunotherapeutics.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5487. doi:10.1158/1538-7445.AM2011-5487
Abstract 5489: An amiloride derivative capable of inducing ER stress and cell death in highly invasive breast cancer
Authors: Leon Leonardo J. , Harley William , Carraway Kermit , Gorin Fredric 
Published: June 2012

Abstract
Metastasis, which is the spread of tumors from their place of origin to other locations in the body via the lymph or blood, is associated with a significant increase in morbidity and mortality. Studies on amiloride, an FDA-approved diuretic, have shown it to suppress metastatic characteristics such as cell invasion and suppression, and impair their proliferation and viability. Here we show that 38B, a cell-permeant amiloride derivative, is more efficacious at causing cell death of cancer cells than amiloride. We also show that the cell death produced by 38B does not seem to be caused by apoptosis, autophagy, or calcium-dependent necrosis. However, bright field and immunofluorescence microscopy reveal vacuole formation and ER stress in cells, characteristics typically associated with a recently discovered type of cell death known as paraptosis. Since cancer cells have shown to be efficient at evading common forms of cell death such as apoptosis, the discovery of alternative pathways of cell death and a good understanding of the drugs that activate them can be can be key in the improvement of cancer therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5489. doi:10.1158/1538-7445.AM2011-5489
Abstract 5490: Mice deficient in uracil DNA glycosylase (UDG) display increased sensitivity to the antifolate pemetrexed
Authors: Weeks Lachelle D. , Liu Min , Liu Lili , Gerson Stanton L. 
Published: June 2012

Abstract
Pemetrexed, a multi-target antifolate, causes genomic uracil incorporation through inhibition of the enzymes thymidylate synthetase (TS) and dihydrofolate reductase (DHFR). Base excision repair (BER), initiated by uracil DNA glycosylase (UDG), actively recognizes and removes misincorporated uracil from the genome. Mice deficient in UDG have been described and display increased genomic uracil accumulation, elevated spontaneous mutation frequency, and higher incidence of B-cell lymphoma. We have previously reported the in vitro induction of UDG in H460 human lung cancer cells after pemetrexed exposure and have illustrated hypersensitivity to pemetrexed in human colon cancer cell lines lacking UDG expression (DLD1 UDG-/-). Here, we have investigated the role of UDG expression on pemetrexed sensitivity in vivo using gene-targeted UDG-/- mice. Mice received either a single 150mg/kg dose of pemetrexed on day 1 or received 3 consecutive 150 mg/kg doses of pemetrexed on days 1-3 and were sacrificed on day 4 or 5, respectively. Compared to UDG+/+ and UDG+/- littermates, UDG-/- mice were markedly myelosuppressed following pemetrexed treatment, as evidenced by a ∼50% reduction in bone marrow cell numbers and a ∼70% reduction in total colony forming units (CFU). Moreover, marrow from pemetrexed-treated UDG-/- mice expressed higher levels of DNA damage markers γ-H2AX and cleaved-PARP than control samples suggesting the formation of DNA double strand breaks and activation of apoptosis in UDG-/- marrow following pemetrexed exposure. Western blot analysis further evinced Chk-1 phosphorylation (p-Chk1, Ser345) in marrow from UDG-/- mice but not UDG+/+ or UDG+/- samples, suggesting inadequate removal of pemetrexed-induced genomic uracil may stall DNA replication and contribute to the cytotoxicity observed. These data in addition with our novel observations of enhanced pemetrexed sensitivity in UDG-/- mouse embryonic fibroblast (MEFs), UDG mutant human lymphoblastoid cell lines (LCLs), and DLD1 UDG-/- cells, strongly suggest that UDG deficiency potentiates pemetrexed cytotoxicity in in vitro as well as in in vivo models. Additionally, our findings indicate a role for genomic uracil accumulation in the mechanism of cytotoxicity for pemetrexed. Furthermore, our data illustrate a synthetic lethal interaction between TS/DHFR inhibition and UDG deficiency and promote UDG as a target for improving pemetrexed efficacy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5490. doi:10.1158/1538-7445.AM2011-5490
Abstract 5526: Epigenetic repolarization of T lymphocytes from chronic lymphocytic leukemia patients using 5-aza-2’-deoxycytidine
Authors: Dubovsky Jason A. , Powers John J. , Gao Yang , Mariusso Luis F. , Sotomayor Eduardo M. , Pinilla-Ibarz Javier A. 
Published: June 2012

Abstract
T cell immune dysfunction has an important role in the profound immunosupression that characterizes chronic lymphocytic leukemia (CLL). Improper polarization of T cells has been proposed as one of the mechanism involved. Mounting data implicates chromatin regulation, namely promoter methylation, in the plasticity of naïve human T cells. Recent in-vitro evidence indicates that this plasticity may be phenotypically altered by using methylation inhibitors which are approved for clinical use in certain types of cancer. These results beg the question: can the ineffective polarization of T lymphocytes in the context of CLL be effectively modulated using methylation inhibitors in a sustainable therapeutic fashion? To answer this question our laboratory has studied the effects of 5-aza-2’-deoxycytidine (5A2) in helper and cytotoxic T lymphocytes from healthy donors and CLL patients in well characterized molecular and epigenetic signaling pathways involved in effective polarization. Moreover, we sought to investigate the consequences of methylation inhibitor treatment on lymphocyte survival, activation intensity, and naïve cell polarization. Our data indicates that 5A2 treatment can repolarize Th2 cells to effectively secrete interferon gamma, signal via T-bet, and achieve demethylation of critical Th1 specific promoters. Moreover, we demonstrate that 5A2 can force Th1 polarization of naïve T cells despite a strong IL-4 stimuli and a lack of IL-12. In conclusion our data seeks to define a modality in which improper or ineffective T cell polarization can be altered by 5AZA and could be incorporated in future therapeutic interventions.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5526. doi:10.1158/1538-7445.AM2011-5526
Abstract 5529: Imaging and therapy with rituximab anti-CD20 immunotherapy in an animal model of central nervous system lymphoma
Authors: Muldoon Leslie L. , Lewin Seth J. , Dosa Edit , Pagel Michael A. , Doolittle Nancy D. , Neuwelt Edward A. 
Published: June 2012

Abstract
Purpose: To evaluate monoclonal antibody (mAb) delivery, tumor volumetrics on magnetic resonance imaging (MRI), and efficacy in a rat model of central nervous system (CNS) lymphoma when delivery of rituximab and/or methotrexate to the brain was optimized with osmotic blood-brain barrier disruption (BBBD).
Experimental Design: Female nude rats with intracerebral human MC116 B-cell lymphoma xenografts underwent baseline MRI and were randomized into five groups (n = 6/group): 1) BBBD saline control; 2) methotrexate with BBBD; 3) rituximab with BBBD; 4) rituximab and methotrexate with BBBD; and 5) intravenous rituximab. Tumor volumes were assessed by MRI at 1 week and rats were followed for survival.
Results: BBBD increased delivery of 90Y-radiolabeled mAb in the CNS lymphoma model. Control rats showed 201 +/- 102% increase in tumor volume on MRI 1 week after entering the study and median 14 day survival (range 6-33). Tumor growth on MRI was slowed in the methotrexate treatment group, but survival time (median 7 days, range 5-12) was not different from controls. Among 17 evaluable rats treated with rituximab, 10 showed decreased tumor volume on MRI. All rituximab groups had increased survival compared to control, with a combined median of 43 days (range 20-60, P&lt;0.001). There were no differences by route of delivery or combination with methotrexate.
Conclusions: Rituximab was effective at decreasing tumor volume and improving survival in a CNS lymphoma model, and was not affected by combination with methotrexate or by BBBD. We suggest that rituximab warrants further study in human primary CNS lymphoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5529. doi:10.1158/1538-7445.AM2011-5529
Abstract 553: Discovery of novel TRK/FMS dual inhibitors as therapeutic candidates for pancreatic cancer
Authors: Tsai James , Zhang Jiazhong , West Brian L. , Wong Bernice , Burton Betsy , Habets Gaston , Marimuthu Adhirai , Light Emily , Powell Ben , Shellooe Rafe , Carias Heidi , Shi Songyuan , Spevak Wayne , Nguyen Hoa , Tsang Garson , Zhang Ying , Ewing Todd , Zhang Chao , Ibrahim Prabha , Bollag Gideon 
Published: June 2012

Abstract
Pancreatic cancer is a deadly malignancy in need of effective treatments. The most common driving oncogenes in pancreatic cancer – KRAS, p53, SMAD4, CDKN2A and CTNNB1 – historically have been difficult drug targets to modulate pharmacologically. An alternative approach could be to target regulators of tumor-stroma interactions. Pancreatic cancer invasion into neural tissue precedes tumor expansion. This perineural invasion is strongly associated with neural hypertrophy, pain and poor survival, and neurotrophins and their receptors (TRKs) are key suspects in mediating this process. At the same time, infiltrating macrophages are an additional component of the tumor microenvironment that supports tumor growth, invasion and inflammation, and the receptor for CSF-1 (FMS) is a key mediator of the function and survival of these macrophages. Both TRKs and FMS are transmembrane proteins with tyrosine kinase activities that can be inhibited with small molecule agents.
We have developed a series of TRK/FMS dual inhibitors to target cancers that exhibit both neural and inflammatory components. These compounds inhibit biochemical TRK and FMS kinases with IC50&lt;20nM and inhibit the proliferation of BaF3 cells engineered to express active TRK and FMS with IC50&lt;50nM. In counterscreens across a broad kinase panel, these inhibitors are highly selective against non-target kinases. The lead compounds show good oral bioavailability in pharmacokinetic tests. Utilizing the engineered BaF3-TRK and BaF3-FMS cells injected into mice as pharmacology models, the lead candidates show growth inhibition of &gt;80% at doses of 20 mg/kg qd, and without body weight changes, showing that efficacy is not due to nonspecific toxicity. In a mouse Complete Freund's Adjuvant (CFA) model, robust efficacy was demonstrated in readouts of paw edema, thermal hyperalgesia and mechanical allodynia, showing that these compounds reduce swelling and pain. In the TRK-driven SK-N-SH xenograft model, tumor growth reduction of &gt;50% was observed. These compounds also showed anti-tumor efficacy of &gt;40% in an orthotopic Panc-1 (pancreatic cancer) model. Evaluation of compound effects on perineural invasion and inflammation is ongoing.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 553. doi:10.1158/1538-7445.AM2011-553
Abstract 5537: Ubiquitination of RRM1 by Ring1B (RNF2) promotes its degradation and nuclear export
Authors: Zhang Yingtao , Li Xin , Chen Zhengming , Freeman Scott , Zhou Jun , Bepler Gerold 
Published: June 2012

Abstract
RRM1 (ribonucleotide reductase M1) is a key enzyme involved in deoxyribonucleotide (dNTP) synthesis and DNA damage repair. It also plays a critical role in acquired resistance to the chemotherapy drug gemcitabine, which directly inhibits the RR holoenzyme. Despite its significant importance, however, the mechanisms that control RRM1 abundance and subcellular localization are unclear. We have identified a ubiquitin E3 ligase, Ring1B (RNF2), as an RRM1-associated protein in a yeast two-hybrid screen. RRM1 interacts with Ring1B both in endogenous and exogenous situations. Additionally, immunofluorescent staining has shown that Ring1B clearly co-localized with RRM1 in a pattern of diffuse nuclear speckles. We found that the protein level of RRM1 is regulated by a proteasome-mediated degradation pathway. Ring1B induces poly-ubiquitination of RRM1 in vivo. Formation of poly-ubiquitin chains on RRM1 is through both Lys48 (K48) and Lys63 (K63) of the ubiquitin. Our study demonstrates that the cytoplasmic fraction of RRM1 was increased upon Ring1B or ubiquitin overexpression, but significantly decreased after nuclear export inhibition by leptomycin B (LMB). This indicates that RRM1 ubiquitination promotes the translocation of RRM1 from the nucleus to the cytoplasm. We also show that hydrogen peroxide (H2O2) promotes the degradation of RRM1 in dose and time-dependent manners. H2O2 can increase the poly-ubiquitination of RRM1, which suggests that RRM1 ubiquitination may participate in cellular responses to oxidative stress-induced DNA damage repair. In summary, our data propose that Ring1B-induced ubiquitination regulates RRM1 activity through RRM1 degradation and nuclear export.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5537. doi:10.1158/1538-7445.AM2011-5537
Abstract 5541: The dual effects of H6D polymorphism of NAG-1/GDF15 in prostate cancer carcinogenesis
Authors: Wang Xingya , Xu Zongli , Chrysovergis Kali , Bienstock Rachelle , Shim Minsub , Bensen Jeannette T. , Fontham Elizabeth , Smith Gary J. , Mohler James , Taylor Jack , Eling Thomas E. 
Published: June 2012

Abstract
Nonsteroidal anti-inflammatory drug-activated gene (NAG-1) is a divergent member of the transforming growth factor beta superfamily. NAG-1 has been implicated in many cellular processes, including inflammation, early bone formation, apoptosis, and tumorigenesis, in several types of cancers. Evidence from recent clinical studies suggests that a C to G single nucleotide polymorphism at position 6 (histidine to aspartic acid substitution, or H6D (G) of the NAG-1 protein is associated with lower incidence, but higher rate of mortality, of prostate cancer. The objective of the current study was to determine the activity of the NAG-1 H6D variant in prostate cancer using two different approaches. First, DU145 cells stably transfected with the H6D NAG-1 gene, wild-type NAG-1 gene, and empty pLXIN vector were injected into nude mice subcutaneously and tumor growth monitored for eight weeks. The H6D variant was less tumorigenic than the wild-type NAG-1, and significantly inhibited tumor growth, 67% by volume and 59% by tumor weight compared to control mice. The growth inhibition by the H6D variant of NAG-1 was associated with significant reduction of serum levels of adiponectin, leptin, and IGF-1, and expression of Cyclin D1 in tumor samples. Second, we examined whether the sequence variant in the NAG-1 gene was associated with prostate cancer tumor aggressiveness in blood samples from the North Carolina-Louisiana Prostate Cancer Project (PCaP). A total of 449 Caucasians Americans and 413 African Americans were examined for allele frequencies using Taqman SNP genotyping assay. Although statistically insignificant, African Americans carrying the H6D (G) allele had an increased risk of more aggressive prostate cancer than those carrying two copies of the C allele (Odds ratio, 1.63; 95% CI, 0.903-2.95; P = 0.25). This result may help to explain the higher mortality rate of prostate cancer in African Americans. In conclusion, our data suggest that the H6D polymorphism of NAG-1 may have a dual effect during the early and late stages of prostate cancer carcinogenesis. More studies are needed to further examine the association of H6D variant of NAG-1 with prostate cancer incidence and progression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5541. doi:10.1158/1538-7445.AM2011-5541
Abstract 5546: Screening the RbBP6 gene for abnormal alternative splicing in colon cancer
Authors: Dlamini Zodwa , Mbita Zukile 
Published: June 2012

Abstract
Cancer arises after a series of mutations that result in uncontrolled cellular differentiation and growth. These result because the genes required for normal cell growth and apoptotic processes are abnormally regulated and thus the progression of cancer and survival is favoured. The RbBP6 gene is amongst the genes which are down-regulated in cancerous cells. RbBP6 is a gene that has been shown to regulate cell cycle control and apoptosis. RbBP6 isoform 3 has been shown to regulate G2/M cell cycle checkpoint while the alternatively spliced RbBP6 transcript 1 product has been implicated in apoptosis regulation and cancer. Expression and regulation of the gene in colon cancer was examined by amplifying cDNA of RNA extracted from three colon adenocarcinoma cell lines obtained from different stages of colon cancer, using RT-PCR with the RbBP6 exon 16 primers and confirmation of the 2 splice variants by NCBI BLAST. Two bands appeared on a 1% Agarose gel, the ratio of the intensity of the two bands was found to be 1:1 in the primary cell line compared to down-regulation in grade II cell line while these alternatively spliced products could hardly be amplified in grade III cell line. RbBP6 has two splice isoforms which are regulated by alternative splicing in colon cancer. The expression of these splice variants was found to be indirectly proportional to colon cancer progression. The primary colon cancer cell line showed more expression of these alternatively spliced products, which decreased significantly in grade II and III. This suggests that RbBP6 alternatively spliced products could be anti-carcinogenic but are de-regulated in favour of carcinogenesis and this further suggests that RbBP6 gene might be somehow involved in the development and progression of colon adenocarcinoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5546. doi:10.1158/1538-7445.AM2011-5546