bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-379: IL-4 induces cathepsin protease activity in tumor-associated macrophages to promote cancer growth and invasion
Authors: Gocheva Vasilena , Wang Hao-Wei , Gadea Bedrick , Shree Tanaya , Hunter Karen , Garfall Alfred , Joyce Johanna A. 
Published: February 2011

Abstract
Innate immune cells can constitute a substantial proportion of the cells within the tumor microenvironment and have been associated with tumor malignancy in patients and animal models of cancer; however, the mechanisms by which they modulate cancer progression are incompletely understood. Here, we show that high levels of cathepsin protease activity are induced in the majority of macrophages in the microenvironment of pancreatic islet cancers, mammary tumors and lung metastases during malignant progression. We further show that tumor-associated macrophage (TAM)-supplied cathepsins B and S are critical for promoting pancreatic tumor growth, angiogenesis and invasion in vivo, and markedly enhance the invasiveness of cancer cells in culture. Finally, we demonstrate that interleukin (IL)-4 is responsible for inducing cathepsin activity in macrophages in vitro and in vivo. Together, these data establish IL-4 as an important regulator, and cathepsin proteases as critical mediators, of the cancer-promoting functions of TAMs.
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 LB-379.
Abstract LB-383: In vitro and in vivo MRI evaluation of a novel metallofullerene nanoparticle
Authors: Adiseshaiah Pavan P. , Stern Stephen T. , Ileva Lilia , Lenk Robert , Macfarland Darren , Kepley Chris L. , McNeil Scott E. 
Published: February 2011

Abstract
Some disadvantages of conventional small molecule contrast agents, such as Magnevist® (Gd - DTPA), are that they extravasate rapidly and are quickly eliminated from blood, limiting the viable MRI time. Macromolecular magnetic resonance imaging (MRI) contrast agents, on the other hand, are useful blood-pool agents and have found application in monitoring tumor vasculature and angiogenesis. There is an urgent need for new MRI contrast agents with higher relaxivity and longer blood half-life. Here, we report in vitro and in vivo characterization of a water-soluble derivatized fullerene nanoparticle contrast agent (NCL124) in comparison to the market standard, Magnevist. In comparison to Magnevist, NCL124 had higher R1and R2 relaxivities in human plasma at 22° C and 37°C. In vivo MRI imaging was performed on a LS174T dual-flank xenografts following a single intravenous injection of NCL 124 or Magnevist contrast agent (0.2 mmol Gd/Kg) using a 3.0 Tesla clinical whole-body MRI. Based on the relaxivity-time profiles, the Vss for NCL124 was similar to that of albumin (∼ 100 mL/Kg), suggesting high protein binding, while the Vss of Magnevist was similar to that of extracellular tissue water (∼200 mL/Kg), as expected for an extracellular diffusible tracer. NCL124 also had a longer blood half-life (∼ 100 min) than Magnevist (19 min). Taken together, the higher concentration (Cmax) and exposure (AUCall) of NCL124 in the blood, coupled with slow elimination, supports the use of NCL124 as a blood-pool contrast agent. Intriguingly, the half-life of NCL124 varied by tumor size, while Magnevist showed similar half-life in both tumors. This suggests NCL124 may have significant utility in predicting differences in tumor vascular and lymphatic permeability, and potentially be useful as a marker for antiangiogenic therapy. Funded by NCI contract # HHSN261200800001E.
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 LB-383.
Abstract LB-384: Targeting overexpressed Aurora kinases in childhood medulloblastoma: Antiproliferative effects of small molecule inhibitors ZM44739, VX680 and shRNA
Authors: Holst Martin I. , Westerhout Ellen , Kool Marcel , Versteeg Rogier , Caron Huib , Clifford Steve , Rutkowski Stefan , Pietsch Torsten 
Published: February 2011

Abstract
Kids Cancer Kinome (KCK) is a European research project investigating aggressive childhood cancers. Focusing on the human protein kinase family nine research centers explore different highly malignant pediatric tumors (medulloblastoma, Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, neuroblastoma, ALL) to validate novel drug targets and develop novel therapeutic options.
Medulloblastomas of the cerebellum represent the most frequent malignant brain tumors of childhood. Previous studies revealed Aurora kinase A (STK15) as independent predictor for an unfavorable outcome of medulloblastoma patients. The Aurora kinases belong to the family of serine/threonine kinases which are involved in the cell cycle by controlling chromatid segregation. It is commonly approved, that defects in the process of cell division are associated with tumorigenesis.
Using mRNA expression profiling (Affymetrix) we compared the Aurora kinase mRNA expression of 62 medulloblastoma tumor samples with normal cerebellar tissue (n=9) and an extensive dataset of various other tumor types (n=2028). We discovered a significant overexpression of Aurora kinase mRNA in primary medulloblastoma tumors, as well as 14 medulloblastoma cell lines compared to non-neoplastic tissues (n=685). Kaplan-Meier scans revealed an inverse correlation between overall survival rates and mRNA expression levels of Aurora kinases.
To investigate the effects of Aurora kinase inhibition on medulloblastoma cells, we first evaluated the effects of the small molecule inhibitors ZM447439 andVX680 on the proliferation of medulloblastoma cell lines. Incubation of medulloblastoma cells with ZM447439 and VX680 for 72h resulted in a concentration dependent decrease of the proliferative activity as measured by MTS proliferation assays. The GI50 for ZM447439 ranged from 0.2 to 20 µm and for VX680 from 0.02 to 10.0 µm. Cytologically, the cells appeared enlarged and multinucleated after Aurora kinase inhibition. In a second approach, we transduced cell lines with lentiviral particles carrying shRNA targeting Aurora A and B kinase. The specific downregulation of the Aurora kinases with lentiviral shRNA was confirmed by Western blotting and had a negative effect on the viability of the medulloblastoma cells. In conclusion, these data suggest that the inhibition of Aurora kinases may represent a promising approach for novel targeted strategies for the treatment of medulloblastoma.
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 LB-384.
Abstract LB-385: The Hippo pathway component YAP1 promotes cerebellar precursor survival after irradiation and can accelerate medulloblastoma onset
Authors: Fernandez-L Africa , Squatrito Massimo , Kenney Anna M. 
Published: February 2011

Abstract
Medulloblastoma is the most common malignant solid tumor in children. These tumors arise in the developing cerebellum, a region of the brain that undergoes rapid expansion after birth. Current treatments for medulloblastoma include radiation, surgery and chemotherapy, all of which are associated with devastating physical and mental side effects in long-term survivors. Recently, cells within medulloblastomas that survive radiation treatment and can repopulate the tumors post-radiation have been identified. These cells reside in regions adjacent to blood vessels, and their post-radiation survival is promoted by PI3 kinase pathway activity. Ideal medulloblastoma therapies will attack the tumors and eliminate the tumor re-initiating cells but spare the rest of the brain. We have recently published that the oncogenic transcriptional co-activator YAP1, which is negatively regulated by the Hippo pathway, is up regulated and amplified in a subset of human medulloblastomas with aberrant Sonic hedgehog (Shh) signaling. YAP1 is found in cells of the perivascular niche, where proposed tumor-repopulating cells reside. Post-irradiation, YAP1 was found in newly-growing tumor cells. We report here that YAP1 is actively involved in survival post-irradiation. CGNPs that over-express YAP1 in vitro proliferate more and present less apoptosis after irradiation than those over-expressing GFP. Among YAP1 target genes in CGNPs we found Securin, which, apart from its known role in mitosis, it has been shown to have roles in survival after DNA damage. We also found Securin highly expressed in human and mouse medulloblastomas. Moreover, injection of YAP 1 over-expressing medulloblastoma cells in postnatal day 4 wild type mice accelerate medulloblastoma onset compared to GFP over-expressing cells. These findings implicate YAP1 as a new Shh effector that may be targeted by medulloblastoma therapies aimed at eliminating medulloblastoma recurrence.
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 LB-385.
Abstract LB-400: Conventional and anti-microbial pesticide exposures and increased risk of lung cancer in Mexican Americans
Authors: McHugh Michelle K , Kachroo Sumesh , Liu Mei , D'Amelio Anthony M. , Dong Qiong , Greisinger Anthony , Hong Waun Ki , Spitz Margaret R. , Etzel Carol J. 
Published: February 2011

Abstract
Objective: We investigated demographic factors, environmental and occupational exposures, and medical and family cancer histories in a population of Mexican-American lung cancer cases and controls from the Houston Metropolitan area.
Methods: Data were collected as a part of a multi-racial/ethnic on-going lung cancer case-control study. Cases included 212 Mexican American lung cancer cases. Controls (n=328) were recruited from Houston's largest multispecialty group practice and frequency matched to the cases by age (±5 years), sex and ethnicity. Odds ratios and 95% confidence intervals were calculated using logistic regression analysis. Environmental and occupational factors were analyzed individually; however pesticides were analyzed as: 1) any exposure to conventional or antimicrobial pesticides; 2) exposure to conventional pesticides only; and 3) exposure to antimicrobial pesticides only.
Results: We detected elevated risks of lung cancer associated with asbestos, wood dust, fibers, SVF, benzene, toluene/xylene, dry cleaning fluids, vehicle exhaust, glues and plastics; however only pesticide exposure was statistically significant. We found both conventional and anti-microbial pesticide exposures were associated with an increased risk of lung cancer in Mexican Americans (conventional pesticides and antimicrobial pesticides combined: OR=1.80, 95%CI 1.13-2.86; conventional pesticides: OR=2.05, 95% CI 1.23-2.39; and anti-microbial pesticides: OR=2.48, 95% CI 1.46-4.21).
Conclusions: Although we found over a two-fold increased risk of lung cancer among Mexican Americans for conventional and anti-microbial pesticides, we were not able to identify individual pesticides. Our findings are descriptive in nature and we believe are a necessary and important preliminary step in identifying factors that are specifically associated with lung cancer risk among this minority subgroup.
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 LB-400.
Abstract LB-410: A single nucleotide polymorphism in human PIGK gene associates with low PIGK expression in colorectal cancer patients
Authors: Dasgupta Santanu , Fu Yumei , Nissan Aviram , Halle David , Sidransky David , Trink Barry 
Published: February 2011

Abstract
Colorectal cancer (CRC) has one of the highest incidences of cancers worldwide and is the fourth most common cancer among men and women in the United States. In Israel, approximately 3000 new CRC cases are being diagnosed annually, representing 13% of all new cases. CRC ranks second in the total number of cancer cases both in the Jewish male and female population. It is uncommon in the non-Jewish (Arab) population.
Phosphatidylinositol glycan, class K (PIGK) is an integral member of the Glycosylphosphatidylinositol transamidase (GPIT) protein complex that attaches a diverse group of macromolecules to the plasma membrane of eukaryotes. It is well established that PIGK catalyzes the endoproteolysis and amidation steps involved in transfer of a GPI-anchor to proteins. However, the role of PIGK in tumorigenesis remains largely unknown. Recently, we found a markedly low expression of PIGK protein in some colorectal cancer (CRC) patients. In order to understand the mechanism behind, we examined all the 10 exons of the PIGK gene by DNA sequencing and genotyping in 20 CRC patients from Israel (16 Jews and 4 Arabs). Corresponding expression of the PIGK protein was also determined by immunohistochemistry in all the above CRC patients. We found a single nucleotide polymorphism (C/C C/G or G/G; rs1048575) in the 3′UTR of the PIGK gene in 65% (13/20) of the CRC patients. Most of the patients with the altered genotype were Jews (12 vs. 1). Three out of four Arab patients (75%) exhibited the ancestral C/C genotype. We also observed a significantly low (P&lt;0.002) expression of PIGK protein in all the patients with the altered allele (C/G or G/G) compared to the ancestral alleles (C/C). Similar observation was made on PIGK expression in a couple of transformed human colon cell lines with the ancestral (C/C) and altered (/C/G) genotype. Our results demonstrate for the first time a link between the SNP-1048575 and low PIGK expression in CRC patients and also suggest a possible association between altered PIGK expression and CRC susceptibility.
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 LB-410.
Abstract LB-411: Genotype and haplotype analysis of cell cycle genes and the risks of sporadic colorectal and pancreatic cancers in the Czech Republic
Authors: Vodicka Pavel E. , Naccarati Alessio , Pardini Barbara , Polakova Veronika , Smerhovsky Zdenek , Vodickova Ludmila 
Published: February 2011

Abstract
The Czech Republic has one of the highest incidences of colorectal cancer (CRC) in the world. Pancreatic carcinoma represents the fourth leading cause of cancer-related deaths in the country, with a minimum of patients surviving 5 years. The etiology and molecular pathogenesis of above cancers are weakly understood. TP53 plays a role in cell cycle and apoptosis and is frequently mutated in solid tumors, including colorectal and pancreatic. Assuming that genetic variation may affect susceptibility to cancer development, the role of polymorphisms and haplotypes of TP53, CDKN1A and CDKN2A in modulating the cancer risk was addressed.
We investigated selected polymorphisms in TP53 (rs17878362:A1&gt;A2, rs1042522:G&gt;C, rs12947788:C&gt;T, and rs17884306:G&gt;A), CDKN1A (rs1801270:C&gt;A and rs1059234:C&gt;T), and CDKN2A (rs3731249:G&gt;A, rs11515:C&gt;G, and rs3088440:C&gt;T) genes in 614 hospital-based cases and 614 matched controls from the country for association with colorectal cancer and 240 cases and controls (for a total of 1827 individuals) for association with pancreatic cancer risk.
For CRC, none of the studied polymorphisms was strongly associated with risk. We observed differential distribution of major haplotypes arising from four polymorphisms in the TP53 gene between cases and controls (global P&lt;0.0001). In comparison to the most common haplotype (A1GCG), the haplotype A2CCG was associated with an increased risk (OR 1.40, 95% CI 1.07-1.82), while four other less frequent haplotypes A1CCG, A2GCG A1GTG, and A1GCA were associated with a decreased risk. The effect of haplotypes in the TP53 gene was similar in colon and rectal cancers. No association with the disease was observed with haplotypes of the CDKN1A and CDKN2A polymorphisms. For pancreatic cancer: carriers of the variant C allele of rs1042522 polymorphism were at an increased risk of (OR 1.73; 95% CI 1.26-2.39; p=0.001). The A2CCG haplotype in comparison with the most common haplotype (A1GCG) was associated with an increased risk (OR 1.39; 95% CI 1.02-1.88; p=0.034), and the A1CCG with a reduced risk (OR 0.30; 95% CI 0.12 -0.76; p=0.011) for this cancer. Genetic variation in TP53 may contribute, alone or in concert with other risk factors, to modify the inherited susceptibility to both colorectal and pancreatic cancers, as well as to other gastrointestinal cancers.
Supported by GACR 310/07/1430.
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 LB-411.
Abstract LB-414: Variation in base excision repair genes and risk of smoking-related non-small cell lung cancer
Authors: Brenda Diergaarde , Buch Shama , Nukui Tomoko , Day Roger , Siegfried Jill , Weissfeld Joel , Romkes Marjorie 
Published: February 2011

Abstract
Base excision repair (BER) is the primary mechanism responsible for the repair of small base lesions in DNA caused by oxidation and alkylation. Given this role, functionally relevant polymorphisms in BER pathway genes may well affect the risk of smoking-related non-small cell lung cancer (NSCLC). We examined the association between 49 single nucleotide polymorphisms (SNPs) located in or near 5 different BER genes (XRCC1, LIG1, PARP1, MPG, and OGG1) and risk of NSCLC among Caucasians in a large case-control study. The study population consisted of 599 cases and 934 controls; all study participants were Caucasian and current or former cigarette smokers who had smoked at least 10.0 pack-years. SNPs were selected using various resources including literature review and data from the International HapMap project, and genotyping was conducted by Illumina Goldengate assay. Deviation from Hardy-Weinberg equilibrium was evaluated with the exact method. Associations between alleles and genotypes and NSCLC risk were examined using a Pearson Chi-square test and a Cochran-Armitage trend test, respectively. Per (minor) allele odds ratios (OR) and corresponding 95% confidence intervals (95% CI) were also calculated for each SNP. Six SNPs (rs3219073, rs747658, rs3219090, rs2048424, rs2666428, and rs8679) in PARP1 were statistically significantly (P&lt;0.01) associated with NSCLC risk in our study population. SNP rs3219073 was in high linkage disequilibrium (r2≥0.8) with rs747658, as were rs3219090 and rs2048424 with rs2666428. The minor alleles of these SNPs were associated with a decreased risk of developing NSCLC (rs747658, OR: 0.7, 95%CI: 0.6-0.9, Ptrend=0.0005; rs2666428, OR: 0.8, 95%CI: 0.7-0.9, Ptrend =0.005). The C allele of SNP rs8679 (3′ UTR) was associated with an increased risk of NSCLC (OR: 1.3, 95%CI: 1.1-1.5, Ptrend =0.005). Additionally, SNPs rs3213255 and rs1799782 (Arg194Trp) in XRCC1 and SNP rs10500298 in LIG1 were also significantly associated with NSCLC risk. The minor alleles of rs3213255 and rs10500298 were associated with an increased risk (OR: 1.3, 95%CI: 1.1-1.5; OR: 1.2, 95%CI: 1.1-1.4, respectively), while the minor allele of rs1799782 was associated with a decreased risk (OR: 0.6, 95%CI: 0.4-0.9). PARP1 polymorphisms have previously been reported associated with other cancers, including breast cancer and colorectal cancer, but this is the first study to report associations with NSCLC risk. To conclude, our results suggest that common variation in PARP1, XRCC1 and LIG1 may be associated with risk of smoking-related NSCLC.
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 LB-414.
Abstract LB-42: PDK1 knockdown selectively inhibits growth of cancer cells harboring activating mutations involved in MAPK signaling
Authors: DeYoung M. Phillip , Gardiner Christine M. , Chadderton Antony R. , Medina Jesus R. , Axten Jeffrey M. , Rabindran Sridhar K. 
Published: February 2011

Abstract
Phosphoinositide-dependent protein kinase-1 (PDK1) is a master regulator of the AGC family of kinases and an integral component of the PI3K/AKT/mTOR pathway which is the most commonly deregulated signaling pathway across all cancers. Increased PDK1 activity confers chemoresistance in tumor cell lines, and reduced PDK1 expression prevents the onset of tumorigenesis in mouse models. To demonstrate that PDK1 is a promising target for cancer therapy, we used a siRNA-based approach to determine the effects of PDK1 knockdown in cancer cells and primary early-passage normal cells. Loss of PDK1 protein caused a significant reduction in phosphorylation of two PDK1 substrates, AKT (T308) and RSK1 (S221). Interestingly, knockdown of PDK1 protein had preferential growth inhibitory effects in cancer cells containing activating mutations of KRAS or BRAF, compared to cells with wild-type KRAS or BRAF. In KRAS/BRAF-mutant cells, apoptosis was evidenced by PARP-1 cleavage and an increase in the number of sub-G1 DNA content. Overexpression of mouse PDK1 rescued these cells from apoptosis, confirming the specificity of the siRNA-mediated effects. Consistent with these observations, stable expression of mutant KRAS (G12V) in NL-20 immortalized normal lung epithelial cells sensitized these cells to apoptosis upon knockdown of the PDK1 protein. Importantly, overexpression of a kinase-dead mouse PDK1 mutant did not rescue cells from apoptosis, suggesting that the kinase activity is required for these PDK1 functions. Based on these results, we sought to identify inhibitors of the kinase activity of PDK1 for development as anticancer agents. GSK2334470 was identified as a potent inhibitor of PDK1 kinase (IC50 0.5 nmol/l) that demonstrated a high level of specificity to PDK1 in an in vitro kinase panel. In cell-based mechanistic assays, GSK2334470 effectively inhibited phosphorylation of the PDK1-dependent phosphorylation sites [AKT T308 (IC50: 100 nmol/L) and RSK S221 (IC50: 291 nmol/L)], but not the PDK1-independent phosphorylation site on AKT, S473 (IC50: &gt;30 umol/L). Antiproliferative effects were seen in several cell lines using low micromolar concentrations of inhibitor; however, no correlation between growth inhibition and KRAS/BRAF mutations was observed. Further optimization may be necessary for improved potency and KRAS/BRAF selectivity. Currently, efforts are underway to better understand the disconnect between siRNA data and compound data in several experimental cancer models, particularly in those where KRAS or BRAF mutations predominate.
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 LB-42.