bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-10: Defective nucleolar localization and dominant interfering properties of a parafibromin L95P missense mutant causing the hyperparathyroidism-jaw tumor syndrome
Authors: Jacob Leelamma P. , Zhang Jian Hua , Dagur Pradeep K. , Simonds William F. 
Published: February 2011

Abstract
The hyperparathyroidism-jaw tumor syndrome (HPT-JT) is a familial cancer syndrome that results from germline loss-of-function mutation of HRPT2/CDC73, a putative tumor suppressor gene that encodes parafibromin, a component of the transcriptional regulatory PAF1 complex with homology to the yeast protein Cdc73p. The vast majority of HRPT2/CDC73 germline mutations identified have been truncation or frameshift mutations, and loss-of-function due to missense mutation is rare. We report here a kindred with HPT-JT due to a germline L95P missense mutation in parafibromin. The mutant parafibromin was studied in vitro to understand the basis of its presumed loss-of-function. When transfected in cultured cells the L95P mutant was expressed to a lower level than wild-type parafibromin, a difference that was not overcome by inhibition of the proteasome degradation pathway. The L95P mutant parafibromin retained the ability to assemble with endogenous PAF1 complex components as evidenced by co-immunoprecipitation. Analysis of subcellular localization showed that the L95P mutant was markedly deficient in nucleolar localization compared to the wild-type, an impairment likely resulting from disruption of a nucleolar localization signal immediately upstream of the L95P mutation. Transfection of the L95P parafibromin mutant, but not the wild type, increased HEK 293 cell survival and stimulated cell-cycle progression in NIH-3T3 cells, properties that appear to result from dominant interference with endogenous parafibromin signaling pathways. The simultaneous loss of nucleolar localization and acquisition of a growth stimulatory phenotype with the L95P mutation raise the possibility that parafibromin must interact with targets in the nucleolus to fully execute its tumor suppressor functions.
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-10.
Abstract LB-102: The p21Cip1/Waf1 cyclin-dependent kinase inhibitor is required for the activation of the FA-BRCA pathway
Authors: Rego Meghan A. , Mauro Maurizio , Harney Julie A. , Shen Mae , Kolling Frederick W. , Howlett Niall G. 
Published: February 2011

Abstract
Fanconi anemia (FA) is a rare recessive disorder characterized in part by pronounced cancer susceptibility. The FA proteins, and the protein products of the major breast cancer susceptibility genes BRCA1 and BRCA2, function cooperatively in the FA-BRCA pathway, to repair damaged DNA and to prevent cellular transformation. A major step in the activation of the FA-BRCA pathway is the mono-ubiquitination of the FANCD2 and FANCI proteins, targeting these proteins to discrete chromatin-associated nuclear foci. Importantly, the regulation of FANCD2 (and FANCI) mono-ubiquitination remains poorly understood. To gain further insight into this important post-translational modification step, here we have examined the roles of p53 tumor suppressor as well its downstream target p21Cip1/Waf1 in the regulation of the mono-ubiquitination of FANCD2.
In this study we have used the isogenic HCT116 p53+/+, p53−/−, p21+/+, and p21−/− cell lines, to determine that p21, and not p53, plays a key role in the regulation of the mono-ubiquitination of FANCD2 following exposure to DNA damaging agents. For example, robust FANCD2 mono-ubiquitination is observed in HCT116 p21+/+ cells 2 h following exposure to 20 J/m2 UV irradiation, while this effect is markedly attenuated in p21−/− cells. Using immunofluorescence microscopy we also demonstrate that p21 is necessary for the efficient recruitment of FANCD2 to nuclear foci following exposure to UV irradiation. Furthermore, preliminary protein-protein interaction analyses in COS-7 cells demonstrate that FLAG-p21 and 6xHis/V5-FANCD2 physically interact.
Interestingly, despite a failure to efficiently activate the mono-ubiquitination of FANCD2 following exposure to DNA damaging agents, p21−/− cells are not hypersensitive to the cytotoxic effects of the DNA crosslinking agent mitomycin C (MMC). However, elevated levels of distinct chromosome aberrations, including telomere associations and dicentric chromosomes, are observed in p21−/− cells compared with p21+/+ cells following exposure to MMC. Taken together, our results demonstrate an important upstream role for the p21 cyclin-dependent-kinase inhibitor in the activation of the FA-BRCA pathway. A greater understanding of the regulation of this important tumor suppressor pathway will lead to improved diagnostic and therapeutic approaches to FA and enhance our understanding of the elevated cancer susceptibility of FA patients.
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-102.
Abstract LB-113: PKC-iota induces uncontrolled glioblastoma cell survival by modulating proapoptotic function of Bad
Authors: Desai Shraddha , Acevedo-Duncan Mildred 
Published: February 2011

Abstract
Brain tumors are a major challenge since they destroy the most important part of the human body. The aggressive and infiltrative behavior is a hallmark of glioblastoma multiforme which makes it highly incurable. PKC-iota is reported to be highly expressed in transformed phenotype of human glioma, benign and malignant meningiomas (Cell Prolif. 41:122-35, 2008) but the signaling mechanism by which PKC-iota induces glioma cell survival remains elusive. Hence, in the current study, we investigated whether PKC-iota phosphorylates and de-activates Bad, a pro-apoptotic BH3-only molecule of the Bcl-2 family. Our results demonstrated that PKC-iota co-localizes as well as directly associates and phosphorylates Bad at Ser-112, Ser-136 and Ser-155. In addition, recombinant PKC-iota induced direct phosphorylation of exogenous as well as endogenous Bad at all three serine residues as shown by in-vitro kinase assay. Recombinant PKC-zeta (is 70% homologous to PKC-iota) and PKC-delta (known to regulate the activity of Bad in rat cardiac myocytes; Mol Cells. 24:224-231, 2007) in contrast phosphorylated Bad only at Ser-112 residue in in-vitro kinase assays. Reduction of PKC-iota upon RNA interference exhibited a corresponding reduction in Bad phosphorylation at these three sites. Conversely, inhibition of PKC-zeta and delta by their corresponding siRNA did not lead to reduction of Bad phosphorylation. Additionally, disruption of Bad/Bcl-XL heterodimerization was not observed in either of the RNA silenced samples. Thus, our data strongly supports the hypothesis that PKC-iota may function as a Bad kinase directly inhibiting its pro-apoptotic function and impeding the normal homeostasis of glioma cells thereby enhancing prolonged survival of glioma cells.
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-113.
Abstract LB-117: A novel tween-80 free, water soluble formulation of docetaxel for cancer treatment
Authors: Tan Lily , Qiao Hongqun 
Published: February 2011

Abstract
Docetaxel is a semi-synthetic anticancer drug in the taxane family. It is a potent treatment for a wide range of tumors. The approved indications include breast cancer, NSCL cancer, ovarian cancer, and prostate cancer. The current docetaxel application, Taxotere, uses tween-80 and ethanol as solvents and has shown undesirable adverse effects, including hypersensitivity from the active as well as inactive ingredients.
Captisol (sulfobutylether cyclodextrin) is a modified cyclodextrin that has been used to improve drugs’ water solubility for parental use, such as in Pfizer's Vfend IV and Geodone IM.
In this paper, we introduce ML-061, an improved water soluble formulation of lyophilized docetaxel with captisol using patented technology. While the efficacy of ML-061 is similar to taxotere at the equivalent dose, a vastly better safety profile has been shown for the new formulation. ML-061 showed no detectable hemolytic activities in a study in Beagle dogs compared to the placebo group, no hypersensitivity effect on blood pressure and serum complement activation while taxotere did.
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-117.
Abstract LB-121: Serrated colorectal adenocarcinoma: Specific copy number alterations
Authors: Tuppurainen Karoliina , Li Yilong , Kaasinen Eevi , Tuomisto Anne , Aaltonen Lauri A. , Karhu Auli , Makinen Markus J. 
Published: February 2011

Abstract
The serrated pathway in the colorectal cancer (CRC) development shows characteristic morphological and genetic differences as compared with the traditional Vogelstein's adenoma-carcinoma sequence. According to current estimations, about 15-20% of colorectal cancers originate from serrated polyps. Activating mutations of BRAF and KRAS genes and microsatellite instability are common features in serrated polyps and cancers. To identify the driver genes behind the serrated colorectal pathway we analyzed gene copy number variations (CNVs) in 19 serrated colorectal carcinomas.
DNA was extracted from fresh-frozen tissues according to standard procedures. By using the Illumina HumanCNV-370 platform we analyzed the samples for somatic copy number alterations. Raw-data were normalized using the built-in Illumina BeadStudio normalization method. To segment the LRRs (tumor vs. normal logarithmic intensity ratios) we used CBS (circular binary segmentation) and BAFsegmentation (B allele frequency) and the driver genomic alterations were searched using GISTIC algorithm. To determine genetic changes specific for serrated adenocarcinomas, the recurrent genomic variations detected were compared with those previously reported in colorectal carcinomas.
The recurrent genomic alterations in serrated carcinomas overlap substantially with the previously reported alterations seen in colorectal carcinomas; losses in 1p, 4p, 4q, 5q, 8p, 17p, 18p and 18q, and the gains in 7p, 7q, 8q, 13q and 20q. However, regions that are frequently altered specifically in serrated carcinomas were also found. For example, the gains of 1q, 5p, 6p and 6q are not commonly found in primary tumors in colorectal cancer, but only in liver metastases. The frequent losses specific for serrated carcinoma occur in 3p, 6q, 9p, 11q, 16p, 22q, Xp and Xq. The highest deletion peaks observed in the current sample set are those located at 9p21.3.
In summary, our whole-genome screening of serrated colorectal adenocarcinomas with SNP arrays revealed several copy number alterations previously reported in colorectal cancers. Moreover, we detected several novel copy number alterations, which were specific for the serrated adenocarcinoma. The upcoming sequence analysis of genes within regions of copy number alterations may allow detection of mutations of genes linked to serrated adenocarcinoma pathogenesis.
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-121.
Abstract LB-141: Multiple protein secretion profiling analysis of cancer cells at single cell and small cell colony level with integrated barcode chip
Authors: Shin Young Shik , Hwang Kiwook , Fan Rong , Heath James R. 
Published: February 2011

Abstract
Pathophysiology of a complex disease such as cancer requires capability to analyze highly heterogeneous cellular events at single cell level, which can measure large numbers of molecular events from individual cells to be analyzed in statistically meaningful manner. Here we report on an approach that integrates microfluidic cell handling and in situ protein secretion profiling to assess the functional heterogeneity of single cells, with extensions to small cell colonies. We measured a dozen proteins secreted from cells for the most aggressive type of primary brain tumor, glioblastoma multiforme (GBM). We observed functional phenotypes in terms of secreted proteins with profound cellular heterogeneity but still in a statistically meaningful manner. The unique features that we confirmed from single cell analysis can present additional useful information to the conventional bulk analysis. Combining physical status of the system such as cell-cell distance and the protein secretion profiles enables to study tumor microenvironment. We further demonstrate the potential application of this platform to the clinic by analyzing solid tumor cells derived from a GBM patient. This platform is inexpensive, requires minute amounts of cells and yields large volume of molecular information, showing great potential for clinical assessment of cellular characteristics in human disease lesions.
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-141.
Abstract LB-148: Depletion of myeloid derived suppressor cells in pancreatric cancer results in decreased tumor growth
Authors: Mitchem Jonathan , Porembka Matthew , Hawkins William G. , Goedegebuure Simon Peter , Linehan David C. 
Published: February 2011

Abstract
Introduction: Pancreatic adenocarcinoma (PA) is a highly aggressive and chemo-resistant malignancy with a median survival of only 6 months. Myeloid derived suppressor cells (MDSC) have been implicated in the immune suppression and growth of several malignancies. MDSC are highly prevalent in the tumor microenvironment, and represent a potential therapeutic target. Here, we assess the tumor-promoting ability of MDSC in a model of PA and explore MDSC targeting strategies using ZA, a drug known to inhibit MDSC.
Methods: C57BL/6 mice were inoculated in the right flank with 100,000 or 50,000 of the syngeneic PA line, Pan02. Tumor volume was determined by standard calculation using caliper measurements. Mice were treated with Gemcitabine 20mg/kg Qwk IP and/or ZA 1ug QOD SQ once tumors were palpable. Analysis for MDSC accumulation was determined in the tumor, spleen and bone marrow of mice at sacrifice using flow cytometry for standard markers of MDSC (CD45, CD11b, Gr1, Ly6G, and Ly6C). MDSC prevalence is expressed as a percentage of total leukocytes (CD45+). Statistical analysis was performed using non-parametric student's t-test.
Results: MDSC are up regulated in the spleen and bone marrow of mice with flank injected Pan02 compared to non-tumor bearing mice. MDSC accumulate over time and increase in number until 4 weeks post-inoculation (CD45 + 11b+Gr1+, Bone Marrow: 26.06% 42.04%, spleen 1.07% 7.18%, p=0.0021). Treatment of tumor bearing mice with ZA decreases tumor associated MDSC (CD45+11b+Gr1+: 50.36 29.38; CD45+11b+Ly6G+: 49.45 30.47) and tumor volume (2.45 1.71 p=0.034). ZA also works in concert with Gemcitabine to decrease MDSC (Gr1 +: 50.36 39.38; Ly6G+: 49.45 37.28;) and tumor volume (2.45 1.02, p=0.0011).
Conclusion: MDSC play an integral role in the development of PA. Depletion of MDSC by ZA results in significantly smaller tumors and can be added to the standard chemotherapeutic regimen (Gemcitabine) successfully. The addition of ZA to Gemcitabine represents an attractive and innovative regimen to improve the treatment of this deadly malignancy.
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-148.
Abstract LB-15: Oncogenic BRAF mutation, IGFBP7 silencing and evasion of senescence in colorectal tumorigenesis
Authors: Spring Kevin J. , Miranda Mariska , Fernando Winnie , Togashi Kazutomo , Young Graeme P. , Leggett Barbara A. 
Published: February 2011

Abstract
Serrated polyps are now recognized as the precursor lesion from which sporadic BRAF (V600E) mutant/CIMP-H colorectal cancers (CRC) develop, but it appears likely BRAF mutation alone is not enough to drive progression to carcinoma. CIMP is generally localized to the proximal colon and may cause the epigenetic silencing of key genes such as IGFBP7 that may act in concert with BRAF mutation to promote neoplasia. We are conducting a detailed molecular analysis of the mechanism of serrated neoplasia involving IGFBP7 and evasion of oncogene-induced senescence (OIS). Normally senescence functions as a defense mechanism against tumorigenesis in precursor lesions.
We have analysed 44 CRCs and 217 colorectal polyps including 45 advanced serrated polyps (sessile serrated adenomas, serrated adenomas and mixed polyps) and 109 simple serrated polyps (goblet cell rich hyperplastic polyps and microvesicular hyperplastic polyps) for BRAF, K-ras and CIMP relative to clinicopathologic variables. In addition a MethyLight assay was developed to determine IGFBP7 methylation patterns in serrated polyps and cancers. For serrated polyps, both BRAF mutation (75.5%) and CIMP (46.6%) was most frequent in advanced serrated polyps (ASPs). Overall the frequency of CIMP was significantly associated with proximal location (P&lt;0.0001) and larger size (P&lt;0.005). When serrated polyps were analyzed separately, histological type and location showed strong associations, with CIMP frequency differing significantly in proximal vs distal BRAF mutant ASPs and GC/MV-HPs. We find that BRAF mutation is highly associated with both SSAs and MV-HPs throughout the colorectum, but only in proximal SSAs is CIMP highly associated with BRAF mutation (70.8%). For CRCs we found IGFBP7 methylation frequently associated with CIMP and BRAF mutation (87%). For serrated polyps, IGFBP7 methylation was significantly associated with ASPs (P&lt;0.0002), larger size (P&lt;0.0002) and proximal location (P&lt;0.0004). In advanced serrated polyps, which harbour both BRAF mutation and exhibit CIMP, methylation of IGFBP7 was observed 65% of cases. We are currently determining p53 expression levels, Ki67 and the senescence markers p19ARF and Dec1 in different serrated polyp types. This investigation will provide evidence for the involvement of IGFBP7 loss, by DNA hypermethylation, in the evasion of senescence and resulting in the progression of BRAF mutant/CIMP-H carcinoma of the colon.
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-15.
Abstract LB-153: PDE4D as a new prostate cancer drug target
Authors: Hammer Kimberly DP , Marker Paul C. 
Published: February 2011

Abstract
We have been conducting a two-species screen for prostate cancer oncogenes that are suitable for use as new prostate cancer drug targets. The initial screen utilized transposon-based somatic mutagenesis in mice to induce prostate tumors and molecularly tag candidate oncogenes. This approach identified several candidate prostate cancer genes including known oncogenes such as Nras and Braf as well as new candidate oncogenes including Pde4d. A secondary screen used human prostate tissue microarrays (TMAs) to validate the relevance of new candidate oncogenes for understanding human prostate cancer. Automated quantitative analysis of PDE4D protein expression on the human TMAs confirmed its over-expression in human prostate cancer patients. The Pde4d mRNA is alternatively spliced to encode a family of related PDE4D enzymes. These enzymes share a common catalytic domain that gives all of the enzymes cAMP-specific 3′,5′-cyclic phosphodiesterase activity. Protein domains outside the catalytic domain allow for differential protein regulation and sub-cellular localization of different PDE4D isoforms. Several small molecules have been identified that are highly selective inhibitors of PDE4D activity including cilomilast and NVP-ABE171. In vitro testing of these small molecules has shown that they inhibit the growth of some but not all commonly used prostate cancer cell lines. Growth-inhibition was associated with down-regulation of the MEK-ERK and Shh signaling pathways. Current studies are investigating the molecular mechanisms associated with differential sensitivity/resistance to PDE4D inhibition as well as the potential use of PDE4D inhibitors as anti-prostate cancer drugs in vivo.
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-153.
Abstract LB-154: Loss of PTEN cooperates with activated RAS in melanoma genesis and progression
Authors: Nogueira Cristina , Kim Kwan Hyun , Paraiso Kim T. , Dannenberg Jan-Hermen , Bosenberg Marcus , Chin Lynda , Kim Minjung 
Published: February 2011

Abstract
MAPK and AKT pathways are frequently co-activated in melanoma through overexpression of receptor tyrosine kinases, mutations in their signaling surrogates, such as RAS and BRAF, or loss of negative regulators such as PTEN. Since RAS is a known positive upstream regulator of PI3-K, it has been suggested that the loss of PTEN and the activation of RAS are redundant events in melanoma pathogenesis (Tsao et al., 2000). Here, in genetically engineered mouse models of cutaneous melanomas, we addressed the genetic interactions of activated HRAS and PTEN inactivation in melanoma genesis and progression in vivo. We showed that loss of Pten cooperates with HRAS activation in Ink4a/Arf−/− background and increased penetrance of melanoma development and emergence of metastasis. Correspondingly, Pten loss increases invasion and migration of melanoma cells and non-transformed melanocytes, which correlates with E-cadherin down-regulation. Together, this study demonstrates a synergistic interaction between Pten inactivation and RAS activation in melanoma development and progression.
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-154.