bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 320: Association of higher Gleason grade with presence of PTEN deletion in prostatic adenocarcinoma
Authors: Yoshimoto Maisa , Evans Andrew , Sweet Joan , Ludkovski Olga , Ding Keyue , Trottier Greg , Song Kyu S. , Squire Jeremy A. 
Published: June 2012

Abstract
Prostatic adenocarcinoma (CaP) is one of the most histologically heterogeneous of epithelial malignancies. The Gleason score is widely accepted as the standard for histologic grading and determining prognosis of prostate malignancies. The tumor often presents with a multifocal distribution though the gland and different Gleason grades may be present in different foci. The current study was undertaken to compare the association of genomic alterations with the Gleason grades of individual adenocarcinoma foci. Genomic deletion of the PTEN gene in routine formalin-fixed paraffin-embedded (FFPE) pathology sections can be readily assayed by fluorescence in situ hybridization (FISH). Data from our group and others has shown that the genomic deletion of the PTEN tumor suppressor gene and the disruption of the ETS gene family, play a central role in prostate cancer and are likely to be associated with Gleason grade. In this study CaP samples were thoroughly analyzed to identify PTEN heterogeneity, within or between foci in multifocal tumors. This study was designed to retrospectively assess the overall frequency with which PTEN deletions and TMPRSS2-ERG fusion rearrangements occur individually and simultaneously, and their clinical impact through FISH analysis using well-annotated high-throughput tissue microarrays (TMAs) derived from 128 patients with CaP. In addition, four-color FISH analysis of the PTEN deletion was used to precisely detect the interstitial deletion of genomic content from this region of chromosome 10q and evaluate the tumor heterogeneity. Genomic PTEN deletion was observed in 55 of 128 (43%) patients with CaP (hemizygous = 41 and homozygous = 14 CaP). TMPRSS2-ERG fusion was observed in 58 of 129 (45%). We specifically examined the relationship between PTEN deletion and TMPRSS2-ERG fusion status, Gleason pattern and clinical behavior of CaP. Importantly, PTEN deletions were significantly associated with a higher primary Gleason pattern grade 4 (p=0.000), lymphovascular invasion (p=0.051), and higher percentage of prostate involved by tumor (p=0.0064). Although TMPRSS2-ERG fusions showed a strong relationship with PTEN deletions (p=0.007), TMPRSS2-ERG fusions did not show any clinical correlation. In conclusion, our findings indicated that PTEN deletion FISH can be applied to CaP samples to accurately stratify patients into risk categories and to guide decision-making with respect to the optimal management of CaP patients.
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 320. doi:10.1158/1538-7445.AM2011-320
Abstract 3219: Isolated tumor cells (ITC) in regional lymph nodes predict colorectal cancer (CRC) relapse
Authors: Mescoli Claudia , Albertoni Laura , Fassan Matteo , Lazzarin Vanni , Lanza Cristiano , Giacomelli Luciano , Pucciarelli Salvatore , Nitti Donato , Rugge Massimo 
Published: June 2012

Abstract
Involvement of the lymph nodes (LN) is the most important prognostic factor in CRC and pN+ve status identifies patients requiring adjuvant chemotherapy. Among pN0-patients, 20-30% develop recurrent disease. ITC+ve LNs in such patients (as assessed by immunohistochemistry) may potentially predict cancer recurrence. No prospective long-term follow-up trial has consistently validated the prognostic meaning of ITCs.
ITCs in regional LNs were prospectively assessed in a cohort of 361 consecutive pN0-CRC patients. From each gross surgical specimen, LNs were microdissected according to a standardized protocol (mean LNs per patient=16.4; range 5-107). In all, 5,920 pN0-ve LNs were collected and immunohistochemically assessed (MNF116 staining was performed in 2 serial histology sections of each LN [11,840 histology specimens in all]). Overall cancer death and recurrence rates were calculated. The prognostic impact of ITC was also tested by multivariate statistics.
ITCs were documented in 200 of 361 patients (55.5%). No relationship was documented between ITC+ve status and overall survival. CRC recurred in 36/361 (9%) cases and 29/36 (80%) recurrences were documented among ITC+ve patients. The prevalence of recurrent CRC among ITC+ve and ITC-ve patients was 14.5% and 4.3%, respectively. ITC+ status significantly correlated with cancer recurrence (p = 0.002, OR = 3.57; 95% CI=1.46-9.95; case-control Pearson's chi-squared) and disease-free interval (p=0.0005). In multivariate analysis, ITC-status was the only variable significantly associated with cancer recurrence.
These results suggest considering ITC+ve status a reliable marker of cancer recurrence, and that pN0 ITC+ve cancer patients form a subgroup of candidates for adjuvant chemotherapy.
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 3219. doi:10.1158/1538-7445.AM2011-3219
Abstract 322: Triple combination array analysis detects the Collagen type1 alpha1 (COL1A1) gene as a new tumor related gene in hepatocellular carcinoma
Authors: Masamichi Hayashi , Nomoto Shuji , Okamura Yukiyasu , Hishida Mitsuhiro , Nishikawa Yoko , Fujii Tsutomu , Sugimoto Hiroyuki , Takeda Shin , Nakao Akimasa 
Published: June 2012

Abstract
Background: Epigenetics is one of the most important mechanisms for inactivating tumor suppressor genes or tumor-related genes in various human cancers. Hepatocellular carcinoma (HCC) is one type of human cancer in which epigenetic gene suppression is frequently found. To effectively detect a tumor-related, we performed triple combination array analysis, which consists of an expression array, a single nucleotide polymorphism (SNP) array, and a methylation array of the same surgical HCC specimen.
Methods: Triple array analysis of one HCC sample from a 68-year-old female patient was performed. Gene expression profiles were determined using Affymetrix HGU133A and B Gene-Chips using RNA. The SNP chip array was conducted using the standard protocol for Affymetrix Gene Chip Mapping 500K arrays. Methylation array analysis used an Illumina Infinium HumanMethylation27 Beadchip Kit. The gene encoding Collagen type1 alpha1 (COL1A1) was identified and verified using HCC cell lines and 48 primary HCC tissues from patients who had undergone hepatectomy at our hospital.
Results: Expression array analysis revealed that COL1A1 gene expression was decreased in tumor tissues (Log2 Ratio -1.1). In addition, SNP array analysis showed that the COL1A1 locus, 17q21, did not show a chromosomal deletion. Importantly, the methylation value (0-1.0) in the tumor tissue was higher (0.557) than that of the adjacent normal tissue (0.008). We hypothesized that the expression of this gene was suppressed by promoter hypermethylation. The suppressed expression of the COL1A1 gene in HCC cell lines was reactivated after 5-aza-2′-deoxycytidine (5-aza-dC) treatment. Sequence analysis identified hypermethylated CpG sites in the COL1A1 promoter region. In 48 HCC samples, 21 cases (44%) also showed COL1A1 gene promoter hypermethylation. The expression values of methylated cases, examined by real-time RT-PCR, were significantly downregulated (p=0.004) compared with unmethylated cases. Downregulation of the gene's expression was significantly correlated with pathological fc positive (p=0.026) and liver damage scores (p=0.011).
Conclusion: Triple combination array analysis successfully revealed that the COL1A1 gene acts as a tumor suppressor gene in HCC via promoter hypermethylation.
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 322. doi:10.1158/1538-7445.AM2011-322
Abstract 3228: Preparation and in vivo evaluation of a phytosphingosine derivative, N,N,N-Trimethylphytosphingosine (TMP), in liposomes for the treatment of tumor metastasis
Authors: Song Chung Kil , Balakrishnan Prabagar , Shim Chang-Koo , Chung Suk-Jae , Chong Saeho , Choi Myeong Jun , Kim Dae-Duk 
Published: June 2012

Abstract
Purpose: The aim of this study is to evaluate the cytotoxicity and anti-metastatic effect of a phytosphingosine derivative, N,N,N-trimethylphytosphingosine.iodide (TMP-I), and to compare it with that of TMP-I liposome. Background: Sphingolipids are known for ortho-signaling and anti-adhesion features as well as intracellular signal messenger in cell differentiation, proliferation and apoptosis. Sphingosine and sphinganine, structural analogs of sphingolipids were recognized as negative modulator of transmembrane signaling through protein kinase C (PKC) that plays an important role in the cancer treatment. Among them, phytosphingosine has been known for antitumor and anti-invasive effect through phytosphingosine-induced apoptosis mechanism. Recently it has been reported that N-monomethylphytosphingosine and N,N-dimethylphytosphingosine induced apoptosis via mitochondria-involved apoptosis such as caspase-8, caspase-3 and caspase-9 and this prompt us for this study. Methods: TMP-I solution was evaluated for cytotoxicity in various cancer cell lines and hemolysis in rat blood cells at various concentrations. The prepared TMP-I liposomes (DPPC:Chol:TMP-I at 5:5:1 mole ratio) were characterized by particle size and studied for in vitro cytotoxicity, cell migration and in vivo angiogenesis in rats. Furthermore, to evaluate the anti-metastatic effect of TMP-I liposomes, C57BL6 mice (n=5) were inoculated with B16F10 cells in tail vein for direct metastasis and footpad for spontaneous metastasis studies. Results: The prepared TMP-I liposomes were with a mean size of 150 nm. TMP-I solution showed significantly higher cytotoxicity and hemolysis (≥100 μg/ml) compared to that of TMP-I liposomes in several cancer cell lines. TMP-I liposomes showed significantly low cell migration and angiogenesis compared to control formulations. The in vivo study in mice showed that the numbers of lung nodules in the mice treated with TMP-I liposomes were significantly lower compared to that of control formulations. Conclusion: Our results suggested that the TMP-I liposome could be used as a potential carrier for the treatment of tumor metastasis.
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 3228. doi:10.1158/1538-7445.AM2011-3228
Abstract 3238: Synthesis and evaluation of 17-oximino-estrone derivatives as potential anti-breast cancer agents
Authors: Joseph Patrick , Cooperwood John S. , Wan Zhongliang 
Published: June 2012

Abstract
The selective estrogen receptor modulator (SERM) tamoxifen (TAM) is the gold standard used in the treatment of estrogen-dependent breast cancer. Although it significantly benefited women with breast cancer, time-dependent tumor resistance and the risk of endometrium cancer are associated with it. Consequently, there is an urgent need for alternative treatments. PURPOSE: Incorporating the oxime moiety in conjunction with various basic side chains associated with the pharmacophore of the SERMs into estrone may yield various estrone derivatives with antiestrogenic activity. The estrone derivatives were compared to 4-hydroxy-tamoxifen (4-OH-TAM) and raloxifene (RAL). METHODS: The estrone derivatives were synthesized using established chemical procedures. The Southern Research Institute in Birmingham, Alabama carried out the cytotoxicity studies in MCF-7, MDA-MB-231 and Ishikawa cancer cells. They tested different concentrations of the six different estrone derivatives ranging from .01 nM to 100,000 nM on 5000 MCF-7 cells/well, on 5000 MDA-MB-231 cells/well and on 5000 Ishikawa cells/well. Cells pre-treated with the various estrone derivatives were incubated at 37°C for 3 days followed by MTS assay. Their IC50 values were generated using GraphPad Prism 5.0. RESULTS: Our compounds demonstrated anti-proliferative activity in MCF-7 cells but they were not as potent as 4-OH-TAM(2µM) or RAL (3µM). Compounds 2, 3, 4, 6, and 7 (31µM, 29µM, 30µM, 30µM, and 29µM respectively) were comparable in potency to RAL (28µM) in MDA-MB-231 cells but all were not as potent as 4-OH-TAM (22µM). Compounds 3, 6, and 7 (20µM, 20µM, and 17µM respectively) were comparable or greater in potency to 4-OH-TAM (20µM) in Ishikawa cells and compounds 2, 3, 6, and 7 (24µM, 20µM, 20µM, and 17µM respectively) were comparable or greater in potency to RAL (23µM). CONCLUSION: Applying the oxime moiety in conjunction with the pharmacophore of the SERMs to estrone produced agents with antiproliferative activity. They also showed antiproliferative activity in estrogen-receptor negative MDA-MB-231 cells. These results suggest that several of the estrone derivatives show promise as potential anti-breast cancer agents.
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 3238. doi:10.1158/1538-7445.AM2011-3238
Abstract 3243: Discovery of novel Rho kinase inhibitors: Hit generation and lead optimization
Authors: Alexander Brian G. , Pireddu Roberta , Sun Nan N. , Yu Huidong , Forinash Kara D. , Martin Matthew P. , Schonbrunn Ernst , Guida Wayne C. , Sebti Said M. , Lawrence Nicholas J. 
Published: June 2012

Abstract
Rho associated protein kinases (ROCKs) are Ser/Thr kinases which require activation by small GTPases of the Rho family. ROCK is often found to be over expressed in ovarian, testicular, bladder, and pancreatic cancers. ROCK has been implicated in cell motility, adhesion, smooth muscle contraction and stress fiber formation. Inhibition of Rho kinase is a novel approach for the treatment of cardiovascular disease, CNS disorders, and, more recently, cancer. ROCK has received increased attention for its affect on cell adhesion and invasion, two key steps in metastasis. We detail the development of ROCK inhibitors from initial small molecule library screening and in-house HTS screening data. We report on the identification and resynthesis of one screening hit (ROCK1 IC50 38.5 ± 3.4 µM). Focused chemical libraries were developed and structure activity relationships will be described. All compounds have been screened in a Z-lyte kinase assay to determine their activity against both ROCK1 and ROCK2. Hit-to-lead optimization and SAR studies resulted in compounds capable of inhibiting ROCK1 at low nanomolar concentrations, RPM1510 (ROCK1 IC50 0.15 ± 0.02 µM) and RPM1533 (ROCK1 IC50 0.12 ± 0.02 µM). Progress in obtaining structural information by X-ray crystallography will be reported along with ROCK inhibitory data. Trends in isoform and kinase selectivity and potency will also be discussed. Members of this class have been shown to inhibit potently, in human lung cancer cells, the phosphorylation of MYPT1, a surrogate for ROCK activity in vivo.
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 3243. doi:10.1158/1538-7445.AM2011-3243
Abstract 3267: Inhibition of angiogenic potential of neuroblastoma cells through regulation of microRNA expression profiles by tumor suppressor gene dipeptidyl peptidase IV
Authors: Lee Raymond , Dempsey Robert J. , Wesley Umadevi V. 
Published: June 2012

Abstract
Neuroblastoma (NB), a childhood cancer of peripheral nervous system generally progress to highly angiogenic and therapy resistant fatal metastatic tumor. We have recently shown that a cell surface protease called dipeptidyl peptidase (DPPIV) is expressed in normal neural crest derived differentiated cells and its expression is lost in proliferating NB, the malignant counterpart. We also demonstrated that re-expression of DPPIV in NB cells leads to their differentiation, apoptosis, and suppression of their migratory and angiogenic potential. Importantly, DPPIV inhibits the tumorigenic potential of NB cells in a xenograft mouse model. To further identify DPPIV-responsive genes and mechanisms, we used Affymetrix microarray analysis. This study showed an association of DPPIV expression with up-regulation of thrombospondin-1 (THBS1), an angiogenesis inhibitor. Interestingly, some of the genes regulated by DPPIV are also altered by microRNA (miRNAs), indicating that at least some of the miRNAs might act as intermediate effectors in mediating DPPIV function. PCR array screening of cancer specific miRNAs, showed that DPPIV indeed alters miRNA profile in NB cells. In particular, DPPIV down-regulated miR-19a which is a part of the miR-17-92 cluster that is known to decrease THBS1 levels. Furthermore, bioinformatics data mining of Sangers MicroCosm Targets v5 predicted THBS1 as a potential target of miR-19a suggesting that down-regulation of miR19a leading to up-regulation of THBS1 was a possible mechanism involved in DPPIV tumor suppressor function. In support of this idea, silencing of DPPIV expression by RNA interference resulted in increased miR-19a and decreased THBS1 expression. Furthermore, transfection of NB cells with anti-miR-19a decreased miR19a and increased THBS1 levels as shown by real time quantitative RT-PCR, immunofluorescence and western blot analysis. Furthermore, DPPIV expression decreased the levels of cMYC, a transcription factor that up-regulates miR-19a expression. These effects were associated with decreased levels of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), two strong downstream pro-angiogenic factors. Taken together, our work identifies a novel and an important mechanism wherein DPPIV inhibits angiogenesis and growth of NB tumor cells through down regulation of miR-19a mediated c-MYC expression and increased expression of THBS1, an angiogenesis inhibitor.
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 3267. doi:10.1158/1538-7445.AM2011-3267
Abstract 3276: A Phase 1 dose escalating study with ACE-041, a novel inhibitor of ALK1 mediated angiogenesis, in patients with advanced solid tumors
Authors: Bendell Johanna C. , Gordon Michael , Hurwitz Herbert , Yang Yijun , Wilson Dawn , Haltom Eric , Attie Kenneth M. , Condon Carolyn H. , Sherman Matthew L. , Sharma Sunil 
Published: June 2012

Abstract
Background: Activin receptor-like kinase-1 (ALK1) is a type I receptor predominantly expressed on activated vascular endothelial cells that mediates signaling by members of the TGFß superfamily of proteins. ACE-041, a soluble receptor fusion protein consisting of the extracellular domain of ALK1 linked to the IgG1-Fc region, binds with high affinity to BMP9 and BMP10 but not TGFß1, 2, or 3, VEGF, or bFGF. ACE-041 is able to inhibit both VEGF- and bFGF-stimulated angiogenesis, indicating that ALK1 is downstream of VEGF and bFGF signaling. In a variety of murine tumors, ACE-041 has demonstrated the ability to decrease both tumor vascularity and growth.
Methods: The primary objective of this ongoing phase 1 study is to evaluate the safety and tolerability of ACE-041. Secondary objectives include identifying MTD, PK, preliminary activity on PD markers, and antitumor activity by RECIST, PET-CT, and DCE-MRI. Cohorts of 3-6 patients were enrolled at escalating dose levels. Once the MTD has been determined, 12-24 additional patients may be enrolled at the MTD or lower dose levels. ACE-041 is administered SC every 3 weeks for a total of 4 doses or until disease progression. Patients with stable or responding disease may continue treatment for up to 12 months.
Results: The dose escalation phase of the study has completed enrollment of 25 patients (13M/12F) at seven dose levels (0.1 to 4.8 mg/kg). An expansion cohort of 12 additional patients at1.6 mg/kg is currently being enrolled. The mean t½ was approximately 13 to 23 days and the mean Tmax was 4 to 7 days. ACE-041 was generally well-tolerated; preliminary data show that common treatment-related AEs included peripheral edema, fatigue, nausea, headache, anorexia, and anemia. Most AEs were Grade 1 or 2. Grade 3 congestive heart failure was reported in one patient as possibly related to drug. Based on preliminary results, stable disease lasting at least 6 cycles was observed in 4 patients having previously progressed on prior therapies. Several patients were noted to have had a positive 18-FDG-PET response with a decrease in metabolic activity approximately 2 weeks following the first dose.
Conclusions: ACE-041 is a first-in-class angiogenesis inhibitor that targets the ALK1 pathway. Treatment by subcutaneous injection every 3 weeks has been generally well-tolerated to date and preliminary evidence of antitumor activity has been observed in this ongoing study.
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 3276. doi:10.1158/1538-7445.AM2011-3276