bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 221: TP53 mutations in serous tubal intraepithelial carcinoma, the putative precursor lesion of ovarian high-grade serous carcinoma
Authors: Kuhn Elisabetta , Kurman Robert J. , Soslow Robert A. , Han Guangming , Wang Tian-Li , Shih Ie-Ming 
Published: June 2012

Abstract
Somatic mutation of TP53 is the most common molecular genetic alteration in high grade serous carcinoma (HGSC) of the ovary, occurring in more than 95% of cases. As serous tubal intraepithelial carcinomas (STICs) have been proposed to be the most likely precursor of HGSC, we undertook a study to determine whether STICs harbor TP53 mutations as well. Mutations of TP53 have been reported in STICs and associated HGSC but that study was limited to 5 cases. We therefore performed TP53 mutational analysis in a larger series of STICs and concurrent HGSCs and correlated the mutational status with p53 immunoreactivity.
Formalin-fixed paraffin-embedded tissue specimens were obtained from 18 HGSCs with concurrent STICs; 8 of them contained two discrete STICs. Approximately 1,000 cells from STIC and normal-appearing fallopian tubal epithelium were laser-capture microdissected, while HGSCs were manually microdissected. Genomic DNA was extracted, PCR amplified and sequenced. TP53 mutations were analyzed from exons 4 to 8. Immunohistochemistry (IHC) for p53 was performed in all the cases.
TP53 mutations were detected in 15 (83.3%) of 18 HGSCs. Importantly, TP53 mutations were not detected in the corresponding FTE samples from the same patients, confirming they are somatic mutations in HGSCs. STIC and associated HGSC shared identical TP53 mutations in 15 (93.8%) of 16 patients including 7 who had two STICs. The discordant case showed TP53 mutation in the HGSC but not in two separate concurrent STICs. By IHC, all the cases demonstrated the same pattern of p53 immunoreactivity (either all positive or completely negative) except the case with wild-type TP53 in the STIC and mutant TP53 in the HGSC. By IHC the STIC was p53 negative and the HGSC p53 positive. The three TP53 wild-type HGSCs and their associated STICs exhibited undetectable nuclear p53 by IHC. In contrast, four p53-negative HGSCs contained mutant TP53 with either a deletion or an insertion mutation.
Our findings provide cogent evidence that TP53 mutations occur in most STICs, and that both STIC and concurrent HGSC share the identical TP53 mutations in the majority of cases. Future molecular genetic studies are necessary to delineate the clonal relationship and tumor progression from STIC to HGSC.
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 221. doi:10.1158/1538-7445.AM2011-221
Abstract 2233: Phage display selection of cancer-specific peptides on human bladder for molecular imaging of bladder cancer
Authors: Pan Ying , Volkmer Jens-Peter , Liu Jen-Jane , Wu Katherine , Mach Kathleen E. , Weissman Irving L. , Liao Joseph C. 
Published: June 2012

Abstract
Introduction and Objectives: Molecular imaging could transform cancer diagnosis by coupling existing imaging modalities with labeled tumor-specific antibodies or peptides. Current diagnosis of bladder cancer is by white light cystoscopy, which has suboptimal specificity for differentiating non-papillary cancer from inflammation. To identify bladder cancer-specific peptides, we applied phage display, an unbiased, combinatorial strategy in which up to 10⁁9 foreign peptides or proteins are individually expressed on bacteriophage to screen against cellular targets (biopanning). We report our effort to identify bladder cancer-specific peptides via biopanning with cystectomy specimens.
Methods: An M13 phage library displaying random linear heptapeptides was instilled into fresh cystectomy specimens (n=2). Non-specific phage were washed away and tumor was excised to extract tumor-bound phage, which were validated by bladder cancer cell line-based ELISA, flow cytometry, and immunofluorescence.
Results: Both bladders had high-grade urothelial carcinoma on pathology. 148 phage were obtained after 2 rounds of selection. 77 of these showed preferential binding to 2 bladder cancer cell lines (HT-1376, T24) by ELISA compared to negative control (insertless phage). 7 phage with &gt;10-fold signals over the negative control were further validated with flow cytometry and immunofluorescence. By detecting cell-bound phage with fluorescently labeled M13 phage antibody, increased staining of T24 cells by all candidate phage compared to negative control was demonstrated by both flow cytometry (2-3-fold) and immunofluorescence. Peptides were sequenced for additional validation of tumor specificity with primary normal human urothelial and bladder tumor cells.
Conclusions: We have developed a technique for efficient biopanning of bladder cancer-specific peptides using whole cystectomy specimens. These peptides could serve as molecular contrast agents for targeted imaging with confocal laser endomicroscopy or fluorescent cystocsopy, and could potentially be utilized for targeted therapy. Compared to prior reports, which utilized cell lines and xenografts as biopanning targets, our approach offers a more clinically-relevant, efficient approach to identify peptides for cancer-specific imaging and 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 2233. doi:10.1158/1538-7445.AM2011-2233
Abstract 2237: Nelarabine is safe and effective in adult relapsed or refractory T cellacute lymphoblastic leukemia (T-ALL) and lymphoblastic lymphoma (T-LBL): The Bologna experience
Authors: Papayannidis Cristina , Iacobucci Ilaria , Abbenante Mariachiara , Lonetti Annalisa , Guadagnuolo Viviana , Ferrrari Anna , Ottaviani Emanuela , Curti Antonio , Paolini Stefania , Parisi Sarah , Clissa Cristina , Baccarani Michele , Martinelli Giovanni 
Published: June 2012

Abstract
Background. Nelarabine (N) is approved for the treatment of T-ALL and T-LBL that have not responded to or has relapsed after treatment with at least 2 chemotherapy regimens.
Aim. To evaluate safety profile and efficacy of N as savage therapy in 16 adult relapsed or refractory T-ALL or T-LBL.
Methods. After obtaining an informed consent, 16 patients (median age 33 years, range 19-45, M/F = 13/3) affected by T-ALL (n=10) and T-LBL (n=6) received savage therapy with N (median cycle=1, range 1-3), administered at standard adult dosage (1500 mg/sqm on days 1, 3 and 5, every 21). Four patients were primary resistant to induction treatment, 7 patients were relapsed after two previous chemotherapy regimens (including allogeneic BMT in 4 cases and autologous SCT in 1 case); the remaining 6 patients had a molecular relapsed disease (MRD positive). Molecular characterization was performed, including NOTCH and WT-1 genes mutational status. GEP analysis, according to Ferrando A. stratification (Cancer Cell 2002), is still ongoing.
Results. Currently, 12 out of 16 patients are evaluable, due to a too short follow up in the other 4 cases. Seven out of 12 patients obtained a complete remission (CR) (5 T-ALL 2 T-LBL);a partial remission (PR) was documented in 2 cases, with an overall response rate (ORR) of 75%. Median duration of CR was 10 weeks (range 2.8-54+). Among these, 2 out of 4 patients in molecular relapse reached a molecular CR and underwent an allogenic BMT (currently in CR after a median follow up of 12 months). Extra- hematological toxicity, not clearly related to the drug, occurred in 3 cases, determining, a complete and irreversible paraplegia, a condition of mental confusion, and a peripheral neuropathy, respectively.
Conclusions. N showed a strong efficacy also in cases with low levels of residual disease, in addition to a good safety profile. Neurological toxicity needs to be strictly monitored.
Acknowledgments. European LeukemiaNet, AIL, AIRC, Fondazione Del Monte di Bologna e Ravenna, FIRB 2006, PRIN 2008, Ateneo RFO grants, Project of integrated program (PIO), Programma di Ricerca Regione – Università 2007 – 2009.
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 2237. doi:10.1158/1538-7445.AM2011-2237
Abstract 2248: Oncogenic actions of HDGF (hepatoma-derived growth factor) in colorectal cancer: Implication for tumor biology/ patient prognosis and modulation by butyrate
Authors: Kudlich Theodor , Wilk Maike , Neun Tilmann , Hartmann Elena , Rogoll Dorothee , Luehrs Hardi , Rosenwald Andreas , Katzenberger Tiemo , Scheppach Wolfgang , Scheurlen Michael , Melcher Ralph 
Published: June 2012

Abstract
HDGF was identified as an oncogene relevant for colon cancer carcinogenesis by cDNA-array analysis, RT-PCR and immunohistochemistry. The analysis were performed in colonic adenoma (Geki2), carcinoma (HT29) and metastasis (SW620) cell lines, and in 50 colorectal cancer tissues and corresponding normal mucosa. By incubation of the cell lines with the short chain fatty acid butyrate (4mM), it was possible to (down-) regulate the HDGF-expression level. In the patients we analysed, HDGF overexpression was not associated with a worse prognosis or any other clinical parameter. To study the mechanisms of action of HDGF we stably transfected a HDGF-siRNA containing plasmid into HT29 colon carcinoma cells, resulting in a almost complete inactivation of HDGF-expression. This blocking leads to altered growth characteristics and cell differentiation and the cells exhibit potent pro-apoptotic properties. An affymetrix-expression array was performed and first results will me shown at the meeting. In conclusion, HDGF might be a potential therapeutic target for human colorectal cancer and a modulation of expression is possible by the short chain fatty acid butyrate. These findings may have major implications in the treatment of colorectal cancer.
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 2248. doi:10.1158/1538-7445.AM2011-2248
Abstract 2250: PKR signaling pathway plays an important role in prognosis for non-small cell lung cancer
Authors: Pataer Apar , He Yong , Correa Arlene M. , Fang Bingliang , Roth Jack A. , Wistuba Ignacio I. , Swisher Stephen G. 
Published: June 2012

Abstract
The role of RNA-dependent protein kinase (PKR) in antiviral defence mechanisms and in cellular differentiation, growth, and apoptosis is well known, but the role of PKR in human lung cancer remains poorly understood. To explore the role of PKR in human lung cancer, we evaluated PKR's expression in tissue microarray specimens from both non-small cell lung cancer (NSCLC) and normal human bronchial epithelium tissue. The NSCLC cells showed lower levels of PKR expression than normal bronchial epithelium cells did. We also found a significant association between lower levels of PKR expression and lymph node metastasis. We found that loss of PKR expression is correlated with a more aggressive behavior, and that a high PKR expression predicts a subgroup of patients with a favorable outcome. Univariate and multivariate Cox proportional hazards regression models showed that a lower level of PKR expression was significantly associated with shorter survival in NSCLC patients. We further validated and confirmed that PKR to be a powerful prognostic factor in TMA-2 lung cancer (HR=0.22, P&lt;0.0001). We also observed that the patients with high p-PKR or p-eIF2a expression had a significantly longer median survival than those with little or no p-PKR or p-eIF2a expression (P = 0.03 and P = 0.032, respectively). Combined expression of PKR and p-PKR or PKR and p-eIF2a increased patient survival (P = 0.001). Combined expression levels of PKR and p-PKR or p-eIF2a can be new markers for predicting the prognosis of patients with NSCLC.
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 2250. doi:10.1158/1538-7445.AM2011-2250
Abstract 2261: Prognostic significance of the low level microsatellite instability phenotype differs with race in colorectal adenocarcinoma
Authors: Katkoori Venkat R. , Salih Chura , Sthanam Meenakshi , Shanmugam Chandrakumar , Callens Tom , Messiaen Ludwine M. , Grizzle William E. , Bumpers Harvey L. , Birdsong George , Manne Upender 
Published: June 2012

Abstract
Purpose: Several studies have examined the prognostic value of microsatellite instability (low, MSI-L, and high, MSI-H) phenotypes in colorectal adenocarcinomas (CRCs), but none have specifically considered patient race/ethnicity to assess the value of MSI-L. Therefore, this study assessed the prognostic value of the MSI-L phenotype in African-American and non-Hispanic Caucasian (NHCA) CRC patients separately.
Experimental Design: CRCs from 276 African-Americans and 377 NHCAs, collected at the hospitals of the University of Alabama at Birmingham and Morehouse School of Medicine, were assessed for microsatellite instability and p53 mutational status (exons 4 through 9). MSI was assessed at 4 CA-dinucleotide MS loci (Mfd 27, Mfd 41, Mfd 47, and Mfd 57) and 2 poly-A repeats (BAT25, BAT26). Samples were considered MSI-H if at least 2 loci showed instability and MSI-L (low) if only 1 marker was unstable. The phenotypes were correlated with clinicopathologic features and patient survival by use of the χ2 test and univariate Kaplan-Meier analyses, respectively.
Results: The incidence of the MSI-L phenotype was higher in African-American patients (49 of 276, 18%) compared to NHCA patients (27 of 377, 7%). In contrast, the frequency of the microsatellite stable (MSS) phenotype was higher in CRCs of NHCAs (72%) than in CRCs of African-Americans (56%). In addition, the incidence of microsatellite instability-high (MSI-H) phenotype was similar in African-Americans (26%) and NHCAs (21%). Presence of the MSI-L phenotype significantly correlated with a higher incidence of missense p53 mutations (64%) and high-grade tumors (31%) and with advanced stages (III and IV) (67%) of CRCs in NHCAs. Such associations, however, were not found in African-American patients. For NHCA patients, CRCs with the MSI-L phenotype had significantly higher mortality (log-rank p=0.044) as compared to MSS or MSI-H. In contrast, for African-American patients, the MSI-L phenotype was associated with a better prognosis (log-rank p=0.043) compared to the MSS or MSI-H phenotypes.
Conclusions: These findings suggest that CRC with the MSI-L phenotype is associated with p53 mutations, high-grade tumors, and advanced tumor stage, and with short survival of NHCAs but not African-Americans. This work was supported by grants from the NCI/NIH (2U54-CA118948-03, R01-CA98932, and R03-CA139629).
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 2261. doi:10.1158/1538-7445.AM2011-2261
Abstract 2264: K-ras mutations in colorectal cancer may predict a pattern of organ-specific metastasis
Authors: Garrido-Laguna Ignacio , Janku Filip , Falchook Gerald S. , Fu Siqing , Naing Aung , Wheler Jennifer , Tsimberidou Apostolia , Hong David S. , Kurzrock Razelle 
Published: June 2012

Abstract
Background: Activating mutations of the K-ras oncogene in colorectal cancer (CRC) are associated with resistance to EGFR antibodies and poor prognosis. We systematically analyzed clinical and pathological characteristics associated with K-ras mutations. Methods: Patients with CRC referred to the phase I program for targeted therapy were analyzed for K-ras mutations using PCR-based DNA sequencing. Patients with mutant K-ras were matched with wild-type (wt) K-ras controls. Multiple clinical and pathological characteristics were analyzed to determine, whether there is a phenotype associated with K-ras mutations. Results: A total of 151 patients with CRC were identified; 61 with K-ras mutations; 80 with wt K-ras and 10 with unknown K-ras status. Patients with K-ras mutations compared with wt K-ras had more frequently lung metastases (80% vs. 63%, p = 0.03). Patients whose tumors had K-ras mutations had higher number of metastatic sites of disease (3.18 vs. 2.65; p = 0.013). There were no associations between K-ras mutations and gender, age at diagnosis, liver metastases, peritoneal metastases, lymphatic involvement or Duke stage at diagnose. Patients with K-ras wt had a trend for longer median survival (283 vs. 222 weeks, p=0.09). There was no difference in the median survival from diagnosis in patients with different types of K-ras mutations (codon 12, codon 13, and codon 61). Dukes staging was the only statistically significant prognostic factor on multivariate analysis (p &lt; 0.05). Conclusions: K-ras mutations in CRC in comparison with wt K-ras were associated with more frequent lung metastases and shorter survival.
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 2264. doi:10.1158/1538-7445.AM2011-2264
Abstract 2284: Investigation of notch-1, ErbB-2, and ERα crosstalk in breast cancer
Authors: Rogowski Allison S. , Osipo Clodia 
Published: June 2012

Abstract
Notch-1 is a breast oncogene that is overexpressed with its ligand Jagged-1 in human breast cancers-associated with the poorest overall survival. Notch signaling can be inhibited by a gamma-secretase inhibitor (GSI). We have recently determined that the estrogen receptor-alpha or ErbB-2 inhibits Notch-1 activation in breast cancer cells. In the current study, we sought to uncover the complex crosstalk between ER, ErbB-2, and Notch-1 and ask whether triple combination treatment can disrupt this complex cross-talk model to inhibit growth of ER positive breast cancer cells (MCF-7) and possibly prevent anti-hormone resistance. The results demonstrated that following 1 week of estrogen deprivation, MCF-7 cells develop resistance and regrow. Canonical Notch gene targets: Hes-1, Hey-1, Hes-5, and Deltex-1 are significantly increased at this 1 week time point. Similarly, ErbB-2 mRNA increased significantly after 72 hours of estrogen deprivation. Upon treatment with fulvestrant, a pure ant-estrogen, ER transcriptional activity as measured by PS2 mRNA is inhibited after one week. Interestingly, the combination of fulvestrant and lapatinib, an anti-ErbB-2 tyrosine kinase inhibitor, synergistically increased both Deltex-1 and ErbB-2 mRNAs which were reduced upon GSI treatment. Western blot analysis showed an increase in ER and tyrosine-phosphorylated ErbB-2 and total ErbB-2 proteins. This increase in protein expression was further increased upon dual treatment with fulvestrant and lapatinib. Conversely, treatment with a Notch inhibitor, GSI caused a decrease in both total and tyrosine-phosphorylated ErbB-2. Cell cycle analysis showed that fulvestrant treatment significantly growth arrested cells in G1 while decreasing cells in S-phase. However, lapatnib or GSI or the combination treatments did not further enhance the growth inhibitory effects of fulvestrant. Similar results were observed using Annexin-V analysis by flow cytometry as a measure of early apoptosis. These results suggest that while inhibiting ER and ErbB-2 simultaneously increases Notch activation in a synergistic manner, this dramatic increase in Notch activity in the short term does not sensitize ER positive breast cancer cells to a Notch inhibitor to undergo cell death.
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 2284. doi:10.1158/1538-7445.AM2011-2284
Abstract 2288: CYP3A4 monoxygenase regulates IGF-1 signaling in ER-positive breast cancer cells
Authors: Guo Zhijun , Mitra Ranjana , Milani Monica , Rodriguez Mariangellys , Yee Douglas , Sachdev Deepali , Potter David A. 
Published: June 2012

Abstract
Cytochrome P450 3A4 (CYP3A4) is an important monooxygenase that metabolizes a wide range of xenobiotics including many drugs and environmental chemicals, as well as endogenous substances such as steroids. Expression of CYP3A4 has been observed in breast tumors and has been associated with nodal metastases and decreased overall survival in breast cancer. To investigate roles of CYP3A4 on breast cancer progression and the mechanisms involved, we performed RNAi knock down studies, demonstrating that CYP3A4 regulates anchorage-dependent proliferation and clonogenicity of the MCF7 line. Unexpectedly, we found that stable CYP3A4 shRNA knock down MCF7 lines exhibited significant higher clonogenicity relative to the non-target control line in soft agar (P&lt;0.05). Further investigation demonstrated that this increased clonogenicity is due to activation of IGF autocrine pathway, which could be abrogated by an antibody to the IGF1R. The PI3-Kinase inhibitor LY294002 abolished the increase of clonogenicty of CYP3A4 silenced lines, indicating the involvement of PI3-Kinase pathway. Phosphorylation of AKT protein is elevated in these lines, consistent with increased IGF-1 signaling. These results indicate that CYP3A4 may play a role in regulating IGF-1 signaling in ER-positive breast cancer cells. These results suggest that inhibition of CYP3A4 in combination with IGF1R function blocking antibody may have enhanced therapeutic efficacy compared to either modality alone.
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 2288. doi:10.1158/1538-7445.AM2011-2288