bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4589: Clinical significance of the EML4-ALK fusion gene and association with EGFR and KRAS gene mutation in 208 Chinese patients with non-small cell lung cancer
Authors: Chen Jun , Liu Hongyu , Yang tong , Wei Sen , Li Ying , Wang Yuli , Li Yongwen 
Published: August 2012

Abstract
Objective: EML4-ALK fusion gene is a potentially relevant oncogenic event in lung cancer, which represents a new subgroup of non-small cell lung cancer (NSCLC) patients who respond positively to ALK inhibitors. The characteristics of EML4-ALK fusion gene in Chinese Patients with NSCLC are poorly understood. In this study, we aimed to analyze the prevalence of EML4-ALK fusion gene and their correlation to epidermal growth factor receptor (EGFR) status, KRAS mutation, and clinico-pathological data in Chinese patients with NSCLC. Methods: EML4-ALK fusion gene was detected by nested RT-PCR and confirmed by sequencing. EGFR and KRAS gene status were evaluated by RT-PCR and sequencing. Survival analysis was performed. A meta-analysis of the EML4-ALK fusion gene in lung cancer patients was also presented. Results: Two hundred eight NSCLC cases were evaluated. There were 51 cases of mutations in EGFR at exons 18-21 (24.5%, 51/208). Among exons 18-21, EGFR mutations occur predominantly (92%) in exons 19 and 21. In concordance with previous reports, these mutations are identified at high frequencies in females (47.5%, 29/61 vs 15.0%, 22/147 in males; P = 0.000); never-smokers (42.3%, 33/78 vs 13.9%, 18/130 in smokers; P = 0.000), and adenocarcinoma patients (44.2%, 42/95 vs 8.0%, 9/113 in non-adenocarcinoma patients; P = 0.000). There were only 6 cases (6/208, 2.88%) of KRAS mutations in our study group. We identified 7 patients who harbored the EML4-ALK fusion gene (3.37%, 7/208) which all confirmed by DNA sequencing. Of these 7 patients, 2 cases displayed the EML4-ALK variant 1 (28.6%), 1 case exhibited variant 2 (14.3%) and 4 cases carried variant 3 (57.1%). All of the positive cases corresponded to female patients (11.5%, 7/61). Six of the positive cases were non-smokers (7.69%, 6/78). The incidence of EML4-ALK translocation in female non-smoking adenocarcinoma patients is as high as 15.2% (5/33). No EGFR/KRAS mutations were detected among EML4-ALK positive patients. The meta-analysis demonstrated that EML4-ALK translocation was 4.71% (125/2652) in unselected patients with NSCLC, and was also predominant in female patients with adenocarcinoma. Conclusion: EML4-ALK translocations are infrequent in the entire NSCLC patient population, but are frequent in the NSCLC patient subgroup of female, nonsmokers, and adenocarcinoma patients. Our results indicate that the detection of the EML4-ALK translocation in subgroups of patients with NSCLC is crucial for applying targeted therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4589. doi:1538-7445.AM2012-4589
Abstract 4591: Biotinylated derivatives of selective high affinity ligand (SHAL) therapeutics as companion diagnostics for prescreening non-Hodgkin's lymphoma patients
Authors: Balhorn Rod , Rebhun Robert B. , Hok Saphon , Baum Richard , Sanger Jorg , Balhorn Monique Cosman 
Published: August 2012

Abstract
Selective High Affinity Ligands (SHALs) are a new class of small molecule targeting agents that can be designed to bind selectively and with high affinity to unique sites located on almost any protein. A series of SHAL-based therapeutics have been developed to target the cell surface antigen HLA-DR10 that is over-expressed on many B-cell derived malignancies. SHALs are created by first identifying subsets of potential ligands, or “recognition elements,” that bind to two or three neighboring unique sites on the surface of the target protein. Bidentate or tridentate SHALs are produced by linking two or three of these recognition ligands together using carbodiimide chemistry and a miniPEG and lysine scaffold. SHAL synthesis is rapid, uses relatively inexpensive, commercially available components, and is very versatile. Multiple forms of the SHAL can be created by combining different recognition elements (ligands) or by attaching a variety of tags (biotin, chelating groups, dyes, inhibitors) to the end of the linker. Using this approach, SH7139 has been developed as a promising therapeutic for treating non-Hodgkin's lymphoma. Previous studies have shown SH7139 to be effective in treating human B-cell lymphoma in a mouse xenograft model at extremely low doses (3.3μg/kg); 70% of the tumors disappeared within 30 days after treatment and did not reoccur during the remainder of the life of the animal. Here we report that a biotinylated derivative of SH7139 can be used as companion diagnostic to prescreen needle aspirates or biopsies from B-cell lymphomas and determine whether or not the tumor is likely to respond to SH7139 therapy. The staining protocol involves detecting the bound biotinylated SHAL using commercially available alkaline phosphatase reagents, and it works equally well with both fixed and unfixed biopsy sections. Biotinylated SH7139 has been used to identify potentially responsive B-cell lymphomas in both canine and human patients. The development of SHAL-based diagnostics in parallel with new SHAL-based therapeutics will help advance individualized therapies and minimize the systemic trauma and valuable time lost by patients given treatments that prove to be ineffective. Our results also suggest this diagnostic may also prove useful in determining whether malignancies over-expressing HLA-DR10 have metastasized and individual lymphoma cells have migrated out of the tumor into surrounding normal tissue. This research was supported, in part, by NIH/NCI SBIR grant 1R43CA159843-01 to Rod Balhorn.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4591. doi:1538-7445.AM2012-4591
Abstract 4594: Dual PI3K/mTOR blockade by NVP-BEZ235 sensitizes head and neck squamous cell carcinoma to radiotherapy
Authors: Gao Ming , Wang Chun-Wei , Fang Chun Sheng , Lu Yen-Shen , Cheng Ann-Lii 
Published: August 2012

Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide accounting for over 500,000 new cases annually. Chemoradiotherapy is a mainstay of treatment. However, long-term survival rate has only improved marginally; and the severe toxicity often associated with chemoradiotherapy advocates a need for better radiosensitization strategies. Akt/mTOR pathway is frequently activated in HNSCC cells. This study sought to explore whether NVP-BEZ235, a novel imidazo [4,5-c] quinoline derivative that inhibits PI3K and mTOR kinase activity, has radiosensitization effect in the treatment of HNSCC. MTT assays revealed that NVP-BEZ235 dose-dependently inhibited the growth of two HNSCC cell lines, SAS and OC3 at low nanomolar concentrations; IC50 values were 27.87 nmol/L in SAS cells and 42.63 nmol/L in OC3 cells. By using clonogenic assay and median effect analysis, we found that dual PI3K/mTOR inhibition effectively sensitized SAS and OC3 cell lines to radiation with CI (combination index) value &lt;1, indicating a synergistic effect. By using flow cytometry analysis, when SAS and OC3 cells were sequentially exposed to NVP-BEZ235 and radiation, an increase in the subG1 population was observed, indicating that NVP-BEZ235 sensitized HNSCC cells to radiation by augmenting apoptotic cell death. In SAS xenograft nude mice model, combination therapy with oral administration of 45mg/kg/day of NVP-BEZ235 and 3 Gy radiation for 5 days was well tolerated and significantly enhanced the antitumor effect of radiation (p=0.005). Our results indicated that dual PI3K/mTOR blockade effectively sensitizes radiotherapy for HNSCC. Clinical trials along this line are warranted. (The study was supported by the grant DOH100-TD-B-111-001)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4594. doi:1538-7445.AM2012-4594
Abstract 4596: Missense mutations in the p53 DNA-binding motifs (DBMs) are associated with shorter time to progression (TTP) in erlotinib-treated, EGFR-mutated patients
Authors: Molina Miguel Angel , Bertran-Alamillo Jordi , Mayo Clara , Massuti Bartomeu , Camps Carlos , Carcereny Enric , Viteri Santiago , Benlloch Susana , Taron Miquel , Rosell Rafael 
Published: August 2012

Abstract
Background: Advanced non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations has an average time to progression (TTP) of 14 months (mo) and overall survival of 27 mo when treated with erlotinib. However, EGFR mutations can only imperfectly predict outcome. In NSCLC cell lines, tyrosine kinase inhibitors (TKIs) induce p53 translocation from the cytoplasm to the nucleus and subsequent up-regulation of Fas and caspase activation leading to apoptosis. This mechanism was defective in p53-null cells. We tested whether mutations in the TP53 gene influence outcome to erlotinib in EGFR-mutated patients (p). Expression levels of the p53 repressor MDM2 were also examined. Methods: We assesed p53 status in pretreatment paraffin-embedded tumor samples from 93 erlotinib-treated, EGFR mutated advanced NSCLC p. Mutations in exons 5, 6, 7 and 8 were screened by High Resolution Melting analysis (HRM) followed by sequencing of the amplified products with non-wild type melt curves. All mutant samples were re-confirmed by standard PCR and sequencing. Expression levels of MDM2 mRNA were determined by quantitative RT-PCR. Results: Mutations in exons 5-8 of the TP53 gene were detected in 26 of 93 p (28%). We found an unusually high frequency of in-frame and frameshift deletions (23% of mutations), indicating that the spectrum of p53 mutations might be different in EGFR-mutated NSCLC. Mutations in the TP53 gene were not associated with sex, age, smoking status, histology, exon 19 vs. 21 mutation, or response, but, within the study population, were significantly less frequent in p with ECOG 2 or above. The mutations were also associated with the presence of the pretreatment T790M mutation. 14 p had mutations in one of the p53 DNA binding motifs (DBMs), and showed TTP to erlotinib of only 9 mo, compared to 19 months for wt p and 27 mo for those carrying a non-DBM mutation. Survival was 24 mo vs. 31 mo, and not-reached, respectively. Finally, MDM2 mRNA levels were significantly lower in tumors with p53 mutations, especially when these affected DBMs. In the case of wt p, high MDM2 expression correlated with a better TTP and survival. Conclusions: TP53 mutations co-exist with EGFR mutations in a significant number of p; and those in the DBMs are associated with poorer response to erlotinib. This finding paves the way for the possibility of combining erlotinib with a drug restoring p53 function in those p harboring DBM mutations in the TP53 gene.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4596. doi:1538-7445.AM2012-4596
Abstract 4604: Some of oral squamous cell carcinomas might originate from minor salivary glands, and these tumors shows aggressive biological behavior and poor prognosis
Authors: Kawamata Hitoshi , Izumi Sayaka , Doi Yutaka , Imai Yutaka 
Published: August 2012

Abstract
Oral cancer massively invades the adjacent tissues and frequently metastasizes to the regional lymph nodes. Most of the oral cancer is histopathologically squamous cell carcinoma, and approximately 10 % of the oral floor cancer is salivary gland cancer, such as mucoepidermoid carcinoma and adenoid cystic carcinoma. According to the clinical behavior and histopathological features of the oral squamous cell carcinoma (OSCC), we hypothesize that OSCC might originate from either oral squamous epithelium or minor salivary glands. In this study, we attempted to clarify the possibility, in which some of the OSCC originated from minor salivary glands by microarray and clustering analysis. Furthermore, by using the eleven molecular markers which were identified by the microarray and clustering analysis, we determined the origin of OSCC, and compared their biological aggressiveness in the patients. The mRNA expression profile of the samples obtained from 6 patients with OSCC was analyzed by the AB1700 Chemiluminescent Microarray Analyzer on the Human Genome Survey Array containing 29,098 genes. Clustering analysis was performed by GeneSping GX 7.3. Clustering analysis by the expression level of the 917 genes, which were differentially expressed at least 3-folds in normal oral squamous epithelium and normal salivary glands, revealed that 6 samples can be divided into 2 groups. The expression profile of one group (4 cases) was similar to that of normal oral squamous epithelium, and that of another group (2 cases) was similar to that of normal salivary glands. Furthermore, we identified 11 genes from the 917 genes which can easily determine the origin of the OSCC. Subsequently, we examined the expression levels of 9 marker genes in 73 OSCC (45 men, 28 women) by RT-PCR and determined the origin of the OSCC. Twelve cases from 73 OSCCs (16%) were considered to originate from minor salivary glands, and these tumors showed highly metastatic potentials and poor prognosis. In conclusion, OSCC originates from either oral squamous epithelium or minor salivary glands. OSCCs originating from minor salivary glands showed aggressive biological behavior. Determination of the origin of the OSCC is helpful to make a treatment plan for the patients with OSCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4604. doi:1538-7445.AM2012-4604
Abstract 4609: Epigenetic regulation of BRM
Authors: Kahali Bhaskar , Gramling Sarah , Reisman David N. 
Published: August 2012

Abstract
BRM is part of the SWI/SNF complex and is key anticancer protein which is silenced in variety of tumor types. SWI/SNF is a prerequisite for the function of many different anticancer proteins such as Rb and p53 and it has essential roles in growth control, differentiation, development, cell adhesion, and DNA repair. Consequently, inactivation or impairment of this complex can stimulate tumor development and tumor progression through the abrogation of a number of anticancer mechanisms. Unlike many tumor suppressor proteins, BRM is not mutated, but rather epigenetically suppressed, which is validated by the fact that HDAC inhibitors were the first compounds found to restore BRM expression. Unfortunately, these compounds are too broadly active and in addition to restoring BRM expression, they inactivate it by acetylation. To try to better understand how BRM is epigenetically regulated, we knocked-out each of the known 11 HDACs, using shRNAs in BRM-deficient and BRM-positive cell lines to determine which ones regulate or inactivate BRM. We found that that shRNA knockdown of only HDAC3 or HDAC9 restores both BRM expression and function, while suppression of HDAC2 induces BRM acetylation. Similarly, we tested the impact of over-expression of 25 different Histone Acetyltransferases (HATs) on BRM expression and acetylation. We found ectopic expression of KAT6A, KAT6B, and KAT7 in BRM-deficient cell lines induces BRM whereas ectopic expression of KAT2B and KAT8 causes BRM acetylation in BRM-positive cell lines. We also uncovered that HDAC9 is greatly over-expressed only in BRM-deficient cell lines and its expression is driven by MEF2D and GATA3. Expression and knockdown experiments directed at MEF2D and GATA3 showed that these transcription factors regulate BRM and HDAC9. Similarly, we found that GATA3 expression is only expressed in BRM-deficient cell lines. This work outlines the complex array of proteins which are tied to the expression and regulation of BRM. It is important to note this epigenetic mechanism is not likely specific to BRM, but rather likely regulates a cadre of anticancer and cellular proteins as well. Hence, determining how BRM is aberrantly regulated is the first step in determining how to target BRM and this mechanism for therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4609. doi:1538-7445.AM2012-4609
Abstract 4614: Karyometry in atypical endometrial hyperplasia: A Gynecologic Oncology Group study
Authors: Alberts David S. , Garcia Franciso AR , Trimble Cornelia L. , Kauderer James , Curtin John , Lim Peter C. , Hess Lisa M. , Silverberg Steven , Zaino Richard J. , Yozwiak Michael , Bartels Hubert G. , Bartels Peter 
Published: August 2012

Abstract
Treatment for atypical endometrial hyperplasia (AEH) is based on pathologic diagnosis. About 40% of AEH is found to be carcinoma at surgery. The histopathologic classification of endometrial lesions is a difficult task requiring extensive experience. The Gynecologic Oncology Group (GOG) conducted a study (GOG 167A) that was designed to estimate the frequency of endometrial cancer in hysterectomy specimens in subjects who had a biopsy diagnosis of atypical endometrial hyperplasia. This study's objective is to derive an objective characterization of nuclei from cases diagnosed as AEH or superficially invasive endometrial cancer (SIEC). Cases from GOG study 167A were classified by a central pathology committee as AEH (n=39) or SIEC (n=39). High resolution digitized images of cell nuclei were recorded. Features of the nuclear chromatin pattern were computed. Classification rules were derived by discriminant analysis. Nuclei from cases of AEH and SIEC occupy the same range on a progression curve for endometrial lesions. Cases of AEH and SIEC both comprise nuclei of two phenotypes: hyperplastic characteristics and premalignant/neoplastic characteristics. The principal difference between AEH and SIEC is percentage of premalignant/neoplastic nuclei. When this percentage approaches 50-60% superficial invasion is likely. SIEC may develop already from lesions at the low end of the progression curve. AEH comprises cases which may constitute a low risk group involving &lt;40% of AEH cases. These cases hold a percentage of &lt;20% of nuclei of a preneoplastic phenotype. AEH cases from the central and high end of progression have &gt;40 % of nuclei of the preneoplastic phenotype. Nuclei of the preneoplastic phenotype in AEH lesions are almost indistinguishable from nuclei in SIEC, where this percentage exceeds 60%. While karyometric assessment does not provide a distinctive diagnostic criterion for an individual patient, it does provide a measure of risk for the development of invasive disease. Studies to support the diagnostic assessment of endometrial lesions by computer aided morphometric analyses go back over 30 years. These efforts were aimed at two objectives, the diagnostic distinction between benign and cancer, and procedures that allow a stratification of patients into risk groups for the development of myometrial invasion. The percentage of nuclei of preneoplastic phenotype in AEH lesions might serve as criterion for assessment of risk for the development of invasive disease.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4614. doi:1538-7445.AM2012-4614
Abstract 4615: Key miRNAs and co-targets in patients of OPSC and OCC
Authors: Cui Shiying , Zhao Henan , Ding Yanfang , Zhao Jinyao , Bi Tie , Jiang Jiyong 
Published: August 2012

Abstract
Objectives: To identify the key microRNAs (miRNAs) and their top co-targets in patients of elderly ovarian papillary serous carcinoma (OPSC) patients with advanced stage and ovarian clear cell carcinoma (OCC), for the insight of possible regulation gene and pathway of epithelial ovarian cancer (EOC) prognosis. Methods: The study was opened to patients with primary, previously untreated EOC referred to member institutions. Pathologic diagnosis was confirmed by central review. High-throughput analysis of the miRNA profile in a panel of OCC and OPSC cells was assessed using a microarray platform. The miRNA-targets and possible pathway were predicted by TargetScans, MicroCosm Targets version 5, miRBase and Ingenuity. Finally, the downstream predicated co-target, activating transcription factor 3 (ATF3) was validated by quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) and immunohistochemical (IHC) assay. Results: Of the 667 miRNAs analyzed from human, we identified 83 as enriched in the OPSC, and 15 in OCC (P&lt;0.01 for all). Seventeen of 667 miRNAs were significantly expressed with at least 3 fold differences in the OPSC versus OCC. The expression of tree miRNAs (miR-30a*, miR-30e*, miR-505*) were most significantly lower in OCC comparing to elderly OPSC patients with advanced stage. ATF3, the top co-target gene of three key miRNAs mentioned above was highly expressed in OCC lesions, and a stronger distribution was shown in protein level of ATF3 by immunohistochemistry in OCC than OPSC lesions. Conclusions: We identified the key miRNAs that differentially expressed in patients of elderly OPSC with advanced stage and OCC tumors, predicted and validated the most popular co-target shared by the key miRNAs, indicating the possible regulation gene and pathway for EOC prognosis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4615. doi:1538-7445.AM2012-4615