bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5568: Constitutively activation of STAT3 is a prognostic factor in activated B-cell subtype of diffuse large B-cell lymphoma
Authors: Huang Xin , Cao Wenfeng , Iqbal Javeed , Meng Bin , Ding B. Belinda , Bi Chengfeng , Jiang Chunsun , Ye B. Hilda , Chan Wing C. , Fu Kai 
Published: August 2012

Abstract
We have previously reported aberrant activation of the signal transducer and activator of transcription 3 (STAT3) pathway promotes cell proliferation and survival in the activated B-cell-like (ABC) subtype, but not in the germinal center B-cell-like (GCB) subtype of diffuse large B-cell lymphoma (DLBCL). Herein, we investigated the effects of small molecular inhibitors of STAT3 in sensitizing DLBCL cell to chemotherapy drugs. ABC-DLBCL lines Ly3 and Pfeiffer were more resistant to vincristine-induced cell death than GCB-DLBCL cells Ly1 and Ly7 were. In ABC-DLBCL cells, constitutive activation of STAT3 provided survival signal and inhibited vincristine-induced apoptosis, while inhibition of STAT3 signaling abrogated IL-6 secretion and promoted cell apoptosis. STAT3 inhibitor and chemotherapy drugs synergistically induced cell apoptosis, with increased caspases 3/7 activity and PARP cleavage, in ABC-DLBCL cells but not in the GCB-DLBCL cells. The effect was correlated with reduced expression of MCL1 in these cells. To investigate the prognostic significance of STAT3 activation in DLBCL patients, we evaluated the levels of phospho-Tyr705-STAT3 (PY-STAT3) expression by immunohistochemistry in a cohort of 309 DLBCL patients treated with R-CHOP regimen. The ABC-DLBCL subgroup had significantly higher number of PY-STAT3 positive cases compared to the GCB subgroup (59.4% vs 36.2%; P = 0.003). Constitutive activation of STAT3 pathway has a significant impact on the overall-survival (OS) and event-free-survival (EFS) in the entire DLBCL cohort (OS, P = 0.010; EFS, P = 0.006) and in the ABC subgroup (OS, P = 0.062; EFS, P=0.016). Moreover, we constructed a subgroup of genes representing STAT3 activation from the gene expression profiling data of STAT3-siRNA treated ABC cell lines and primary DLBCL samples. Attributions of these genes include repression with the STAT3 knockdown in DLBCL cell lines, overexpression in the PY-STAT3-positive DLBCL tumors, and containing one or more STAT3 binding motif within their promoter regions. Eleven genes were obtained when trained this gene subgroup with patient survival through a semi-supervised algorithm. Averaged expression of the eleven genes predicted the OS (P &lt; 0.001) and EFS (P &lt; 0.001) in the entire DLBCL cohort, as well as in the ABC-DLBCL subgroup (OS, P = 0.029; EFS, P = 0.025). In conclusion, our study demonstrated that STAT3 activation is a significant prognostic factor in DLBCL and suggested that STAT3 may be a new therapeutic target in this aggressive malignancy.
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 5568. doi:1538-7445.AM2012-5568
Abstract 5569: DNA methylation status of MLH1, p16, SOCS1, ER and CDH1 in Puerto Rican patients with acute myeloid leukemia
Authors: Tirado-Gomez Maribel , Fonseca Sharon , Munoz Cristina , Cordero Paul , Bernabe Raul , Lacourt Mercedes , Rivera Noridza , Cotto Maribel , Ortiz Eddiemar , Acosta Mirelis 
Published: August 2012

Abstract
Background: DNA methylation of gene promoters have been show to play a role in the pathogenesis of acute myeloid leukemia (AML). We present in this study a preliminary report of the methylation status of MLH1, p16, SOCS1, ER and CDH1 in Puerto Rican patients with AML. Methods: Peripheral blood was obtained from 24 patients with diagnosis of acute myeloid leukemia before and after their induction treatments. DNA was isolated and further modified with sodium bisulfite. Methylation-specific polymerase (MSP) chain reaction was performed to detect aberrant promoter methylation of MLH1, p16, SOCS1, ER and CDH1. Results: Samples from a total of 24 patients were analyzed. The mean age was 47 years (range 22-70) with 21/24 patients younger than 60 years (88%). Most of the patients were female (13/24, 54%). Ten patients had diploid cytogenetics (42%), 4 had low risk cytogenetics (17%) and 10 had high risk cytogenetics (42%). Nineteen patients were de Novo AML (79%). Sixteen patients (67%) presented with WBC counts higher than 10 x 109/L. Seventeen patients (71%) achieved a complete response at the end of the induction therapy. Frequencies of gene methylation before treatment were as follows: MLH: 3/24 (13%); p16: 6/24 (25%); SOCS1:13/24 (54%); ER: 16/24 (67%) and CDH1: 4/24 (16.7%). Conclusions: No correlation between methylation status of p16 and MLH1 before treatment and clinicopathological characteristics was noted. Unmethylated CDH1 was more common among the novo AML patients. Methylation of SOCS1 was more common among patients that achieve a CR after induction therapy. This sample is a small one, so any correlation must be further tested in a more ample sample. Collection of more patient's samples and correlation with clinical data and patient's ultimate outcome is ongoing.
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 5569. doi:1538-7445.AM2012-5569
Abstract 5571: Inflammatory response as a novel prognostic parameter in patients with metastatic renal cell carcinoma treated with pazopanib
Authors: Lingerfelt Brian M. , Akbashev Mikhail Y. , Master Viraj A. , Harris Wayne B. 
Published: August 2012

Abstract
Over sixty thousand patients were diagnosed with metastatic renal cell carcinoma (mRCC) in 2010, yet no tumor markers have been identified. Standard prognostic systems only measure characteristics at baseline and do not assess the potential benefit of therapeutic intervention. The introduction of receptor tyrosine kinase inhibitors has significantly changed the management of mRCC. Pazopanib, a selective, multi-targeted, receptor tyrosine kinase inhibitor, was approved for mRCC in 2009. The modified Glasgow Prognostic Score (mGPS), a prognostic system based on inflammatory biomarkers (serum C-reactive protein (CRP) and albumin), has been validated in the pre-treatment setting for mRCC treated with surgery or cytokines. In this study, we present data demonstrating the correlation of serial mGPS measurements with objective responses to targeted therapy with pazopanib in patients with mRCC. We conducted a retrospective chart review of patients seen at the Winship Cancer Institute for whom serial CRP and albumin measurements as well as imaging studies were available while taking pazopanib. In these patients we assessed the correlation of pre- and post-treatment mGPS scores to objective responses by imaging. Twenty patients met inclusion criteria. Of these patients, 12 (60%) had progressive disease, and 8 (40%) had clinical benefit response (defined as stable disease, partial response, or complete response) by imaging. An elevated pre-treatment mGPS score had 75% sensitivity (95% confidence interval 35.5%-95.5%; P&lt;0.01) and 83.3% specificity (95% confidence interval 50.9%-97.1%; P&lt;0.01) for disease progression at the end of treatment. On the other hand, an elevated post-treatment mGPS score had 100% sensitivity (95% confidence interval 59.8%-100%; P&lt;0.01) and 100% specificity (95% confidence interval 69.9%-100%; P&lt;0.01) for disease progression at the end of treatment. Although these data require prospective validation, they suggest that serial measurements of serum inflammatory biomarkers may improve the sensitivity and specificity of mGPS for response to therapy. If confirmed, inflammatory response rates based on mGPS may become a valuable and cost effective tool to guide patient care and drug development for mRCC.
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 5571. doi:1538-7445.AM2012-5571
Abstract 5575: Promoter methylation of SNFP4 gene as potential diagnosis biomarker in cervical cancer: Exploratory study phase I
Authors: Peña Kathleen Saavedra , Mieville Priscilla Brebi , Gangas Carmen Ili , Llaneza Maria Furrianca , Figueroa Paula González , Campos Ángela Riffo , Strauch Juan Carlos Roa 
Published: August 2012

Abstract
BACKGROUND: Cervical cancer (CC) is the second most prevalent neoplasia in women and fifth cause of death by cancer in this population worldwide. Pap smear and HPV infection test have been the most widely used tools to detect cytological abnormalities and women's risk of developing cancer. However, they cannot distinguish between lesions that will progress to an invasive carcinoma and those that will not. Methylation biomarkers could be useful in early detection and progression for cervical carcinoma. Thus, the aim of this study was evaluate the promoter methylation status of a selected gene as possible biomarker for early detection and progression of cervical carcinogenesis in women in the South of Chile. METHODS: DNA isolated from 12 normal samples and 7 cervical cancers was enriched with Methylated DNA Immunoprecipitation (MeDIP) and hybridized to Nimblegen 385K CpG Islands plus Promoter arrays. Bioinformatics strategies were used for background correction, array normalization and data analysis of differentially methylated genomic regions between tumor and normal tissue. The promoter methylation status of selected gene was validated by Methylation Specific PCR (MSP) in biopsies samples of the cervix: 44 normal, 22 Low Grade Lesions (LSIL), 22 High Grade Lesions (HSIL) and 45 cervical cancers (CC). The associations between methylation status of selected gene and different stages of progression of cervical cancer were analyzed using a Chi-square test. FINDINGS: SPRP4 gene was selected from microarray as potential biomarker, because it showed a high score of methylation in cancer, according to bioinformatic analysis. The methylation frequency of SPRP4 through MSP was 0% in normal samples, 50% in LSIL, 27% in HSIL and 100% in tumor samples. Thus, promoter methylation of SPRP4 was associated to cervical cancer and related lesions (p&lt;0.05). INTERPRETATION: The promoter methylation status of SFRP4 has potential use as a biomarker for diagnosis of cervical cancer. Therefore, the validation of this marker in a case-control cohort is warranted. FUNDING: National Cancer Institute grant U01-CA84986; Oncomethylome Sciences, SA, Comisión Nacional de Ciencia y Tecnología (CONICYT; Chile, Becas Chile; Conicyt No24090095; CORFO 07CN13PBT-222). Postdoctoral Fondecyt Research Project 3120141.
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 5575. doi:1538-7445.AM2012-5575
Abstract 5585: Phase I clinical trial of continuous infusion of tyroserleutide in patients with advanced hepatocellular carcinoma
Authors: Jinbin Jia , Zhen-Yu Xiao , Xiao-Ping Chen 
Published: August 2012

Abstract
Hepatocellular carcinoma (HCC) is usually diagnosed in advanced stage, which causes difficulty of using surgical treatment. Previous studies demonstrated that tyroserleutide (YSL), an immunologically active tripeptide compound, could suppress the proliferation and tumor formation of some liver cancer cell lines. We aimed to investigate the feasibility and toxicity of continuous administration of YSL by a portable infusion pump to patients with advanced HCC and its biologically effective but non-toxic doses used in outpatient setting. Forty patients (12 in stage 1, 28 in stage 2, total 10 treated in each dose cohort) were treated with YSL 6, 12, 18 or 24 mg/d lasting for 5 days. No treatment-related mortality was observed. The overall response rates were 25% (3/12) and 7.2% (2/28) in stages 1 and 2 respectively. The median 6-month overall survival (OS) in stage 1 were 75, 64, and 41 days for 6, 18, and 24 mg/d groups respectively; all patients survived in the 12 mg/d group. The median OS in stage 2 were 68, 72, and 60 days for 12, 18, and 24 mg/d groups respectively; all survived in the 6 mg/d group. The most common adverse reactions were abnormal liver function (59/107) and hemogram (22/107). The dose limiting toxicities of 24 mg/d group contained abdominal distention (1/10), sicchasia (1/10), hyponatremia (1/10), myocardiac ischemia (1/10), and abnormal hemogram (6/10). We conclude that the continuous administration of YSL by portable infusion pump was well tolerated. Treatment responses of doses 6 and 12 mg/d were better than other two groups. Further studies of continuous infusion of YSL to determine its efficacy are warranted. Keywords tyroserleutide • hepatocellular carcinoma • clinical trial • portable infusion pump [Supported by China Postdoctoral Science Foundation-funded project (No. 20080440077 and 200902203)]
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 5585. doi:1538-7445.AM2012-5585
Abstract 5593: Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers
Authors: Katayama Ryohei , Shaw Alice T. , Khan Tahsin M. , Mino-Kenudson Mari , Iafrate Anthony J. , Engelman Jeffrey A. 
Published: August 2012

Abstract
ALK fusion oncogenes represent a novel molecular target in a small subset of non-small cell lung cancers (NSCLC). The vast majority of patients with ALK-positive NSCLC are highly responsive to ALK tyrosine kinase inhibitor (TKI) therapy. However, these patients invariably relapse, typically within one year, due to the development of resistance. Herein, we report findings from the first series of patients with acquired resistance to the ALK TKI crizotinib. In approximately one-third of patients, we identified a diverse array of secondary mutations distributed throughout the ALK TK domain. We also identified aberrant activation of other kinases as alternative mechanisms of crizotinib resistance. Additionally, we generated laboratory models of acquired crizotinib resistance which closely recapitulate the diversity of resistance mechanisms observed in patients. Our results highlight the marked heterogeneity of TKI resistance mechanisms in ALK-positive NSCLC, and provide the rationale for pursuing combinatorial therapeutic strategies in patients who relapse on crizotinib.
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 5593. doi:1538-7445.AM2012-5593
Abstract 5594: ALK-driven lung cancer: Potential therapeutic strategies for treatment and prevention of drug resistance
Authors: Pilling Amanda B. , Le Anh T. , Tan Aik-Choon , Kim Jihye , Singleton Katherine R. , Heasley Lynn E. , Helfrich Barbara , DeGregori James , Doebele Robert C. 
Published: August 2012

Abstract
The identification of oncogenic molecular drivers in non-small cell lung cancer (NSCLC) has allowed biologically targeted therapies to improve clinical outcomes in the treatment of NSCLC. ALK gene rearrangements are observed in a sub-set of NSCLC patients who demonstrate high response rates to treatment with the oral kinase inhibitor, crizotinib. Unfortunately, disease progression is inevitable, either through intrinsic or acquired resistance. A recently completed series of crizotinib-resistant, ALK+ NSCLC patients by our group demonstrates two broad categories of resistance: (1) continued reliance on ALK signaling (via secondary mutations in the ALK kinase domain or ALK gene fusion copy number gain) or (2) loss of reliance on ALK signaling (e.g. via reliance on alternate oncogene signaling). Here we investigate potential therapeutic strategies when ALK signaling is retained. In an effort to minimize drug resistance to crizotinib in ALK+ NSCLC, we performed a genome-wide shRNA synthetic lethal screen to identify genes whose depletion synergizes with crizotinib in ALK+ NSCLC lines. We identified several genes involved in nucleotide synthesis and DNA metabolism, including dihydrofolate reductase (DHFR) and the trifunctional enzyme encoded by GART, which are substrates for inhibition with pemetrexed. Indeed, ALK+ NSCLC cell lines show increased sensitivity to pemetrexed in vitro. Identification of this cellular process as critical for ALK+ NSCLC is also consistent with clinical data demonstrating that patients with ALK+ NSCLC exhibit an increased clinical benefit on pemetrexed compared to other molecular subgroups of NSCLC. We also identified genes involved in chaperone function in our synthetic lethal screen. As such, we investigated whether proper folding and prevention of degradation was essential for continued reliance on ALK signaling. Both non-mutated EML4-ALK wild-type and EML4-ALK containing kinase domain mutations (including a novel mutation, G1269A) are sensitive to HSP inhibition with 17AAG. By identifying critical cellular processes in ALK+ lung cancer and employing therapies that target these pathways, improved treatment strategies can be derived to treat and prevent resistance in this molecular subtype of NSCLC.
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 5594. doi:1538-7445.AM2012-5594
Abstract 56: Stromal fibroblasts in the microenvironment of gastric carcinomas promote tumor metastasis through upregulated TAGLN expression
Authors: Liu Bingya , Yu Beiqin , Li Jianfang , Su Liping 
Published: August 2012

Abstract
Fibroblasts play a significant role in tumorigenesis, tumor progression and metastasis, but their detailed molecular characteristics and clinical significance are unclear. TAGLN is an actin-binding protein played an important role in tumorigenesis. Here, we aimed to the interaction between cancer cells and their microenvironments to study how the fibroblasts isolated from human gastric carcinomas facilitate tumorigenesis through TAGLN. Gene expression profiling and real-time PCR and Western blot in gastric carcinoma samples indicated that TAGLN expression was up-regulated in gastric carcinoma. However, further investigation by IHC shown that TAGLN was expressed in tumor stoma, not in tumor cells. TAGLN expression was promoted mutually by fibroblasts and MKN-45 co-culture. Decreased expression of TAGLN suggested that carcinoma-associated fibroblasts (CAF) can enhance tumor metastasis through upregulated TAGLN by MMP-2 and the FAK pathway.
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 56. doi:1538-7445.AM2012-56
Abstract 5607: TLE4 is a key modulator of resistance to mTOR pathway specific inhibition in glioblastoma
Authors: Laks Dan R. , Phillips Tiffany , Paucar Andres A. , Orozco Nicholas , Visnyei Koppany , Mischel Paul S. , Coppola Giovanni , Trinidad Jonathan C. , Burlingame Alma L. , Bradshaw Ralph A. , Kornblum Harley I. 
Published: August 2012

Abstract
Rapamycin, a selective inhibitor of TOR (target of rapamycin), has been used in clinical trials for the treatment of glioma (Cloughesy et al., 2008). However, even though some patients respond temporarily to rapamycin treatment, virtually all recur. The mechanisms underlying this resistance to therapy are unknown. Here, we utilized patient-derived glioblastoma (GBM) neurosphere cultures to examine these mechanisms. GBM cell cultures exposed to chronic rapamycin yield a population of rapamycin resistant cells with an increased malignant phenotype upon removal from treatment, enhanced sphere formation in vitro and enhanced tumorigenesis. We used an unbiased, proteomics-based approach to discover phosphopeptides that were upregulated during rapamycin treatment in vitro. Amongst the peptides that we uncovered was Tle4/Groucho, a global co-repressor and known modulator of several key signaling pathways, including the Wnt and Notch pathways. In an expression microarray, Tle4 was found to be significantly upregulated within chronic rapa treated GBM cells. We show that TLE4 is a key modulator of resistance to mammalian target of rapamycin (mTOR) pathway specific inhibition. While TLE4 knockdown has no clear effect on naive cells, this knockdown promotes sensitivity under chronic rapamycin treatment as evidenced by reduced neurosphere formation. TLE4 mediate rapamycin resistance through activation of the quiescent population. Our results indicate that chronic mTOR specific inhibition imparts TLE4 mediated resistance through both ERK activation and inhibition of mTOR. The identification of this role for TLE4 in rapamycin resistance provides a novel target for mTOR pathway-associated chemotherapeutic agents. References: Cloughesy, T.F., Yoshimoto, K., Nghiemphu, P., Brown, K., Dang, J., Zhu, S., Hsueh, T., Chen, Y., Wang, W., Youngkin, D., et al. (2008). Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma. PLoS Med 5, e8.
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 5607. doi:1538-7445.AM2012-5607