bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5539: Therapeutic efficacy of novel selenium-containing HDACi in acute leukemia
Authors: Sachdev Mansi , Desai Dhimant , Muthusami Sunil , Gowda Chandrika , Song Chunhua , Amin Shantu G. , Dovat Sinisa 
Published: May 2015

Abstract
Despite tremendous advances in treatment of leukemia that have resulted in increased survival of patients with this disease, therapy for high-risk and relapsed leukemia remains a clinical challenge. This necessitates the development of novel, more potent therapeutic modalities. Epigenetic therapy with various types of inhibitors of histone deacetylases (HDACi), have demonstrated therapeutic efficacy in a range of malignancies, often with minimal side effects. Dr. Shantu Amin's group recently reported the development of a potent, novel, selenium-containing HDAC inhibitor (SelSA-1), which showed efficacy against Hodgkin's lymphoma and chronic myelogenous leukemia cells, as well as against lung cancer and melanoma cell lines. Here we expand efficacy studies of selenium-containing HDAC inhibitors to include a broad range of hematopoietic malignancies and begin to address the drug effects on cellular functions. We tested the therapeutic efficacy of two novel HDAC inhibitors - SelSa-1 and SelSa-2 on acute lymphoblastic leukemia, acute myelogenous leukemia and non-Hodgkin's B cell lymphoma. Cell proliferation assays demonstrated sharp dose-dependent cytotoxic effects in all the above cell lines at 96-hours post-treatment. Quantitative analysis showed that SelSa-1 and SelSa-2 have distinct effects in different types of hematopoietic malignancies. In T-cell acute lymphoblastic leukemia (T-ALL) and in non-Hodgkin's lymphoma, both SelSa-1 and Selsa-2 have similar therapeutic activity with IC50 = 1uM and 1-2uM, respectively. In B-cell acute lymphoblastic leukemia, SelSa-1 has superior therapeutic activity compared to SelSa-2 with IC50 = 0.2 uM vs. 1.25, respectively. In acute promyelocytic leukemia (APML) without the t:15:17 translocation, SelSa-1 was superior to SelSa-2 (IC50= 0.25uM and 1uM respectively), while APML with the t:15:17 translocation showed similar sensitivity to both compounds with an IC50 of 1-2uM. Cell cycle analysis performed by flow cytometry revealed that these agents induce G1-cell cycle arrest in leukemia cells. Preliminary data suggest that both SelSa-1 and SelSa-2 have a synergistic effect with standard chemotherapeutic agents that induce DNA-damage. In summary, these results demonstrate the effectiveness of two selenium-containing analogs of SAHA, SelSA-1 and 2, on leukemia cells from multiple hematopoietic lineages. Additional studies to identify detailed mechanisms of the effects of these drugs on cellular function are underway.
Citation Format: Mansi Sachdev, Dhimant Desai, Sunil Muthusami, Chandrika Gowda, Chunhua Song, Shantu G. Amin, Sinisa Dovat. Therapeutic efficacy of novel selenium-containing HDACi in acute leukemia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5539. doi:10.1158/1538-7445.AM2014-5539
Abstract 555: DNA methylation patterns are associated with subpopulations of diffuse large B-cell lymphoma
Authors: Wu Jenny , McCord Ron , Sandmann Thomas , Walter Kim , Bourgon Richard , Soriano Robert , Modrusan Zora , Darbonne Walter , Mundt Kirsten E. 
Published: May 2015

Abstract
Diffuse large B-cell lymphoma (DLBCL) comprises two predominant molecular subtypes: germinal-center B-cell-like (GCB) and activated B-cell-like (ABC). These subtypes were initially identified by their gene expression profiles, which are reminiscent of the cell of origin of the lymphoma. Though histologically indistinguishable, these subtypes are associated with distinct clinical outcomes and may be predictive for response to novel therapies. The development of improved diagnostic biomarkers for these DLBCL subtypes could therefore inform clinical decision-making by enabling selection of patients likely to respond to such novel therapies.
To investigate regulatory mechanisms potentially responsible for the differential gene expression patterns seen in the DLBCL subtypes and to identify potential biomarkers for these subtypes, we performed whole genome methylation profiling of 15 DLBCL cell lines and 21 DLBCL patient tissues and identified distinct DNA methylation patterns associated with the two DLBCL molecular subtypes.
Analysis of the methylation patterns of several DLBCL classifier genes known to be differentially expressed in ABC compared to GCB revealed the classic DNA methylation correlation pattern: high mRNA expression was associated with low methylation in the vicinity of the transcriptional start site (TSS), and vice versa. Furthermore, comparison of differential methylation profiles with corresponding RNA-seq data further supports the notion that DNA methylation profiles underlie the gene expression patterns that are currently used to classify ABC and GCB DLBCL subtypes. Collectively, these data suggest that DNA methylation may contribute to the regulation of expression of key ABC and GCB DLBCL classifier genes and further, that the DNA methylation state at these loci could potentially serve as useful diagnostic biomarkers for the DLBCL subtypes.
Citation Format: Jenny Wu, Ron McCord, Thomas Sandmann, Kim Walter, Richard Bourgon, Robert Soriano, Zora Modrusan, Walter Darbonne, Kirsten E. Mundt. DNA methylation patterns are associated with subpopulations of diffuse large B-cell lymphoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 555. doi:10.1158/1538-7445.AM2014-555
Abstract 5573: p62/IMP2 promotes breast cancer cell progression
Authors: Li Yang , Peng Bo , Ning Jing , Qian Wei , Francia Gulio , Zhang Jianying 
Published: May 2015

Abstract
Breast cancer is one of the major causes of cancer-related death for women throughout the world. Although the early detection of breast cancer is improving, the strategies available to treat the advanced stages of this disease remain limited. Therefore, the identification of key molecules that regulate the metastatic process is necessary to provide the rationale for further therapeutic interventions. The IGF2 mRNA-binding Protein 2 (IMP2/IGF2BP2/p62) is a member of the IMP family. Expression of IMPs in cancer cells is associated with cancer progression. Our previous studies showed that p62/IMP2 is overexpressed in breast cancer tissue compared to the adjacent normal breast tissue. However, the role of p62/IMP2 in breast cancer progression remains unknown. Here, we present evidence that transfection of p62/IMP2 into two p62/IMP2 negative cell lines (MDA-MB-231 and MCF7) increases 5 to 10 folds (P &lt; 0.05) in-vitro wound healing and reduces 2 to 3 folds (P &lt; 0.05) cell adhesion to the extracellular matrix. Unexpectedly, the overexpression of p62/IMP2 did not affect cell proliferation in our breast cancer cell lines.
Our analysis shows that the overexpression of p62/IMP2 leads to increased c-myc expression in MDA-MB-231 cells but not MCF-7 cells at both the transcriptional and translational levels. In contrast, beta-catenin expression is increased by p62/IMP2 only in MCF7 cells. Since c-myc and beta-catenin gene products are important regulators of metastasis in breast cancer, and their increased expression is observed in our p62/IMP2 transfectants, our data suggests that p62/IMP2 may be an important mediator of breast cancer progression, although its mechanism of action may vary depending on the cellular context in which it is expressed.
Citation Format: Yang Li, Bo Peng, Jing Ning, Wei Qian, Gulio Francia, Jianying Zhang. p62/IMP2 promotes breast cancer cell progression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5573. doi:10.1158/1538-7445.AM2014-5573
Abstract 5589: Molecular diagnostic, prognostic and therapeutic role of mir-221 in pancreatic cancer
Authors: Sethi Seema , Sarkar Shaan , Dubaybo Hala , Ali Shadan , Goncalves Priscila , Kollepara Spilakshmi , Philip Philip , Li Yiwei 
Published: May 2015

Abstract
Background: Comprehensive molecular profiling of microRNAs (miRNAs) and subsequent target gene analysis of pancreatic cancer (PaCa) can provide tumor specific miRNAs signatures to improve diagnostic accuracy, refine prognostic and predictive capabilities, and may also serve as therapeutic targets. In PaCa such a comprehensive analysis has not been reported.Design: RNA extracted from scant amounts of formalin fixed paraffin embedded PaCa tumor and normal pancreatic tissues were profiled for miRNA expression using microfluidic biochip microarrays (which interrogate 2019 unique mature miRNAs,LC Sciences). The expression of abnormal miRNAs was then validated and quantified using real time RT-PCR. Data was statistically analyzed using the Student's t-test. Survival data obtained in each case was correlated with the miRNA data using Kaplan-Meier analysis. Oncogenic potential, therapeutic modulation and downstream target genes of altered miRNA were evaluated by real time RT-PCR using PaCa cells for mRNA expression.Results: miRNA profiling showed high expression of miR-221 in PaCa tissues compared to normal pancreas (p=0.001). These findings were validated and quantified using qRT- PCR (p=0.0029) . Survival analysis using Kaplan-Meier, demonstrated shorter survival of patients with higher expression of miR-221 compared to those with relatively lower levels of miR-221 . The cell proliferation index of PaCa cells was increased by miR-221 mimics transfection and decreased by miR-221 inhibitors. The predicted target genes of miR-221 identified by RT-PCR were PTEN, p27kip1, p57kip2 and PUMA.Conclusions: High throughput miRNA expression profiling showed high expression of miR-221 in PaCa tissues. Higher levels of miR-221 demonstrated poorer prognosis, suggesting the oncogenic potential of miR-221 in PaCa. Its target genes are PTEN, p27kip1, p57kip2 and PUMA which are tumor suppressors, and found to be deregulated by over-expression or under-expression of miR-221 transfection studies in PaCa cells. These results provide molecular evidence of oncogenic potential of miR-221 in PaCa which may have a significant clinical impact on prognosis & risk stratification and in designing novel targeted molecular therapeutics in the future to achieve the goal of personalized and precision medicine.
Citation Format: Seema Sethi, Shaan Sarkar, Hala Dubaybo, Shadan Ali, Priscila Goncalves, Spilakshmi Kollepara, Philip Philip, Yiwei Li. Molecular diagnostic, prognostic and therapeutic role of mir-221 in pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5589. doi:10.1158/1538-7445.AM2014-5589
Abstract 5606: Detection of circulating tumor DNA in early and late stage human malignancies
Authors: Bettegowda Chetan , Sausen Mark , Leary Rebecca , Kinde Isaac , Agrawal Nishant , Bartlett Bjarne , Wang Hao , Luber Brandon , Kinzler Kenneth , Vogelstein Bert , Papadopoulos Nickolas , Diaz Luis 
Published: May 2015

Abstract
The development of minimally-invasive methods to detect and monitor tumors continues to be a major challenge in oncology. We used digital PCR-based technologies to evaluate the ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types. We initially use targeted, exomic, or whole genome sequencing to identify sequence or structural alterations in tumor tissues of 410 patients using targeted, exomic, or whole genome sequencing. We found that at least one tumor-specific mutant molecule could be identified in &lt;5 mL of plasma in &gt;75% of patients with advanced ovarian, colorectal, bladder, gastroesophoageal, pancreatic, breast, melanoma, hepatocellular and head and neck cancers, but in less than 50% of primary brain, renal, prostate, or thyroid cancers. In patients with localized tumors, ctDNA was detected in 73%, 57%, 48% and 50% of patients with colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, respectively. Circulating tumor DNA was often present in patients without detectable circulating tumor cells, suggesting that these two biomarkers are distinct entities. In a separate panel of 206 patients with metastatic colorectal cancers, we showed that the sensitivity of ctDNA for detection of clinically relevant KRAS gene mutations was 87.2% while and its specificity was 99.2%. Finally, we assessed whether ctDNA could provide clues into the mechanisms underlying resistance to epidermal growth factor receptor (EGFR) blockade in 24 patients who objectively responded to therapy but who subsequently relapsed. Twenty-three (96%) of these patients developed one or more mutations in genes involved in the mitogen-activated protein kinase (MAPK) pathway. Remarkably, nearly half (45%) of the observed mutations observed were in codon 61 of either the KRAS or NRAS gene. Taken together, these data suggest that ctDNA is a broadly applicable, sensitive, specific and robust biomarker that can be used for a variety of clinical and research purposes in patients with several multiple different types of cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Chetan Bettegowda, Mark Sausen, Rebecca Leary, Isaac Kinde, Nishant Agrawal, Bjarne Bartlett, Hao Wang, Brandon Luber, Kenneth Kinzler, Bert Vogelstein, Nickolas Papadopoulos, Luis Diaz. Detection of circulating tumor DNA in early and late stage human malignancies. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5606. doi:10.1158/1538-7445.AM2014-5606
Abstract 562: Impact of ERα expression status and ESR1 genetic variation on progression in tamoxifen-treated breast cancer patients
Authors: Babyshkina Nataliya , Vtorushin Sergey , Patalyak Stanislav , Dronova Tatyana , Slonimskaya Elena , Cherdyntseva Nadejda 
Published: May 2015

Abstract
Background. Resistance to tamoxifen remains a major clinical challenge in the treatment of breast cancer. The aim of this study was to evaluate the influence of the intensity and the pattern of estrogen receptor α (ERα) expression and common single nucleotide polymorphisms (SNP) in the estrogen receptor 1 gene (ESR1, rs2228480:2014G&gt;A; rs2077647:+30T&gt;C) on disease progression in breast cancer patients who received adjuvant tamoxifen.
Material and methods. Formalin-fixed paraffin-embedded tumor tissue samples were retrospectively collected from 61 patients, who had distant metastasis versus distant metastasis-free breast cancers (n = 37 versus n = 24, respectively, with a 9-year follow-up). Protein expression of ER, PR and HER2 were assessed by immunohistochemistry. Real-time polymerase chain reaction analysis was used to determine the ESR1 SNPs.
Results. We found that the heterogeneous distribution of ERα was statistically significant related with a low expression level and intensity of ERα in tumor tissue samples (p=0.002 and p=0.0002, respectively). In addition, the level and intensity of ERα expression was lower in patients with distant metastasis compared to distant metastasis-free cases, but these differences were not significant (P&gt;0.05). Nonetheless, the ESR1 2014A allele was associated with a heterogeneous distribution of ERα expression (p=0.02). We showed the higher risk of distant metastasis development for the patients carrying the ESR1 2014A mutant allele compared with women with ESR1 2014G variant (p=0.04).
Conclusion. These data suggest that the expression level and intensity of ERα with ESR1 2014G&gt;A genetic variation could be a useful molecular markers for predicting tamoxifen treatment prognosis in breast cancer patients.
Citation Format: Nataliya Babyshkina, Sergey Vtorushin, Stanislav Patalyak, Tatyana Dronova, Elena Slonimskaya, Nadejda Cherdyntseva. Impact of ERα expression status and ESR1 genetic variation on progression in tamoxifen-treated breast cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 562. doi:10.1158/1538-7445.AM2014-562
Abstract 565: Telomerase reverse transcriptase promoter alterations in human bladder cancer
Authors: Turan Sevilay 
Published: May 2015

Abstract
The telomerase reverse transcriptase (TERT) gene encodes the catalytic subunit of the enzyme telomerase, (aka telomere terminal transferase), which contains both protein and RNA subunits. TERT is a RNA-dependent polymerase which increases the length of telomeres at the ends of each chromosome by adding TTAGGG repeats. TERT polymerase uses RNA as a complementary primer to elongate telomeric G-rich repeat sequences in the 5’ to 3’ direction. TERT is essential and active in germ cells, stem cells, primary tumors, and immortalized cells and acts to maintain adequate telomeres. However, in somatic cells, TERT expression is reduced or absent and telomeres gradually shorten during the S phase of each cell cycle due to replication-dependent loss of telomere terminal sequences. Adequate telomere length is important for preserving genome stability, regulating cell replication, and preventing cell death. Somatic TERT promoter alterations were recently reported in melanoma, glioma, and in small sample sets from other cancers including bladder cancer. These are thought to drive re-expression of TERT in cancer cells. In this study, given recent reports of somatic TERT promoter alterations in bladder cancer, polymerase chain reaction and Sanger sequencing were performed to examine a region of the TERT promoter in 58 bladder tumors. The TERT promoter was altered in 90% of 58 tumors by 44 germline (21 unique, 20 novel) and 53 somatic variants (11 unique, 4 novel). Somatic alterations were observed in 67% of tumors. The majority of variants were C&gt;T DNA changes, three variants occurred as both germline and somatic, and a subset of variants created or altered transcription factor binding sites and promoter CpGs. Analyses of telomere length showed significantly shorter telomeres in tumor tissue versus adjacent normal tissue from the same patient (p=0.004) indicating TERT may not sufficiently lengthen telomeres in rapidly proliferating cancer cells. Interestingly, somatic TERT promoter alterations were not associated with stage, grade, or alterations in other bladder cancer genes identified by exome sequencing. We speculate that TERT promoter alterations are frequent and early events in bladder cancer and identification of TERT alterations in urine may provide a biomarker for early diagnosis and monitoring of bladder cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Sevilay Turan. Telomerase reverse transcriptase promoter alterations in human bladder cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 565. doi:10.1158/1538-7445.AM2014-565
Abstract 59: PDK1 in melanoma development and metastasis
Authors: Scortegagna Marzia , Ruller Chelsea , Feng Yongmei , Lazova Rossitza , Kluger Harriet , Li Jian-Liang , De Surya K. , Rickert Robert , Pellecchia Maurizio , Bosenberg Marcus , Ronai Ze'ev 
Published: May 2015

Abstract
Phosphoinositide-dependent kinase-1 (PDK-1) is a serine/threonine protein kinase that phosphorylates members of the conserved AGC kinase superfamily, including AKT and PKC, and is implicated in important cellular processes including survival, metabolism and tumorigenesis. In large cohorts of nevi and melanoma samples, PDK1 expression was significantly higher in primary melanoma, compared with nevi, and was further increased in metastatic melanoma. Selective inactivation of Pdk1 in the melanocytes of BrafV600E::Pten-/- or BrafV600E::Cdkn2a-/-::Pten-/- mice delayed the development of pigmented lesions and melanoma induced by systemic or local administration of 4-HT. Melanoma invasion and metastasis were significantly reduced or completely prevented by Pdk1 deletion. Administration of the PDK1 inhibitor GSK2334470 (PDKi) effectively delayed melanomagenesis and metastasis in BrafV600E::Pten-/- mice. Pdk1-/- melanomas exhibit a marked decrease in the activity of AKT, p70S6K and PKC. Notably, genetic inactivation or pharmacological inhibition of PDK1 were even more effective in attenuating melanoma development and metastasis of human tumors with Pten WT as in genetic model of BrafV600E::Cdkn2a-/-::Pten+/+ mice, representing an additional fraction of human tumors harboring such mutation. Gene expression analyses identified Pdk1-dependent changes in FOXO3a-regulated genes and inhibition of FOXO3a restored proliferation and colony formation of Pdk1-/- melanoma cells. PDK1 effect on FOXO3a and melanoma development and progression appears to be AKT independent. Our studies provide direct genetic evidence for the importance of PDK1, in part through FOXO3a-dependent pathway, in melanoma development and progression.
Citation Format: Marzia Scortegagna, Chelsea Ruller, Yongmei Feng, Rossitza Lazova, Harriet Kluger, Jian-Liang Li, Surya K. De, Robert Rickert, Maurizio Pellecchia, Marcus Bosenberg, Ze'ev Ronai. PDK1 in melanoma development and metastasis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 59. doi:10.1158/1538-7445.AM2014-59